Marvin A. Schneiderman, Ph.D., of Bethesda, Maryland, is a statistician and epidemiologist who is the former Chief of Statistics and Epidemiology and the former Director for Science Policy of the National Cancer Institute and is currently a consultant. His curriculum vitae is attached. Dr. Schneiderman will testify concerning mathematical models, statistics, and epidemiology in the area of cancer. He will first discuss the epidemiology of dioxins and their contaminants to human cancer insofar as it relates to soft tissue sarcomas, and particularly the EPA peer review group conclusions in regard thereto, stomach cancers and lymphomas. In that regard, he will discuss the relationship of exposure to the time the disease appears, the so-called latency period. He will also discuss the multiplication of base rates in the production of such cancer. Next, Dr. Schneiderman will present a multi-stage model of cancer induction. He will discuss age relationships and the stage of cancer development as they are affected by dioxins and their contaiminants or other materials. He will also present certain pertinent animal data and discuss it as a predictor for human experience. He will also testify that TCDD is more toxic than many other carcinogens, including being more carcinogenic by a factor of 4 or 5 than benzene, for example. He will also explain the concept of risk assessment and how judgments as to such are capable of being made with regard to humans. This will include discussion of a mathematical model for association of the multi-faceted presentation of symptoms and signs in the same veteran to exposure to Agent Orange as a causative factor. 238° He will also discuss the population incidences of these rare cancers, presenting a comparison of the onset ages for them in the general population with the ages of onset for the cancers observed in. the Vietnam veterans. He will also discuss the relationship of cancer induction to immune deficiencies or deficits. He will place special emphasis upon lymphomas and soft tissue sarcomas and explain how the ex­ perience with transplant patients validates his opinions in this regard. Finally, he will discuss the question of a threshold in the induction of cancer. This will include testimony to the effect that there is no "safe" dose for a carcinogen and that a single exposure may cause cancer. He will also discuss the disease-producing behavior of generalized carcinogens, i.e., the chance of a single carcinogen leading to cancer at multiple sites. \ C^O MARVIN A. SCHNEIDERMAN Dr. Schneiderman is a Clement Associates Senior Science Advisor with principal responsibilities in biostatisticsf epidemiologyr risk assessment, and health surveillance. He has more than 30 years of experience in cancer research and related subjects, and he is the author of more than 130 scientific papers in areas of biostatistics, epidemiology, risk assessment, and science and regulatory policy. During his career with the National Cancer Institute (NCI), he was, successively, Associate Chief of the Biometry Branch, Associate Director for Field Studies (Epidemiology) and Statistics,•and Associate Director for Science Policy. In this last position, he was one of the princi­ pal advisors to the Director of the Institute. Dr. Schneiderraan is a member of the adjunct faculty of the Georgetown University Graduate School, and Professor of Biostatistics at the Uniformed Services University of the Health Sciences. He has held teaching positions at the University of Pittsburgh Graduate School of Public Health and the University of Miami (Florida), as well as at the Georgetown University Medical School. He was also a Rockefeller Public Service Fellow at the London School of Hygiene and Tropical Medicine. He has served on a number of expert advisory committees and is or has been an associate editor of Cancer Research, Blood, Journal of the National Cancer Institute, Biometr ics, Statistics in Medicine, American Journal of Industrial Medicine, and a number of other'scientific journals DEGREES Ph.D., Statistics, American University, Washington, D.C., 1961 M.S., Statistics, American University, Washington, D.C., 1953 B.S., Mathematics and Statistics, City College of New York, 1939 NON-DEGREE EDUCATION Harvard University Graduate School of Business, 1945 Management sciences, economics, statistics Ohio State University Graduate School, 1946-1947 Economics London School of Hygiene and Tropical Medicine, 1959-1960 Epidemiology, medical research involving humans, controlled trials, biostatistics i*> r.-N a X #£< 0 4 SCHNEIDERMAN, page 2 EMPLOYMENT HISTORY 1983-present Senior Fellow, Environmental Law Institute, Washington, D.C. 1981-present Professor (Division of Biometrics), Department of Preventive Medicine, USUHS, Bethesda, Md. 1980-present Senior Science Advisor, Clement Associates 1975-present Associate Professor, Graduate Faculty, Georgetown University 1980 Expert Consultant, Office of the Director, National Cancer Institute (NCI), National Institutes of Health (NIH) 1978-1980 Associate Director for Science Policy, Office of the Director, NCI 1970-1978 Associate Director NCI, Field Studies and Statistic Program, Division of Cancer Cause and Prevention, NCI 1967-1978 Adjunct Professor, Biostatistics, Graduate School of Public Health, University of Pittsburgh 1966-1975 Clinical Associate Professor, Medical Statistics, Georgetown University Medical School 1960-1970 Associate Chief, Biometry Branch, NCI 1960-1965 Professorial Lecturer, Georgetown University Medical School 1959-1960 Rockfeller Public Service Fellow, Statistical Research Unit of the British Medical Research Council, London School of Hygiene and Tropical Medicine 1955-1959 Mathematical Statistician and Acting Chief, Therapeutic Trials Section, NCI 1948-1955 Mathematical Statistician, Biometrics Section, NCI 1939-1948 Private Industry, Military Service Federal government agencies (USAF), Other "1 (*it 9n,toK xj . X i. SCHNEIDERMAN, page 3 T T /’W l/'M " * O n u i'iU A D Distinguished Lecturer, Lawrence Livermore Laboratories, Univer­ sity of California, 1982 American Conference of Government Industrial Hygienists, Symposium Speaker Award, June, 1982 Samuel Wilkes Public Lectureship, Princeton University, 1980 Keynote Lecturer, Society of Occupational and Environmental Health, 1979, North Carolina Public Health Association, 1980 Environmental Defense Fund, Public Interest Science Award, 1977 Distinguished Service Award, Department of Health, Education and Welfare (DHEW), 1974 Superior Service Award, DHEW, 1968 Rockefeller Public Service Fellow, London School of Hygiene and Tropical Medicine, 1959-1960 Phi Beta Kappa, 1939 SELECTED ADVISORY COMMITTEES Committee on Toxicity Data Elements, National Academy of Science 1981-present Subcommittee on the Geochemical Environment in Relation to Health and Disease, NAS/NRC, 1980-present Science Evaluation Board, National Health and Medical Research Council of Australia, 1980-present American Cancer Society, Analysis and Projections Committee, 1976-1978, Institutional Grants Committee, 1980-present Science Advisory Board, Howard University Cancer Center, 1979present (External Review Committee) Center for Science in the Public Interest, Board of Directors, 1983-present Food Safety Council, Board of Directors, 1978-1982 Advisory Committee, Biomedical and Environmental Assessment Division, Brookhaven National Laboratory, 1978-present f', Q f* SCHNEIDERMAN, page 4 Advisory Committee, International Cancer Research Data Bank (CIDAC), Franklin Institute, Philadelphia, 1981-present Task Force on Heart Disease Epidemiology, National Heart, Lung, and Blood Institute, 1979-1980 Science Advisory Board, National Center for Toxicological Research, 1974-1979 Ad Hoc Subcommittee on Asbestos-Related Health Problems, Armed Forces Epidemiology Board, 1978-1979 International (American) Chairman, U.S./U.S.s.R. Working Group on the Epidemiology of Cancer, 1973-1979 Committee on Maritime Hazardous Materials, National Academy of Sciences, 1978 Committee to Coordinate Toxicology and Related Programs, DHEW, 1978 President's Biomedical Panel, 1975-1976 Consultative Panel on Hazards of Chemical Pesticides, National Academy of Sciences, 1974-1976 Chairman and Executive Secretary, Committee of Presidents of Statistical Societies, 1973-1976 Board of Directors, American Statistical Association, 1972-1974 International Council, International Biometric Society, 1971-1973 Immunology-Epidemiology Segment, Special Virus Cancer Program, NCI, 1969-1971 Advisory Panel on Carcinogenicity of Pesticides, Secretary's Commission on Pesticides and Their Relationship to Environmental Health, 1969-1970 Chairman, Subcommittee on Medical Biostatistics, American Thera­ peutic Society, 1967-1968 Subcommittee on Biologic Effects of Atomic Radiation, NAS/NRC, 1964-1965 SCHNEIDERMAN, page 5 SELECTED SOCIETIES American Association for Cancer Research American Society for Preventive Oncology (Founding Member) American Statistical Association (Fellow) Biometric Society (International) International Epidemiological Association Royal Statistical Society (Fellow) Washington Statistical Society American Association for the Advancement of Science (Fellow) International Statistical Institute (Fellow) Society for Occupational and Environmental Health SELECTED PUBLICATIONS Schneiderman, M.A. Standard setting: Implications of sensitivity and a search for an ethical base. In: Protection of the Sensitive Individual, Annals of the American Conference of Government Industrial Hygienists, 3:133-138 (1932) Schneiderman, M.A. A personal reminiscence (Austin Bradford Hill). Statistics in Medicine 1:307-308 (1982) Schneiderman, M.A. Discussion of "Some Aspects of Cancer Epidemi­ ology" by Abraham Lilienfeld. Biometrics (Supplement) 38:161-165 (1982) Davis, D.L., Bridbord, K., and Schneiderman, M.A. Cancer preven­ tion: Assessing cause, exposure, and recent trends in mortality for U.S. males, 1968-1978. Teratogenesis, Carcino­ genesis and Mutagenesis. Pp. 105-135 (June 1982) Schneiderman, M.A. Trends in cancer mortality and incidence in the United States: Is the future clear or clouded? In Mike, V., e d . Statistics in Medical Research. John Wiley and Sons, New York. Pp. 71-107 (1982) Schneiderman, M.A. Description and reliability of trends in ' cancer incidence. In Magnus, K. Trends in Cancer Incidence. Hemisphere Publishing Corp., Washington, D.C. Pp. 1-2 (1982) Schneiderman, M.A. Cost-benefit, social values and the setting of occupational health standards. In Lee, J.S., and Rom, W.N eds. Legal and Ethical Dilemmas in Occupational Health. Ann Arbor Science, Ann Arbor, Michigan, pp. 191-205 (1982) ■¥* <*% r" try SCHNEIDERMAN, page 6 Peto, R. , and Schneiderman, M. , eds. Quantification.of Occupa­ tional Cancer: Banbury Report No. 9. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York (1981) . Davis, D.L., Bridbord, K., and Schneiderman, M.A. Estimating cancer risks: Problems in methodology production trends. In Peto, R . , and Schneiderman, M . , eds. Quantification of Occupational Cancer: Banbury Report No. 9. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. Pp. 285315 (1981) Schneiderman, M.A. Summary comments. In Crandall, R.W., and Lave, R . , eds. The Scientific Basis of Health and Safety Regulation. The Brookings Institution, Washington, D.C. Pp. 297-299 (1981) Schneiderman, M.A. Regulation of carcinogens in an imprecise world. Ann. N.Y. Acad. Sci. 363:217-232 (1931) Schneiderman, M.A. Extrapolation from incomplete data to total or lifetime risks at low doses. Environ. Health Perspect. V. 42, Pp. 33-38 (December 1981) Schneiderman, M.A. Toxic Substances in Our Environment-Can we manage them so 'chat they don't manage to harm us? Health Forum 81, The Coalition for Health and the Environ­ ment, Washington, D.C. (1981) Schneiderman, M.A. Epidemiology: What Can it Tell Us? Pro­ ceedings of the Conference on Environmental Risk, New Orleans, Louisiana, December 10, 1980. The Electric Power Research Institute, Palo Alto, California, EPRI EA-2064, Project 1316-6. Pp. 369 - 3-89 (October 1981) Schneiderman, M . A . , Nisbet, I., and Brett, S.M. Assessment of Risks Posed by Low Levels of Asbestos in the General Environment. Berichte: Bundesgesundheitsamt. No. 4, 1981. Dietrich Reimer Verlag, Berlin. Pp. 3/1-3/28 (1981) Schneiderman, M . A . , and Levin, D.L. Needs, problems and prospects in cancer epidemiology. In Levin. D.L., ed. Cancer Epidemi­ ology in the U.S.A. and U.S.S.R. U.S. Department of Health and Human Services, P H S , Bethesda, Maryland. NIH Publication No. 80-2044 (1980) Schneiderman, M.A. The Relationship Between Diet, Occupation, the Environment and Cancer. Proceedings: US/Egypt Symposia", on the Biomedical Effects of Technology Transfer, Cairo, Egypt (February 9-13, 1980) (In Press: Environmental Health Perspectives) 12989 SCHNEIDERMAN, page 7 Schneiderman, M.A. Scientific Issues in a National Cancer • Policy. Proceedings of the 4th Toxic Control Conference. Government Institutes, Inc., Washington, D.C. Pp. 95-107 (1980) Schneiderraan, M.A. The uncertain risks we run: Hazardous materials. In Schwin, R.C., and Albers, W . A . , Jr., eds. Societal Risk Assessment. Plenum Press, New York. Pp. 19-41 (1980) Schneiderman, M.A. What's Happening to Cancer in our Advanced Industrial Society? Have the Risks been Overstated? Keynote Address: Society for Occupational and Environmental Health, Washington, D.C. (In Press: Proceedings) (December 3-5, 1979) Blokhin, N.N., and Schneiderman, M.A., eds. Epidemiology of Cancer in the USSR and USA. Meditsina, Moscow (Russian) (1979) Schneiderman, M.A., DeCoufle, P., and Brown, C.C. Thresholds for environmental cancer: Biologic and statistical consider­ ations. Ann. N.Y. Acad. Sci. 329:92-130 (1979) Schneiderman, M.A. Alpha, beta manitonne— a new industrial material with unknown benefits and risks. In Carcinogenic Risks/Strategies for Intervention. International Agency for Research on Cancer (IARC), Lyon, France. IARC Sci. Publ, 25:237-239 (1979) Schneiderman, M.A. The Links Between the Environment and Health. Proceedings: National Conference on the Environment and Health Care Costs, .U.S. House of Representatives (August 15, 1978) Biersteker, K. , and Schneiderman, M.A. Epidemiologic Aspects of Drinking Water-Health Relationship. Proceedings of the Health Effects Committee of the NATO committee on challenges of Modern Society. 3onn, W. Germany (April 23• 27 , 1978) Schneiderraan, M.A., Mason, T.J., and Hoover, R. Cancer, geography, and geology— a problem for interdisciplinary cross-fertili­ zation. In Geochemistry and the Environment. Vol. 3. National Academy of Sciences, Washington, D.C. (1978) Schneiderman, M.A. Legislative possibilities to reduce the impact of cancer. Prev. Med. 7:424-438 (1978) 12390 SCHNEIDERMAN, page 8 Schneiderman, M.A. Water and epidemiology. In Russell, C.S., ed. Safe Drinking Water: Current and Future Problems. Proceedings of the National Conference on Resources for the Future. Pp. 111-1.48 (1978) Schneiderman, M.A. Extrapolating animal and microbiological tests to humans. In Coling, G., e d . Environmental Cancer (Causes, Victims, Solutions). Proceedings of a conference of the Urban Environment Coalition, Inc. Pp. 9-11 (1978) Schneiderman, M.A. Environmental Factors and Cancer Prevention Marcel Dekker, New York (1978). (Third National Symposium on Detection and Prevention of Cancer, New York (April 26-30, 1976) Schneiderman, M.A. Risk assessment of the health effects of water chlorination. In Jolley, R.L., Gorchev, H., and Hamilton, D.H., eds. Water Chlorination— Environmental Impact and Health Effects. Ann Arbor Science Publications Ann Arbor, Mich. Vol. 2, pp. 509-515 (1978) Schneiderman, M.A., and Brown, C.C. Estimating cancer risks to a population. Environ. Health Perspect. 22:115-124 (1978) Schneiderman, M.A. Eighty percent of cancer is related to the environment. Laryngoscope 88:1-16 (1978) Schneiderman, M.A. Time Trends in Cancer: United States, 1953-1973. Laryngoscope 88, Supp. 8:1-6 (1978) Fears, T.R., Scotto, J., and Schneiderman, M.A. Mathematical models of age and ultraviolet effects on the incidence of skin cancer among whites in the United States. Am. J. Epidemiol. 105:420-427 (1977) DeVesa, S.S., and Schneiderman, M.A. Increase in the number of cancer deaths in the United States. Am. J. Epidemiol. 106:1-5 (1977) Schneiderman, M.A. The numerate sciences— epidemiology and biometry. JNCI 59:633-644 (1977) Schneiderman, M.A., and Levin, D.L. Epidemiology of cancer and tobacco use: Trends and trend indicators. In Steinfield, J., Griffiths, W . , Ball, K. , and Taylor, R.M., eds. Smoking and Health: II. Health Consequences, Educa tion, Cessation Activities, and Governmental Action. Proceedings of the Third World Conference on Smoking and Health, New York. Pp. 73-84 (1977) j 9 n 91 SCHNEIDERMAN, page 9 Schneiderman, M.A. Health effects— a scientific and.statistical analysis. In Miller, M.L., ed. Proceedings of the First Toxic Substances Law Seminar. Washington, D.C. .(1977) Levin, D.L., and Schneiderman, M.A. Cancer. In Miller, S.S., ed. Symptoms. Thomas Y. Crowell, New York (1976) Fears, T.R., Scotto, J., and Schneiderman, M.A. Skin cancer, melanoma, and sunlight. Am. J. Public Health 66:461-464 (1976) Schneiderman, M.A. Carcinogenesis as an end point in health impact assessment. In Anderson, E.C., and Sullivan, E.M., eds. Impact of Energy Production on Human Health: An Evaluation of Means of Assessment. National Technical Information Service, Springfield, Va. Pp. 65-74 (1976) Schneiderman, M.A. Sources, resources, and tsouris. In Fraumeni, J.F., ed. Persons at High Risk of Cancer: An Ap­ proach to Cancer Etiology and Control. Academic Press, New York (1976) Hoel, D.C., Gaylor, D.W., Kirschstein, R.L., Saffiotti, U., and Schneiderman, M.A. Estimation of risks of irreversible, delayed toxicity. J. Toxicol. Environ. Health 1:133-151 (1975) Mantel, N . , and Schneiderman, M.A. Non-parametric interval estimation of relative potency for dilution assays, includ­ ing the case of non-monotone dosage response curves. Biometrics 31:619-632 (1975) Mantel, N . , and Schneiderman, M.A. Estimating "safe" levels— a hazardous undertaking. Cancer Res. 35:1379-1386 (1975) Schneiderman, M.A., Mantel, N . , and Brown, C.C. From mouse to man— or how to get from the laboratory to Park Avenue and 59th Street. Ann. N.Y. Acad. Sci. 246:237-248 (1975) Schneiderman, M.A. How do you know you've done any better? Cancer 35:64-68 (1975) Schneiderman, M.A. Digestive system cancer among persons sub­ jected to occupational inhalation of asbestos particles: A literature review with emphasis on dose response. Environ. Health Perspect. 9:307-311 (1974) Schneiderman, M.A. Safe dose? The problems of the statistician in the world of trans-science. J. Wash. Acad. Sci. 64:6878 (1974) 12392 SCHNEIDERMAN, page 10 Fears, T.R., and Schneiderman, M.A. Pathologic evaluation and the blind technique. Science 183:1144-1145 (1974) Elashoff, R.M., Sobel, M . , and Schneiderman, M.A. A proposal for economical first stage screening for tumorigens with a posssible "joint action" bonus. In Pratt, J.W., ed. Statistical and Mathematical Aspects of Pollution Problems. Marcel Dekker, New York (1974) Van Belle, G., and Schneiderman, M.A. Some statistical aspects of pollution and protection. Int. Stat. Rev. 41:315 (1973) Wynder, E.L., and Schneiderman, M.A. Exogenous hormones— boon or culprit? JNCI 51:729-731 (1973) Gehan, E.A., and Schneiderman, M.A. Experimental design of clinical trials. In Holland, J.F., and Frei, E., eds. Cancer Medicine. Lea and Febiger, Philadelphia. Po. 499519 (1973) Schneiderman, M.A., and Mantel, N. The Delaney clause and a scheme for rewarding good experimentation. Prev. Med. 2:165-170 (1973) Schneiderman, M.A., and Levin, D.L. Parallels, convergences, and departures in case-control studies and clinical trials. Cancer Res. 33:1498-1503 (1973) Graham, S., and Schneiderman, M.A. Social epidemiology and the prevention of cancer. Prev. Med. 1:371-379 (1972) Scotto, J., and Schneiderman, M.A. Predicting survival in terminal cancer. Br. Med. J. 4:50 (1972) Schneiderman, M.A., and Levin, D.L. Trends in lung cancer: Mortality, incidence, diagnosis, treatment, smoking and urbanization. Cancer 30:1320-1325 (1972) Johnson, R.E., Thomas, L.B., Schneiderman, M.A., Glenn, D.W.., •: Faw, F., and Habermann, M.D. Preliminary experience with total nodal irradiation in Hodgkin's disease. Radiology 96:603-608 (1970) Schneiderman, M.A., and Scotto, J. Computer-Investigator Inter­ actions in Small-Scale Clinical Trials. Proceedings of the Fifth Scientific Meeting of the International Epidemiol­ ogy Association, Primosten, Yugoslavia. Pp. 449-467 -(1970) SCHNEIDERMAN, page 11 Gold, G .L . , Shnider, B.I., Salvin, L.G., Schneiderman, M . A . , Col sky, J., Owens, A.H., Krant, M.J., Miller, S , Frei, E., Ill, Hall, T.C., Spurr, C.L., McIntyre, O.R., Hopgstraten, B. and Holland, J.F. The use of mechlorethamine, cyclophospha­ mide, and uracil mustard in neoplastic disease: A coopera­ tive study. J. Clin. Pharmacol. 10:110-120 (1970) Schneiderman, M.A. How to read the drug literature— or any other organized collection of numbers from experiments. Mod. Med. 37:92-96 (1969) Malmgren, R.A., Bennett, J . M . , DelVecchio, P.R., DeWhitt, S.H., Feld, M . , Kazam, E., and Schneiderman, M.A. Evaluation studies of peripheral blood leucocyte changes in malignancv. Acta Cytol. 13:149-153 (1969) Schneiderman, M.A. Quantitative thinking in medicine— biosta­ tistics. (Using numbers to mark the route from cause to effect and back.) In Cantor, P., e d . Traumatic Medicine and Surgery for the Attorney. Matthew Bender, New York. ?p. 419-477 (1969) Givelber, H., DiPaolo, J.A., and Schneiderman, M.A. The influence of actinomycin D on survival of x-radiated RF mice. Cancer Res. 28:2484-2488 (1968) Pipberger, H.V., Schneiderman, M.A., and Klingeman, J.D. The love-at-first-sight effect in research. Circulation 38:822825 (1968) Carbone, P.P., Spurr, C. , Schneiderman, M.A., Scotto, J., Holland, J.F., and Shnider, B. Management of patients with malignant lymphoma: A comparative study with cyclophosphamide and vinca alkaloids. Cancer Res. 28:811-822 (1963) Hall, T.C., Nevinny, H.B., Holland, J.F., Maldia, G . , Schneiderman M.A., Salvin, L . , Shnider, 3.1. , Gold, G.L., Frei, E., Ill, Carbone, P.P., Colsky, J., Franzino, A., Grob, D., Matiasevic, D., Olson, K.3., Horton, J., Owens, A., Santos, * ^ G.W. , Chalmers, T.C. , and Krant, M.J. Comparison of anti­ metabolites in the treatment of breast and colon cancer. JAMA 200:770-778 (1967) Schneiderman, M.A. The Shin Tokaido to developing new treatments in medicine: Unbiasedness. In Harris, R.J.C.,ed. Pro­ ceedings of the 9th International Cancer Congress. SpringerVerlag, Heidelberg. Pp. 194-198 (1967) Bull, B.S., Schneiderman, M.A., and Brecher, G. w? c i u J . dilution system for the hematology laboratory Clin. Pathol. 47:549-553 (1967) a u L u n i a u i u SCHNEIDERMAN, page 12 Schneiderman, M.A. Mouse to man: Statistical problems in bringing a drug to clinical trial. In LeCam, L., and Neyman, J., eds. Biology and Problems of Health. Univer­ sity of California Press, Berkeley. Vol. 4, pp. 855-866 (1967) Schneiderman, M.A. Non-objective art and objective evaluation of cancer chemotherapy. In Brodsky, I., and Kahn, S.B., eds. Cancer Chemotherapy. New York, Gruñe and Stratton. Pp. 67-76 (1967) Spurr, C.L., Carbone, P.P., and Schneiderman, M.A. Comparative evaluation of cyclophosphamide and vinca alkaloids in lymphomas. Proceedings of the 57th Annual Meeting of the American Association of Cancer Research 7:67 (1966) Myers, M.H., Schneiderman, M.A., and Armitage, P. Boundaries for closed (wedge) sequential t-test olans. Biometrika 53:431-437 (1966) Schneiderman, M.A. Experimental design considerations in multi­ clinic trials. In Radouco-Thomas, C., exec, e d . Interna­ tional Encyclopedia of Pharmacology and Therapeutics. Pergamon Press, Oxford. Vol. 2, pp. 617-636 (1966) Schneiderman, M.A. The value of controlled trials. In Hayward, J.L., and Bulbrook, R.D., eds. Clinical Evaluation in Breast Cancer. London, Academic Press. Pp. 249-259 (1966) Cutler, S.J., Greenhouse, S.W., Cornfield, J., and Schneiderman, M.A. The role of hypothesis testing in clinical trials. J. Chron. Dis. 19:857-882 (1966) Bourgeois, L.D., Hart, L.J., Herman, L.G., Schneiderman, M.A., and Young, V.M. Effect on varying preincubation and diffu­ sion times and antibiotic disc susceptibility testing. In Day, R.A., e d . Antimicrobial Agents and Chemotherapy— 1965. Waverly Press, Baltimore. Pp. 283-288 (1966) Schmeiderman, M.A., and Krant, M.J. What shall we measure on whom: Why? Cancer Chemother. Rep. 50:107-112 (1966) Dawson, J.M., Hall, T.C., Schneiderman, M.A., Shnider, B.I., Owens, A.H., Andrews, J.R., Baxter, D.H., Brenner, S., Hunter, C., Levene, M.3., Sheehan, F.R., and White, G. The objective evaluation of change in tumor size in lung cancer patients with non-measurable disease. Cancer 19:415-420 (1966) 12995 SCHNEIDERMAN, page 13 Schneiderman, M.A. Looking backward: Is it worth the crick in the neck? Or: Pitfalls in using retrospective data. AJR 96:230-235 (1966) Bull, B.S., Schneiderman, M.A., and Brecher, G. Platelet counts with the Coulter counter. Am. J. Clin. Pathol. 45:678-688 (1965) Schneiderman, M.A. How can we find an optimal dose? Appl. Pharmacol. 7, Supp. 2:44-53 (1965) Toxicol. Schneiderman, M.A. The optimal dose and the ranking of drugs. J. Oral Ther. Pharmacol. 2:118-119 (1965) Carbone, P.P., Krant, M.J., Miller, S.P., Hall, T.C., Shnider, 3 Colsky, J., Horton, J., Hofley, H., Miller, J.M., Frei, E.J., III, and Schneiderman, M.A. The feasibility of using randomization schemes early in the clinical trials of new chemotherapeutic agents: Hydroxyurea (NSC-32065). Clin. Pharmacol. Ther. 6:17-24 (1965) Schneiderman, M.A. The proper size of a clinical trial: m a 's strudel" method. J. New Drugs 4:3-11 (1964) "Grand Schneiderman, M.A. Defensive design of clinical trials. In Sternberg, T.H., and Newcomer, V.D., eds. The Evaluation of Therapeutic Agents and Cosmetics. McGraw-Hill, New York. Pp. 66-73 (1964) Schneiderman, M.A., Myers, M.H., Sathe, Y.S., and Xoffsky, P. Toxicity, the therapeutic index, and the ranking of drugs. Science 144:1212-1214 (1964) Schneiderman, M.A. Is it really bad? A proposal for the toxi­ city-testing of drugs. J. Soc. Cosmetic Chem. 14:227232 (1963) Schneiderman, M . A . , and Armitage, P. Biometrika 49:359-366 (1962) Closed sequential t-tests. Brecher, G., Jakobek, E.F., Schneiderman, M.A., Williams, G.Z., and Schmidt, P.J. Size distribution of erythrocytes. Ann. N.Y. Acad. Sci. 99:242-261 (1962) Schneiderman, M . A . , and Armitage, P. A family of closed sequen­ tial procedures. Biometrika 49:41-56 (1962) Schneiderman, M.A. The clinical excursion into 5-fluorouracil. J. Chron. Dis. 51:283-295 (1962) 12396 SCHNEIDERMAN, page 14 Schneiderman, M.A. Controlled clinical trials: Monday's count­ down for Tuesday's launching. J. New Drugs 1:250-255 (1961) Schneiderman, M.A. Statistical problems in the screening search for anticancer drugs by the National Cancer Institute of the United States. In Quantitative Methods in Pharmacol­ ogy. North Holland Publishing Co., Amsterdam. Pp. 232247 (1961) Zubrod, C.G., Schneiderman, M.A., Frei, E . , III, Brindley, G., Gold, G.L., Shnider, B., Oviedo, R . , Gorman, J., Jones, R., Jr., Jonsson, G . , Colsky, J . , Chalmers, T . , Ferguson, B., Dederick, M . , Holland, J., Selawry, 0., Regelson W . , Lasagna, L., and Owens, A.H. Appraisal of methods for the study of chemotherapy of cancer in man: Comparative therapeutic trial of nitrogen mustard and triethylene, thiophosphoramide. J. Chron. Dis. 11:7-33 (1960) Leiter, J., Wodensky, I., Bourke, A.R., and Schneiderman, M.A. Screening data from the Cancer Chemotherapy National Service Center screening laboratories, III. Cancer Res. 19:438575 (1959) Leiter, J., and Schneiderman, M.A. Screening data from the Cancer Chemotherapy National Service Center screening laboratories. Cancer Res. 19:31-279 (1959) Schneiderman, M.A. Mathematical models in the regulation of granulocyte production. In Stohlman, F., Jr., ed. Kinetics of Cellular Proliferation. Gruñe and Stratton, New York. Pp. 259-264 (1959) Brindley, C.O., Markoff, E . , and Schneiderman, M.A. Direct observations of lesion size and number as a method of following the growth of human tumors. Cancer 12:139-146 (1959) Freireich, E.J., Schmidt, P.J., Schneiderman, M.A., E., III. A comparative study of the effect of of fresh and preserved whole blood on bleeding with acute leukemia. N. Eng. J. Med. 260:6-11 and Frei, transfusion in patients (1959) Armitage, P., and Schneiderman, M.A. Statistical problems in mass screening program. Ann. N.Y. Acad. Sci. 76:896908 (1958) Frei r E . , III, Holland, J.F., Schneiderman, M.A., Pinkel, D., Selkirk, G. , Freireich, E.J., Silver, R.T., Gold, G.L. , and Regelson, W.A. A comparative study of two regimens of combination chemotherapy in acute leukemia. Blodd9QQ7 13:1126-1148 (1958) SCHNEIDERMAN, page 15 Schneiderman, M.A. Epidemiology of carcinoma of the.breast. Med. Ann. Dist. Columbia 27:275-280 (1958) Silver, R . T . , Beal, G.A., Schneiderman, M.A., and McCullough, N.E The role of the mature neutrophil in bacterial infections in acute leukemia. Blood 12:814-821 (1957) Stohlman, F., Jr., Brecher, G., Schneiderman, M.A., and Cronkite, The haemolytic effect of ionizing radiation and its relation ship to the hemorrhagic phase of radiation injury. Blood 12:1061-1085 (1957) Brecher, G . , Schneiderman, M . A . , and Williams, G.Z. Evaluation of an electronic red blood cell counter. Am. J. Clin. Pathol. 26:1439-1449 (1956) Olivier, L . , and Schneiderman, M.A. A method for estimating the density of aquatic snail populations. Exp. Parasitol. 5:109-117 (1956) Stohlman, F., Jr., and Schneiderman, M.A. Application of the cr: technique to the study of experimental hemolysis in the dog. J. Lab. Clin. Med. 47:72-87 (1956). Cutler, S.J., Schneiderman, M.A., and Greenhouse, S.W. Some statistical considerations in the study of cancer in industr Am. J. Public Health 44:1159-1166 (1954) Prehn, R.T., Main, J.M., and Schneiderman, M.A. Factors influ­ encing tumor distribution among the mammary glands of the mouse. JNCI 14:895-904 (1954) Olivier, L . , and Schneiderman, M.A. Acquired resistance to schistosoma Mansoni infection in laboratory animals. Am. J. Trop. Med. H y g . 2:298-306 (1953) Brecher, G. , Schneiderman, M . A . , and Cronkite, E.P. The reproduc ibility and constancy of platelet counts. Am. J. Clin. Pathol. 23:15-26 (1953) Heston, W.E., and Schneiderman, M.A. Analysis of dose-response in relation to mechanism of pulmonary tumor induction in mice. Science 117:109-111 (1953) Plum, C . M . , Clemmesen, J., and Schneiderman, M.A. In vitro study of bone marrow v. erythropoiesis of bone marrow from cases of pernicious anemia and leukosis. Acta Med. Scand. 143:237-248 (1952) 12S98 Dr. Ellen Silbergeld, Ph.D., is an environmental scientist and toxicologist who is the Chief Toxicologist for the Environmental Defense Fund and a Research Scientist in the Reproductive Toxicology Laboratory of the National Institutes of Health in Bethesda, Maryland. Her curriculum vitae is attached. Dr. Silbergeld will testify as to the scientific models for TCDD toxicity. She will emphasize the receptor model, its role in physiology, how to detect receptors and how to link receptors to function. She will discuss how receptors recognize TCDD by virtue of structural "fine-tuning". She will testify as to the existence of receptors in humans and in their various organs, together with the implications of their presence for TCDD potency. She will also discuss the extrapolations which are possible between animals and humans. She will further testify as to the mechanisms of toxicity including the sensitivity of the reproductive system, both endocrine and gonadal, to the receptor-mediated effects of TCDD. Finally, she will discuss the consequences of receptor inter­ action with TCDD insofar as that interaction produces results involving RNA-DNA, AHH induction, and heme synthesis regulation, among others. In the field of neurotoxicity, she will discuss the experimental and clinical studies with particular emphasis upon dose-response mechanisms, acute versus chronic exposures and early versus long latency effects. She will also discuss iti@899 SCHNEIDERMAN, page 16 Schneiderraan, M . A . , Mantel, N . , and Brecher, G. The effect of rejection procedures on the accuracy of blood counts. Am. J. Clin. Pathol. 21:973-978 (1951) Schneiderman, M.A., and Brecher, G. The relative frequency of sparse cell elements— an application to reticulocyte blood counts. Biometrics 6:390-394 (1950) Brecher, G., and Schneiderman, M.A. the counting of reticulocytes. 20:1074-1083 (1950) A time saving device for Am. J. Clin. Pathol. Williamson, C.R., and Schneiderman, M.A. The use of mass x-ray survey films for heart disease case finding. Mass. Health 30:7-14 (1950) 13000 biochemical and morphological effects of TCDD, the electro­ physiology involved and the effects of TCDD on such things as cognition, mood, and affect. She will also emphasize the basic mechanisms of toxicity on both the central and peripheral nervous systems, specifically dealing with the role of altered porphyrin synthesis on the nervous system. will be discussed: Three aspects of this problem First, the effects of decreased cellular energy supply on neuronal activity and viability; second, the effects of decreased heme systhesis on the integrity of myelin; and third, the neuroactive properties of certain porphyrin precursors. 13001 CURRICULUM VITAE Name: _ -Ellen Kovner Silbergeld Date and Place of Birth: July 29. 1945, Washington. DC Education: 1967 - A.B. 1972 - Ph.D. Vassar College Johns Hopkins University Chronology of Employment: 1967 19681969- 71 1972-75 1975 1975-79 1979-81 1982 Instructor. California International Summer Program, Uppsala Sweden 70 Secretary and Program Officer. National Academy of Sciences. National Research Council. Washington. DC "Nader's Raiders". Center for the Study of Responsive Law. Washington, DC Postdoctoral Fellow in Environmental Medicine and Neurosciences. Johns Hopkins University. Baltimore. Maryland Assistant Professor. Department of Environmental Medicine. School of Hygiene and Public Health. Johns Hopkins University Staff Fellow and Head. Unit on Behavioral Neuropharmacology. Experimental Therapeutics Branch. NINCDS.NIH Chief. Section on Neurotoxicology. NINCDS.NIH Chief Toxics Scientist. Environmental Defense Fund. Washington. DC Guest Scientist. Reproductive Toxicology Section. Pregnancy Research Branch, NICHD.NIH Other Professional Appointments: Consultant. NSF Energy Program. 1974-1975 Member, Nutrition Foundation National Committee on Food Additives and Hyperkinesis. 1975-1980 Member. USDHEW-FDA Committee to Coordinate Toxicology and Related Programs. 1977-1981 Member. US Delegation of the Joint US-USSR Health Agreement on Environmental Health. 1977-78 Member. Society for Neuroscience Committee on Social Issues, 1978 Member. OECD Chemicals Program Ad Hoc Expert Review Committees on Reproductive Toxicity and Neurotoxicity. 1982 - 13002 Member Member. Member. Member. Member. Member. US Delegation to OECD Expert Meetings on Existing Chemicals. 1983 Hazardous Waste Task Force and Hazardous Waste Facilities Siting Board, State of Maryland. 1983 Govenor1s Blue Ribbon Panel on Binghamton. NY, State Office Building. 1982 Executive Committee. Science Advisory Board, US EPA. 1983 Board on Toxicology and Environmental Health Hazards. National Academy of Sciences. 1983 Public Policy Committee. American Society for Neurochemistry. 1983 - Professional Society Memberships: American Public Health Association Society for Occupational and Environmental Health Society for Neuroscience Association of Women in Science American Association for the Advancement of Science International Brain Research Organization American Society for Neurochemistry American Society for Pharmacology and Experimental Therapeutics Engineering Society of Baltimore Other Activities Secretary-Treasurer. Society for Occupational & Environ­ mental Health. 1983Editorial Board: Neurobehavioral Toxicology. 1979Aroerican Journal of Industrial Medicine. 1980Neurotoxicology. 1981Environmental Research. 1983Hazardous Waste. 1983 Participant. NIH Consensus conferences. 1979 and 1982 Expert consultant on lead poisoning. U.S. Secret Service. 1979-81 Chairperson. Society for Occupational and Environmental Health Special Committee on El Paso Lead Poisoning. 1977-1979 Preceptor. NIGMS Pharmacology-Toxicology Research Associateship Program. 1977-1981 Graduate board examiner. University of Pittsburgh and University of Toronto Lecturer, continuing medical education courses in environ­ mental medicine (Johns Hopkins) and occupational medicine (NIOSH) 2 Elected councillor. NIMH-NINCDS Assembly of Scientists. 1979- 1981 Elected representative. NINCDS EEO Committee. 1977-1980 Co-^organizer. Women in Neuroscience Member, Solovey Lectureship selection committee. NIH. 1980- 1981 Environmental Health Consultant. Oil. Chemical and Atomic Workers Union. AFL-CIO, Washington. D.C.. 1970 Reviewer. EPA documents on lead, manganese. mercury, dioxin, risk assessment, and exposure. 1981Ad Hoc Member. Occupational Safety and Health Study Section. NIOSH. 1983Member. NIMH Committee on Frontiers of Neuroscience. 1983Grants reviewer. National Foundation - March of Dimes; National Science Foundation; Nutrition Foundation; Thrasher Foundation; Hereditary Diseases Foundation. NIH Manuscript reviewer. Life Sciences. Biochemical Pharmacology. Environmental Journal Pharmacology. Science. Neurotoxicology. Neurobehavioral Toxicology Teratology. Pharmacology Biochemical Behavior. Procs. Society Experimental Biological Medicine. Experimental Neurology, etc. Honors and Awards: Graduated sumroa cum laude. 1967 elected to Phi Beta Kappa. 1967 undergraduate academic scholarship. 1963-1965 Woodrow Wilson National Foundation Fellow. 1967-1968 Leverhulme and Fulbright Fellowships to University of London. 1967 National Science Foundation Graduate Traineeship. 1968-1972 Public Health Service Research Fellowship to Woods Hole. 1970 Rockefeller Foundation predoctoral research fellowship. 1971-1972 NIH postdoctoral fellowship in environmental health sciences. 1972-1972 Joseph P. Kennedy, Jr. Fellowship in neurosciences. 1974-1975 Pharmaceutical Manufacturers Association Foundation Research Starter Award. 1974-1975 National Academy of Sciences Exchange Fellow to Yugoslavia. 1976 George Miller lectureship in environmental studies. University of Illinois. 1984 Professional Interests: Neuropharmacology & Toxicology Environmental Risk Assessment 3 13004 BIBLIOGRAPHY ELLEN KOVNER SILBERGELD A. SCIENTIFIC PUBLICATIONS 1. Silbergeld. E.K.: Dieldrin: Effects of chronic sublethal exposure on adaptation to thermal stress in a freshwater fish. Environ. Sci. Technol. 7:846-849. 1973. 2. Silbergeld. E. K.: and Goldberg. A.M.: A lead-induced behavior disorder. Life Sci. 13.(9): 1275-1283. 1973. 3. Silbergeld. E. K.: Blood glucose: A sensitive indicator of environmental stress in fish. Bull. Environ. Contam. Toxicol 11.(1): 20-25. 1974. 4. Silbergeld. E. K.. Fales. J. T. and Goldberg. A.M.: Lead: Evidence for a prejunctional effect on neuromuscular function. Nature 247:49-50. 1974. 5. Silbergeld. E. K.. Fales. J. T. and Goldberg. A.M.: Lead: The effects of inorganic lead on the neuromuscular junction. Neuropharmacology 13.: 146-157. 1974 . 6. Silbergeld. E. K. and Goldberg, A.M.: Lead induced behavioral dysfunction: An animal model of hyperactivity. Exp. Neurol. 42.:146-157, 1974. 7. Silbergeld. E. K. and Goldberg, A.M.: Hyperactivity: A lead induced behavior disorder. Environ. Health Persp. 7:227-232. 1974. 8. Silbergeld. E. K. and Goldberg. A.M.: Pharmacological and neurochemical investigations of lead induced hyperactivity. Neuropharmacology 14.:431-444. 1975. 9. Morrison. J. H.. Olton. D. S.. Goldberg. A.M. and Silbergeld. E. K.: Alteractions in consummatory behavior of mice produced by dietary exposure to inorganic lead. Dev. Psychobiol. 8.(5) :389-396. 1975. 10. Silbergeld. E.K.: Neurochemical and pharmacological studies of central nervous system lead toxicology. In Carnov, B.W. (ed.): Health Effects of Occupational Lead and Arsenic Exposure. USDHEW, PHS, CDC, NIOSH. Washington. D.C., pp. 74-85. 1976. 4 --------- 13005 11. Silbergeld. E. K. and Chisolm. J. J.. Jr.: Lead poisoning: Altered urinary catecholamine metabolites as indicators of intoxication in mice and children. Science 192U53-155. 1976. 12. Fitzgerald. R. S.. Garfinkel. F.. Silbergeld. E. K. and Loscutoff. S.C.: Factors in the interpretation of mouth occlusion pressure during measurements of chemosensitivity. Chest 70.(1): 145-149. 1976. 13. Silbergeld. E. K. and Goldberg, A. M. : Hyperactivity. In. Goldberg. A.M. and Hanin. I. (eds): Biology of Cholinergic Function. Raven Press. New York, pp. 619-645. 1976. 14. Silbergeld. E. K. : Interactions of lead and calcium on the synaptosomal uptake of dopamine and choline. Life Sci. 20(2):309-318. 1977. 15. Carroll. P. T.. Silbergeld. E. K. and Goldberg. A. M . : Alteration of central cholinergic function by chronic lead acetate exposure. Biochem. Pharmacol. 26,:397-402. 1977. 16. Silbergeld. E. K. and Pfeiffer. R. F.: Differential effects of three dopamine agonists: Apomorphine. bromocriptine and lergotrile. J. Neurochem. 28:1323-1326. .1977. 17. Silbergeld, E. K.: Na+ regulates release of Ca++ sequestered in synaptosomal mitochondria. Biochem. Biophys. Res. Comm. 77.(2) :464-469. 1977. 18. Silbergeld. E. K.. Adler, H. S. and Costa. J. L.: Subcellular localization of lead in synaptosomes. Comm. Chem. Pathol. Pharmacol. 17:715-725. 1977. Res. 19. Goldberg. A. M. and Silbergeld. E. K.: Animal models of hyperactivity In Hanin. I. and Usdin. E. (eds.): Animal Models of Psychiatry and Neurology. Pergamon Press, New York. pp. 371-384. 1977. 20. Silbergeld. E. K.. Adler. H. S.. Kennedy. S. and Caine. D. B.: the roles of presynaptic function and hepatic drug metabolism in the hypothermic actions of some novel dopaminergic agonists. J. Pharm. Pharmacol. 29:632-635. 1977. 5 1.2008 21. Silbergeld. E. K. : Neuropharmacology of hyperkinesis. iji Valzelli. L. and Essman. W. B. (eds.): Current Developments in Psychopharmacoloqv. vol. 4. pp. 181-214. 1977. 22. Silbergeld, E. K. and Adler. H. S.: Subcellular mechanisms of lead neurotoxicity. Brain Res. 148.(2):451-567. 1978. 23. Silbergeld. E. K.. Carroll. P. T. and Goldberg. A. M . : Neurotoxicity of lead: A review of experimental studies. Proc. International Conference on Heavy Metals in the Environment. University of Toronto Press. Toronto. Canada, pp. 213-228. 1978. 24. Silbergeld, E. K. and Costa, J. L.: synaptosomal calcium metabolism studies by electron microprobe analysis. Exp. Neurol. 61:277-292. 1979. 25. Caine, D. B.. Kebabian. J., Silbergeld, E. K. and Evarts. E.: Advances in the neuropharmacology of Parkinsonism. Ann. Int. Med. 90(2):219-229. 1979. 26. Silbergeld. E.K. and Walters. J.R.: Synaptosomal uptake and release of dopamine in substantia nigra: effects of GABA and substance P. Neurosci. Lett. 12.: 119-126, 1979. 27. Walsh. M.J. and Silbergeld. E.K.: Rat rotation monitoring for pharmacology research. Pharmacol. Biochem. a Behavior 10:433-436. 1979. 28. Hruska. R.E., Kennedy. S.. and Silbergeld. E.K.: Quantitative aspects of normal locomotion in rats. Sciences 25:171-179. 1979. Life 29. Hruska, R.E. and Silbergeld. E.K.: Abnormal locomotion in rats after bilaterial intrastriatal injection of kainic acid. Life Sciences 25.:181-193, 1979. 30. Silbergeld. E.K.. Hruska. R.E.. Weir, R.. and Kennedy. S.W.: Dopaminergic and serotonergic effects of ergot drugs. In: Fuxe. K. and Caine. D.B.. eds. Dopaminergic Ergot Derivatives and Motor Function. Pergamon, Oxford, pp. 223-235. 1979. il. Lafferman. J.A.. and Silbergeld. E.K.: Erythrosin B inhibits dopamine transport in rat caudate synaptosomes. Science 205:410-412. 1979. 6 32. Silbergeld. E.K.. Miller. L.P.. Kennedy. S.. and Eng. N . : Lead. GABA and seizures: effects of subencephalopathic lead exposure on seizure sensitivity and GABAergic function. Environ. Res. 19.:371-382. 1979. 33. Silbergeld. E.K. and Hruska, R.E.: Effects of ergot drugs on serotonergic function: behavior and neurochemistry. Eur. J. Pharmacol. 58.: 1-10. 1979. 34. Silbergeld. E.K. and Hruslca. R.E.: Effects of kainic acid on behavioral and biochemical aspects of cholinergic function. In: Chase. T.N.. Wexler. N.S., and Barbeau. A., eds.. Advances in Neurology, Vol. 23 (Huntington's Disease). Raven, N.Y.. pp. 633-644, 1979. 35. Silbergeld. E.K. and Hruska, R.E.: Lisuride and LSD: Dopaminergic and serotonergic interactions in the "serotonin syndrome". Psychopharmacology 65.:233-237. 1979. 36. Silbergeld. E.K. and Hruska, R.E.: Tremor: Role of striatal cholinergic neurons and the effect of intrastriatal kainic acid. Neurosci. Letters 15:235-242. 1979. 37. Silbergeld. E.K. and Goldberg. A.M.: Problems in experimental studies of lead poisoning. In Singhal, R.D. and Thomas. J.A. (eds.): Lead Toxicity. Baltimore: Urban and Schwartzenberg.. pp. 19-42. 1980. 38. Hruska. R.E. and Silbergeld. E.K.: Estrogen treatment enhances dopamine receptor sensitivity in the rat striatum. Eur. J. Pharmacol. 62.:397-400, 1980. 39. Silbergeld. E.K., Goldstein. G.W.. and Wolinsky, J.: Electron probe microanalysis of isolated brain capillaries poisoned with lead. Brain Res. 189:369-376. 1980. 40. Silbergeld. E.K.. Hruska. R.E.. Miller. L.P.. and Eng. N . : Effects of lead in vivo and in vitro on GABAergic neurochemistry. J. Neurochem. 14:1712-1718. 1980. 41. Hruska, R.E. and Silbergeld, E.K.: Increased dopamine recepton sensitivity after estrogen treatment using the rat rotation model. Science 208:1466-1468. 1980. 42. Hruska, R.E. and Silbergeld, E.K.: Cortical neurochemical changes after intrastriatal injection of kainic acid. Brain Res. 191:572-576. 1980. 7 13008 43. Hruska. R.E. and Silbergeld, E.K.: Effect of ergot derivatives on post-decapitation convulsions. Conunun. Psychopharm. 4^57-62. 1980. 44. Hruska. R.E.. Ludmer. L.M., and Silbergeld. E.K.: Hypophysectomy prevents the striatal dopamine receptor supersensitivity produced by chronic haloperidol treatment. Eur. J. Pharmacol. £5:455-456 (1980). 45. Silbergeld, E.K. and Hruska. R.E.: Neurochemical investigations of low level lead exposure. In: Needleman. H.L.. ed.. Low Level Lead Exposure: The Clinical Implications of Current Research. Raven. N.Y.. pp. 135-157.1980. 46. Hruska. R.E. and Silbergeld. E.K.: Inhibition of [ H]splroperidol binding by in vitro addition of ethanol. J. Neurochem. ,35:750-752. 1980. 47. Silbergeld. E.K.. and Lamon. J.M.: Role of altered heme synthesis in lead neurotoxicity. J. Occup. Med. 22.: 680-684. 1980. 48. Hruska. R. E. . Ludmer. L.M.. and Silbergeld. E. K.: Characterization of the striatal dopamine receptor supersensitivity produced by estrogen treatment of male rats. Neuropharmacol. 19.: 923-926. 1980. 49. Silbergeld. E. K.: Detection of neurotoxicity using neurochemical methods In: R.M. Gryder and V. H. Frankos. (eds.). The Effects of Foods and Drugs on the Development and Function of the Nervous System: Methods for Predicting Toxicity. FDA (No. 80-1076), Washington. D.C.. pp. 99-105. 1980. 50. Silbergeld, E. K.: Erythrosin B is a specific inhibitor of high affinity 3H-ouabain binding and ion transport in rat brain. Neuropharmacol. 20.: 87-90. 1981. 51. Silbergeld. E. K.. and Caine, D. B.: parkinsonism. Pharmacol. Ther. 12.: 52. Goudsmit, J.. Rohwer. R. G.. Silbergeld. E. K., and Gadjusek, D. C.: Hypersensitivity of central serotonin receptor activation in scrapie-infected hamsters and the effects of serotonergic drugs on scrapie symptoms. Brain Res. 220: 372-377. 1981. 8 Animal models of 159-166. 1981. 53. Hruska, R. E.. and Silbergeld, E. K.: Inhibition of neurotransmitter binding by ergot derivatives. J. Neurosci. Res. 6.:1-11, 1981. 54. Silbergeld, E. K.. Lamon, J. M . , Bradley. D., Hruska. R.E.. Pitman. K.. Hess. R. A., and Frykholm, B. C.: Heavy metal neurotoxicity: porphyrinopathic mechanisms. Procs. Internat. Symp. on Heavy Metals. WHO-EEC-EPA. Amsterdam, pp. 561-564, 1981. 55. Chisolm, J. J., and Silbergeld, E.K.: Increased excretion of homovanillic acid in children with increased lead absorption. Procs. Internat. Symp. on Heavy Metals. WHO-EEC-EPA. Amsterdam, pp. 565-568. 1981. 56. Weir. R. L., Hruska. R. E.. and Silbergeld. E. K.: Binding of antiparkinsonian ergot derivatives to the dopamine receptor. Psychopharmacol. 7!5: 119-123, 1981. 57. Silbergeld. E.K.: Neurocheraical and ionic mechanisms of lead neurotoxicity. In: (Vernadakis. A., and Prasad. K. N . , (eds.). Mechanisms of Action of neurotoxic Substances. Raven. New York. pp. 1-24. 1982. 58. Hruska. R. E.. Pitman. K. T.. Silbergeld. E. K., and Ludmer. L. M . : Prolactin increases the density of striatal dopamine receptors in normal and hypophysectomized male rats. Life Sci. 30: 547-553. 1982. 59. Hruska. R. E.. Ludmer. L. M . , Pitman. K. T.. DeRyck. M . . and Silbergeld. E. K.: Effects of estrogen on striatal dopamine receptor function in male and female rats. Pharmacol. Biochem. Behav. ¿6.: 285-291. 1982. 60. Silbergeld. E. K.. and Anderson. S. M . : Artificial food colors and childhood behavioral disorders. Bull. N.Y. Acad. Med. 58.: 375-295. 1982. 61. Morris, S. J.. Silbergeld. E. K. . Brown. R. R.. and Haynes, D. N.: Erythrosin B (USFD&C Red 3) inhibits calcium transport and ATPase activity of muscle sarcoplasmic reticulum. Biochem. Biophys. Res. Commun. 104: 1306-1311. 1982. 62. Silbergeld. E.K.: Current status of neurotoxicology, basic and applied. Trends in Neurosci. 8.:291-294, 1982. 9 ----- 12010 63. Silbergeld. E.K.. Anderson. S.M., and Morris. S.J.: Interactions of erythrosin B (U.S. F. D S. C Red 3) with rat cortical membranes. Life Sci. 2 i :957-969. 1982. 64. Sflbergeld. E. K.. Hruska, R. E.. Bradley. D.. Lamon. J. M . . and Frykholm. B. C . : Neurotoxic aspects of porphyrinopathies: lead and succinylacetone. Environ. Res., 29:459-471. 1982. 65. Silbergeld. E. K.: Experimental and environmental neurotoxins: correlation of behavioral and biochemical effects. In Levy. M. and Spiegelstein. A. (eds.) Behavioral Models and the Analysis of Drug Action Elsevier-North Holland. Amsterdam, pp 297-315, 1982. 66. DeRyck. M . . Hruska. R.E.. and Silbergeld. E.K.: Estrogen and haloperidol-induced versus handling-related catalepsy in male rats. Pharmacol. Biochem. Behav. 17:1027-1035. 1982. 67. Silbergeld. E. K.. Lafferman. J., and Finkel. T.: In vitro testing for neurotoxicity. In: Kolber. A.. Wong. T.K. . Grant. L.D.. Dewoskin. R.S.. and Hughes. T.J. (eds). In Vitro Toxicity Testing of Environmental Agents. New York. Plenum, pp 473-486. 1982. 68. Silbergeld. E.K.. and Lamon. J.M.: Effects of altered porphyrin synthesis on brain neurocheraistry. Neurobehav. Toxicol. Teratol. 4,: 635-642. 1982. 69. Hruska, R. E., Weir, R. L.. Pitman. K. T., and Silbergeld. E. K . : Ergot derivatives are potent drugs at CNS aminergic receptors: correlations•to behavior and aging. In: Agnoli. A., Trabucchi. M . . and Spano. P. F. (eds). Aging Brain and Ergot Alkaloids. New York. Raven, pp 215-226. 1983 . 70. Silbergeld, E.K.: Experimental studies of lead neurotoxicity: Implications for mechanisms, dose-response, and reversibility. In Rutter. M . . and Russell-Jones. R. (eds) Lead Versus Health. London. John Wiley, pp 191-216. 1983. . 71. Silbergeld. E.K.: Effects of lead on reproduction: a review of experimental studies. In Rutter. M . , and Russell-Jones. R. (eds) Lead Versus Health. London. John Wiley, pp 217-227. 1?83. 10 72. Silbergeld. E.K.: Indirectly acting neurotoxins. Psychiat. Scand. 67_ Suppl. 303. 16-25, 1983. Acta 73. Mattison. D.R., Takizawa. K.. Silbergeld. E.K., Nightingale. M.S., Jerina. D.. and Yagi. H . : Genetics of ovarian benzo(a)pyrene. metabolism, oocyte destruction, and impaired fertility. In Rydstrom, J.. Monteluis. J., and Bengtsson, M. (eds) Extrahenatic Drug Metabolism and Chemical Carcinogenesis. Amsterdam. Elsevier, pp 337-350. 74. Silbergeld, E.K.: Localization of lead: implications for mechanisms of neurotoxicity. Neurotoxicol. 4/.193-200, 1983. 11 13012 IN PRESS: Silbergeld. E.K.: Behavioral teratology of lead. In Yanai. J. (ed) Behavioral Teratology. Elsevier/North Holland. Silbergeld. E.K.: Neurotoxicity of lead. Blum. J. (eds) Neurotoxicology. Dekker. In Manzo. L. and Fowler. B.F., and Silbergeld. E.K.: Mechanisms of metal toxicity. In Nriagu. J.. and Hornig. D.F. (eds) Changing Geochemical Cycles of Metals and Implications for Human Health. Berlin. Springer Verlag. Mattison. D.R., and Silbergeld. E.K.: Occupational risks to reproduction. In Osofsky. H. (ed) Advances in Gynecology and Obstetrics. Baltimore, Williams & Wilkins. Silbergeld. E.K.: Mitochondrial mechanisms of lead neurotoxicity. In Narahashi. T. (ed) Cellular and Molecular Mechanisms of Environmental Neurotoxins. Raven Press, NY. in press. Silbergeld. E.K.: Review of occupational health studies on PCBs. In Kuiper. H. (ed) PCBs, Marcel Dekker. in press. Silbergeld. E.K.: Effects of PCBs in Occupational Populations. In Visser. R. (ed) PCBs. Amsterdam. Elsevier. Mattison. D.R., and Silbergeld. E.K.: Reproductive toxicity of TCDD. In Lowrance. W. (ed) Dioxins. Rockefeller University Press. IN PREPARATION: Silbergeld. E.K., and Mattison. D.R.: Effects of three polycyclic aromatic hydrocarbons on fertility in female mice: A lifetime study of the effects of single-dose treatment. Silbergeld. E.K.: A Textbook in Neurotoxicology. 12 12013 B. ABSTRACTS1. Silbergeld, E. K.: Effects of lead on neuromuscular functions: In vitro evidence for site of action at the presynaptic level. Fed. Proc. 22.:275, 1973. 2. Silbergeld. E. K. and Goldberg. A. M . : Lead poisoning: an animal model of hyperactivity. Pharmacologist 15.: 143 . 1973. 3. Silbergeld. E. K. and Goldberg. A. M . : cholinergic-aminergic interactions in lead induced hyperactivity. Pharmacologist 16.:335. 1974. 4. Goldberg. A. M. and Silbergeld. E. K.: aspects of lead induced hyperactivity. Neurochem. p.185. 1974. 5. Silbergeld. E. K.. Carroll. P. T. and Goldberg. A. M . : Monoamines in lead-induced hyperactivity. Pharmacologist 13:203. 1975. 6. Goldberg, A. M . . Carroll. P. T. and Silbergeld. E. K.: Cholinergic aspects of hyperactivity. Fifth Internatl. Meeting for Soc. Neurochem.. 1975. 7. Pfeiffer. R. . and Silbergeld. E. K.: Differential behavioral and neurochemical effects of three dopaminergic agonists. Neurosci. Abst. ri:720. 1976. 8. Silbergeld, E. K. and Miller. L. P.: Lead intoxication: changes in seizure threshold and gamma-aminobutyric acid function. Neurology 4L(27):405. 1977. 9. Adler. H. S. and Silbergeld. E. K.: Intrasynaptosomal interactions of lead and calcium in dopaminergic neurotransmission. Pharmacologist 19.(2) :40, 1977. 10. Silbergeld. E. K. and Walters. J. R.: Dopamine uptake and release in substantia nigra: Effects of gamma-aminobutyric acid and substance P. Pharmacologist 19.(2} :544. 1977. 11. Silbergeld, E. K., Miller. L. P., Kennedy. S. and Eng. N . : Lead and seizures: Role of gamma-aminobutyric acid. Neurosci. Abst. Ill:1039. 1977. 12. Adler. H. S. Costa. J. L. and Silbergeld. E. K . : X-ray microanalysis in neurochemistry: Localization of an 13 Neurochemical Trans. Amer. Soc. elemental neurotoxin and manipulations of mitochondrial Ca++. Neurosci. Abst. Ill:1235. 1977. 13. Baring. M. D . , Walters. J. R.. Silbergeld. E. K., Eng. N . . and Lakoski. J. M. : Effect of systemic apomorphine on firing rates of dopamine cells in rats with striatal kainic acid lesions. Neurosci. Abst. 4., 267, 1978. 14. Hruska, R. E. and Silbergeld. E. .: Ergot drugs inhibit spiroperidol and serotonin receptor binding. Soc. Neurosci. Abst. 4.: 425, 1978. 15. Silbergeld. E. K., Hruska. R. E.. Walters. J. R.. Kennedy. S.. Eng. N., and deSantis. S.: Effects of intrastriatal kainic acid on motor behavior in rats. Soc. Neurosci. Abst. 4: 49. 1978. 16. Kennedy. S., Hruska, R. E.. and Silbergeld. E. K.: Serotonergic-dopaminergic effects of ergot drugs. Soc. Neurosci. Abst. ±: 426. 1978. 17. Silbergeld, E. . Hruska, R. E.. Lamon. J. M . . Frykholm, B. F.. and Hess. R. A.: Neurotoxic mechanisms in porphyria and lead intoxication: Possible role of a-aminolevulinic acid. Clin. Res. 22:307A. 1979. 18. Lamon. J. M . , Silbergeld. E. K.. Frykholm. B. F.. and Hruska, R. E.: Extra-erythropoietic heme metabolism in lead intoxication. Clin. Res. 21_: 299A, 1979. 19. Silbergeld. E. K.. Hruska. R. E.. Lamon. J. M . . Frykholm. B. F.. and Hess. R.A.: The effects of lead (Pb) on hepatic heme synthesis and drug metabolism. Pharmacologist 21: 209. 1979. 20. Silbergeld, E. K.. Hruska. R. E.. and Lafferman. J. A.: Actions of lead (Pb) on GABAergic neurotransmission: Discrepancies between in vivo and in vitro effects. Soc. Neurosci. Abst. 5.: 416, 1979. 21. Lafferman, J. and Silbergeld. E. K.: Erythrosin B (Food. Drug and Cosmetic Red No. 3) inhibits dopamine uptake in rat caudate synaptosomes: a kinetic study. Soc. Neurosci. Abst. 5. 562. 1979. 22. Hruska. R. E. and Silbergeld, E. K.: Increased dopamine receptor sensitivity after estrogen treatment. Soc. Neurosci. Abst. 5: 73 (1979). No. 236. 14 1Lo n\J J / 23. Silbergeld. E. K.. Hruska, R. E.. Schwarcz. R.: GABA in the basal ganglia: effects of selective lesions. Brain Res. Bull.. 4: 696. 1979. 24. Weir. R. L., Hruska. R. E. and Silbergeld. E. K.: of dopamine agonists on 3H-spiroperidol receptor binding. Soc. Neurosci. Abst. 5: 81. 1979. 25. Hruska. R. E.. Ludmer. L. M . . and Silbergeld. E. K. : Prolactin increases the number of striatal dopamine receptors. Pharmacologist 22.:220 (1980), No. 338. 26. Silbergeld. E. K.: Erythrosin B: ouabain-like actions of an artificial food dye in rat brain tissue. Pharmacol. 22.: 198. 1980. 27. Hruska. R. E.. Ludmer. L. M . . and Silbergeld. E. K.: The striatal dopamine receptor supersensitivity produced by estrogen may be mediated through prolactin. Soc. Neurosci. Abst. 6.: 441. 1980. 28. Chisolm. J. J., and Silbergeld. E. K. : Increased excretion of homovanillic acid (HVA) in urine by young children with increased lead absorption. Neurosci. Abst. vol. 6.:508, 1980. 29. Silbergeld. E. K.. and Anderson. S. M . : Erythrosin B: specific inhibitor of high affinity [3H]-ouabain binding and ion transport in rat brain. Neurosci. Abst. vol. 6.:56, 1980. 30. Silbergeld. E. K.. Anderson. S. M . . DeRyck. M . . Chronwall, B.. and Morris. S. J.: Neurotoxicity of an artificial food color (erythrosin B ) : methods for rapid testing. Abstr. 8th Meeting Internat. Soc. Neurochem.. p. 238, 1981. 31. Ptiman. K. T.. Hruska. R. E.. Ludmer. L. M . . and silbergeld. E. K.: Prolactin increases the density of striatal dopamine receptors in normal and hypophysectomized male rats. Soc. Neurosci. Abstr. 1_'. 217, 1981. 32. DeRyck. M . . Hruska. R. E.. and Silbergeld. E. K. : Estrogen potentiates haloperidol-induced catalepsy/akinesia in male rats. Soc. Neurosci. Abstr. 7: 217, 1981. 33. Silbergeld. E.K.: The biochemical basis of lead neurotoxicity. Abstr. Ann. Mtg. AAAS. Toronto. 1981.1 Effects 15 1oh 1Q L Ô -j7. Canadian 13031 DP What EFT will Mean to the Consumer. CIPS Reviw, 5(3) 16-17» nay/June. Vci Ventilatory Function Changes Over a workshift. Er. J. c Industrial hecicir.e. 38 : 152-lbb. (H. Dinich, senior author.) Unionization anc its Implications. Proceedings of the Sec or. Annual Office Automation Conference, March 23-2b, 1981, Houston Texas. Possible Risks to Human Lungs from nagnetometric Dust Clearanc Experiments. Journal of Applied Physics, Vol. 52 (3, Part II 2575-2577. Use of Gas Hanots tor Cooking me. Heating in groan Dwellings Journal of the Air Pollution Control Association, February, Vo: 31 (2) 162-165. Engineers Threaten Domination or DP Jobs. CIP3 Review, Jan./Fel Vol. 5(1): fc-b. 1980 The Health Effects of Lcw-level of Ionizing Radiation: W.E. (ess.) , Heal Dialogue. In Horn, w.N. and Archer, Ann A m o r Sciem Implications oi New Energy Technologies. Publishers, Inc., Ann Arbor, Hich. Pages 150-164. Stressing Design Rather Than Performance Standards to Ensu: In Hoffman, N. (ed . Protection of Information: Comments. Inc Computers ana Privacy in the Next Decade. Academic Press, 102-107. Smoking, Occupation and Respiratory Disease. Report to ti American Lunc Association, Occupational Health Task fore Meeting, April 5, 1980, Clearwater, Florida. The Social Impacts of Electronic Fund Transfers, The Financi. Post, Special Report, March 8, I960, s11 . The Health Effects cf Low-Dose Radiation on Atomic Workers: Case Study of Employ er - Directed Research. International Journt of Health Services, January, 10(1): 37-46. Cover-up at Hanforu: The Effects of Low-Dose Radiation. Humanii in Canada, Spring (No. 52) XII, No. 1: 5-d. The Computer Ombudsman, A Possible Model of AccountaDil^lty Amo; Professionals, Transactions of Society, 17(2): 31-35. 13032 iy7y Statistical Problems in Eulti-Variate (Etiological) Surveys. Canadian Journal ot Statistics, 7(2): 205-215. The Mutual Relationship Between Smoking, Occupation and Disease. Proceedings of the XIX International Congress on Occupational Health. Supplement to vcl. 30. Consumer Difficulties with Computerized Transactions: An Empirical Investigation. Communications or the ACE, Eay, 22(5): 283-26V. Carbon Monoxide Levels in Kitchens ana Homes witn Gas Cookers. J. Air Pollution Control Association, March, 2L? (J) : 239-241. What Consumers Say About Computer Errors, Canacian Datasystems, 11 (1 2) : b4 -b7 . What happens When Major Errors Are Discovered Long Alter An Important Report Has Eeen Published?, Invited talk to the Annual [■‘eeting of the American Statistic Association, Washington, D.C., August, 1y7y. 197» Computers in Developing Nations: A Cautionary Tale. Reprinted in Personal Computing. February, 27-jl. Smoking Patterns by Occupation, Industry, Sex, and Race. Archives of Environmental Health. Novjiter, 33(b) : 313-317. Processing Errors Among the Pjolic: Their Frequency ina Crigin. Prcceeamgs ot the Session '7d Canadian Computer Conference, CIPS, Edmonton, Alberta. May. Does Smokinc Kill Workers or working Hill Smokers, International Journal of healtn Services, 6(3) : '137-452 . Follow up: New Evidence Concerning Smoking ana health, Med. J. Australia, b5: 364-387* Frequency cf Computer Related Errors Among Holders of Credit, Charge or Bank Accounts, CIPS REVIEW, June, 5: 17. High Level Language Programming. In belzer, J., Holzman, A.G., ana Kent, A. Encyclopedia of Computer Science and Technology, Earcel bekker, y: ¿57-283. 13033 Humanizing Information Systems. In belter, J., iioizman, A •G . and Kent, A. Encyclopedia of Computer Science and Technology, Marcel Dekxer, S : 3 6 1 - 5 7 1 . Natural Language Compilers and Interpreters in hadiation Treatment Planning or Nous radons Anglais Setter Than Jeae Andere Sprache. In V. Rosenow (eo), Computers in Radiation Therapy: Proceedings of the Sixth International Congress on the Use or Computers in Radiation Therapy, University 01 Goettingen, Goettingen, FRG. 19 77 Computers in Developing Nations: A Cautionary Communications of the ACM. December, 20(12): 971-972. New Evidence Concerning Smoking and Health. Medical Australia, October, 2: 538-542. Tale. Journal of Fold, Spindle and Mutilate. Humanist in Canada, March. 40/15-20. Exposure to Pollutants in Enclosed "Living” Environmental Research, February, Voi 13: 1-13. I,4,5-T .... Teratogenic n c re s U.S.A., 7/7. Smoke Gets m Em Droyotoxic, Spaces. Fetocenic, Mutogenic, ’ /our Eyes. Humanist in Canada. '42: 2-5. 197o Humanizing Information Systems. Datamation. Decemcer. Smoking Characteristics by Type of Emoloyment. J. Occup. Datasystems, August, Medicine, November, 1b (11 ) : 743-754. Do we Neec A Computer Ombudsman? Canadian 62-64. Programming. In Ralston, A., ana Meek, C.L. (Editors), Encyclopedia of Computer Science, Petrcce11i-Charter , New /oik, p p . 1127-1156. "Statements, Ralston, A., and Meek, C.L. (Editors), Encyclopedia of Computer Science, Fetrocelli-Charter, New jfork , pp. 326-1329. A Singie-TracK Universal Curriculum INFOR, February, 14: 1, 40-52. for Computing Science. 13034 ran Acainst Himself - Biological Dangers trom the Herbicices. Humanist in Canada, February, IV (3) : 2-7. Use ot Additional Comments on the Critical Assessment of the Evidence Tearing on smoking as the Cause or Lung Cancor. American Journal of Pufciic Health. February, Vol 66(2): 161-164. Relation ot Place or Birth and Migration in Cancer Mortality in the D.S. - A study of Ohio Residents (1959-1967), reprinted in the 1976 Year Booh of Cancer» 1y75 Humanizing Computerized Information Systems: Guidelines Their Implications. Science, December, Vol 190: 1168-1172. ana A Critical Reassessment of the Evidence Bearing on Smoking as the Cause ot Lung Cancer. American Journal of Public Health. September, Vol 65(9): 939-953. A Critical Review of Reports on the Effect of Smoking on Sex and Fertility. Journal of Sex Researcn. August, Vol 11(3) 201-217. Lung Cancer Among Black ana -hits Migrants In the U.S. Etiological Considerations. Journal oi the National Medical Association, ilarch, Vol 67(2): 10&-111, 102. (T.F. Mancuso, senior author.) 197L Relation of Place ot Eirth ana Migration in Cancer Mortality in the U.S. - A Study of Ohio Residents (1959-1967). Journal or Chronic Diseases. Vol 27: U59-474. (T. F . Mancuso, senior author.) Guidelines tor Humanizing Computerizes Information Systems: A Report from Stanley House. Communications of the ACM. November, Vol 17 (11): 609-613. (Reprinted in AEDS Journal, Vol 10 (1), Fall 1976: 1-10. Teaching Simulators of Ideal Teaching Machines. S1GSCS Bulletin , ACM. June, Vol & (2): 45-56. X : Proposal for a N'ew Curriculum Approach. Jniversity Simon Fraser University, Burnaoy, 3.C. nay, ?p. 6-7. Affairs. Ideal Teaching Machines -- A Solution- to the Pedagogic Language. Communications of tne ACM. April, vol 1b: 207-208. 12035 The Use or an Information System to "humanize" Procedures in a Rehabilitation Hospital. International Journal of bio-Medical Computing. Vol 5: 51-57. Information for Public Policy. Computers ini Society. Vcl 5(2): 2. (Invited editorial). The Simon Fraser One-Track Universal Curriculum for Computing Science. SIGSCE Bulletin, AC.1. February, vol 6 (1 ): 28-32 . 19 73 The Statistician vis-a-vis Issues of Public Healtn. The American Statistician. December, Vcl 27(5): 212-217. Extending the General Fieli Equation to fit the Dose Distributions of a Variety of Therapy Units. British Journal of Baoiolcgy. Voi U6: 933-990. (J. «e inkam, senior author.) Air Pollution and Smoking. Environment. Voi 15(6): 3-5, 25-26. Dynamic Display ot Radiotherapy Plans Using Films. Radiology. June, Vol 107: 639-691. Computer-Produced Humanists ana the Computer Community. Humanist 2 5 : 2-6 . in Canada. Vol Computing and the humanization of Medicine. International Journal ot mioraeaical Computing. Editorial, July, Vol h(3): 159. 1972 Difficulties ot heasurinc the Effects of Air Pollution vs the Effects of Smoking. Presented at the 139th fleeting of the American Association for tne Advancement of Science, December 1972 . a Versatile System for Three-Dimensional Radiation Dose Computation and Display, RTP. Computer Programs m Biomedicine. Vol 2: 178-192. (J. Weinkara, senior author.) Fitting the General Field Equation to the Siemens Gainaatron 3. Technical Report on Research Agreement fio. 1051/CF for the International Atomic Energy Agency, Vienna, Austria. The Incidence of Lung Cancer in the U.S. Since 1955 in relation to the Etiology of the Disease. American Journal ot Public Health. February: 152-158. 1¿ U d o A 1y 71 A Critical Assessment of the Evidence on the Cigarette Smoicinq Lung Cancer Relationship. Presented at the 130th fleeting of the American Association for the Advancement of Science, Symposium on Smoking and health Now. Philadelphia, December, 1971. Difficulty or Evaluating tne Toxicity and Teratoqenicity of 2,N,5,-T from Existing Animal Experiments. Science. December, Vol 17n: 1353-13bS. Some Thoughts on Treatment Strategy. Computers in Radiotherapy (proceedings of the uth International Conference on Computers in Radiotherapy, Glasgow, September 1970). Edited by A. S. Glicxsiran, .1. Cohen, and J. H. Cunningham. Published as Special Report No. 5 (1971) by the British Institute of Radiology, London. Three-Dimensional Treatment Plan Display Filins. Computers in Radiology, op.12-1d. on Computer-Produced A Review of the Claim that Excess 'loraidity m u Disability Can Be Ascnb&Q to Smoking. Journal of tna American Statistical Association. Vol to (33d): 251 -257. A Critical Reassessment of the Evidence Bearing on Smoking as the Cause or Lung Cancer. Special Report on the Washington University Project on the Review of Crucial Data Searing on the Snoxinc and Health Issue, St. Louis. Robot Data Screening, An Intelligent (?) Data Search Technique. AGAftD Conference Proceedings No. 9d on Artificial Intelligence, 2-1-2-r, Tecnnical Editing and Reproduction Limited, London. Comment on Smoking Docs. Letter to tne Environmental Health, vol. 22: 631-632. Editor. Archives of 1970 Problems in Determining if a Commonly-Used Herbicide (2,4,5-T) Has an Effect on Human Health. Proceedings of the Sixth Berkeley Symposium on r.atnematical Statistics uni Probability, Held at the Statistical Laboratory, University cf California. University ...ot California Press, pp. u79-49u. Experience with a "Universal” Introductory Course in Computer Science. Proceedings of SIGCSE Technical Symposium on Academic Education m Computer Science, November 16, 1970. Houston, Texas. SIGCSE Bulletin, Vol 2(3), Association for Computing Machinery, hew York. 13037 Robot L'ata Screening, An Autonatic Search Technique. lio-Medical Computing. Voi 1: 61-74. (From the Proceedings ot the Conference on Statistical Computation, University of Wisconsin, April, 1969 .) Report on Progress in the Development of Visual Prosthesis, ¿he New Outlook for the alind. Feoruary, Voi 64: 41-45. 1969 Automatic Data Screening: A Practical Solution to the Multivariate P r o d e m in Clinical Data. Annals of tne New York Academy of Sciences. Vol 161: 632-640. A Comment on "Air Pollution — The Industrial viewpoint” . Journal of Occupational Medicine. July, Vol 11: 3u1-3d3. Robot Lata Screening -- A Ubiquitous Automatic Search Technique, in nilton, C. h. and Nelder, J. A. (lid.) # Statistical Computation, Academic Press, .New Yor*, pp. 31 9-333 . Measuring tr.e Effect of Air Pollution on Ur can Morbidity. Archives of Environmental Health. April, Vol 13: 485-494. 19 68 Computer Interface, Input rietnocs, ana Presentation of Results. Role or Computers in Radiotherapy, International Atomic Energy Agency, Vienna. Paper No. 15, pp. 135-141. Optimization as a Joint Result of Planning and Implementation. Role ot Computers ir. Radiotherapy, International Atomic EnergyAgency, Vienna, pp. 163-167. Display Devices tor Computer Translated Sraille. Proceedings Conference cn New Processes for S m i l e Manufacture, 196c, Center for Sensory Aids Evaluation and Development, Massacnusets Institute ot Technology. February, pp. 14-20. 19 67 Automation of Radiation Treatment Planning, VI: A General Field Equation to Calculate Percent Deptn Dose in the Irradiatea Volume of a Cobalt 60 Beam. British Journal of Radiology. Vol 40: 463-468. Urban hospital Morbidity and Air Pollution: Second Archives ot Environmental Health. Vol 15: 162-374. Report. A New Direction in Pehabi1itaticn Through Advances Instrumentation and Ceraputation. Journal of the American Medical Association'. Vol 200 (7): 625-629. The Use ot Computers in Theraoeutic Radiology, Summary Report of an International Conference held in Camoridge, England, Junt 19tb (Editor). m t i s h Institute of Radiology, London. Final Narrative Report, Traininq of the Blind tor Proiessionai Computer Work. Department of Health, Education, and Welfare, KD-1485-S-b7-C2. 1966 Robot Lata Screening: A Solution to Multivariate Type Proclems in the biological and Social Sciences. Communicatons of the ACM. Vol 9(7): 529-532. A Biologically-Oriented Computer Language. Annals or the hew York Academy ot Sciences. Vol 128(3): 755-765. (S. V. Pollack, senior eaitcr.) Cancer Therapy - Computation ana Visualization Distributions in External seam Therapy. Journal Diseases. Vol 19: 523-539. Use . ct the Computer to Teach Introductory Coamunicatiens of the ACM. Vol 9: 274-27b. Computers: No Longer a Eig Bargain Coraouters ana Automation. Vol 1b: 1-4. author .) of Dose of Chronic statistics. for 'Jneducated (S.V. Pollack, Users. senior The Selection, Training, and Placement of Elind Computer Programmers. Report of the Association for Computing Machinery. Is Medical Diagnosis a General Computer Problem? Journal of American Medical Association. Vol 196(3): 281-286. the Befogging the Issue: California has discovered that laws can't control auto exhaust fumes. Barron's, May 2, pp. 5, 14-15. Urban Borcidity and Air Pollution: A first Report. Environmental Health. Vol 13: 158-170. Archives of The Blind as Computer Programmers. 7 (1): 7-1 0. Record. Vol Role ot Statistics in the World of Computers. Annals of the York Academy of Science. Vol 128(3): 1108-1115. New Rehabilitation 13039 The Role ot the Blind in Data Processing. Presented at Third Annual Conterence on Computer Personnel Research Group, held at Washington University, 1965. Reprinted in Computers ana Automation. Voi lb: 2U-27. Proceedings on tne Braille Research and Development Conference, Sensory Aids, Evaluation and Development. Massachusetts Institute ct Tocnnoicgy, November, 1966. 1965 Automation c t Radiation Treatment Planning, v: Calculation ana Visualisation cf the Total Treatment Volume. British Journal or Radiology. Voi 30: 906-913. Robot Data Processing Techniques for Multivariate Epidemiological Predictions. Annals of the New York /-.cademy ot Science, v oi 126 (2): 779-79«!. The Role of the Blind in Data Processing. Procedures of Third Annual Computer Personnel Research Conference, June 1u6b. (M. H. Gotterer, ec.) Computers in Personnel Research Group, Silver Spring, Md.; pp. 31-39. Computation of Radiation Dosages. In Stacy, N. ana Nasnan, &., (Ed.), Computers in Biomedical Research. Academic Press, New York,. Vol 1 (Chapter 1if). Toward an Undergraduate Matnematics Researchers in the Fields of Biology and Proceedings. Vol 2U(1): 5-9. Program for future Medicine. Federation Careers for the Blind in Electronic Data Processing. iiectronic Data Processing. Occupational Outlook quarterly. Vol 9(1): 1- U . Employment Potential tor the blina in Computer Related Fields. The International Journal for Education of the blind. October, pp. 1-5. The Blind the Blind. in EDP. ACM Committee on Professional Activities ot 196U Mathematical Analysis of Lead Burdens. Archives of Environmental Health. 8: UU-51. Design ana Operation of a Medical Computing Center. Annals of the New York Academy of Science. vol 115(2): 591-599. (E. Saenger, senior author) . 13040 Planning Radiation Treatment on the Computer. Annals or tne Kew York Academy ot Science. Vol 11b (2): 976-997. Professional Computer Work for the Blind. Communications of the ACM. Ycl 7 (U) : 22b-2 31 . Coaputer Worn as a Profession P.ehaDi li ta tion . Vol 3C: 20-21. for the B lmu. Journal of Epidemiology of Disease Associated with Lead. Archives ot Environmental Health. Vol 8: 333-346. Hatnomatical Analysis of lead Burdens. Archives of Environmental Health. Vol 6: 44-51. Automation of Radiation Treatment Planning, IV: Derivation ot a Hatnematicai Expression ter the Per Cent Depth Dose surface ot Cobalt 60 Beams anc Visualisation of Multiple Field Dose Distrirutions. British Journal of Radiology. Vol 37(439): 54-4—55 0 . Locatinc Placenta Praevia. Procedures or the Rochester Conference on Data Acquisition and Processing m Biology and Medicine, New York, 1963. Pergamon Press, New for*, op. 103-111. 19(.3 Do Malignancies Result from Diagnostic and Therapeutic Radiation? Genetics and the Epidemiology of Chronic Disease, U .5. Dept, cf healtn. Education ana Welfare, pp. 3o5-37l. MEDCOMP, Part 1, Statistical Systems. Medical Computing University of Cincinnati, Ohio. Center, Eoron. Cadmium, Chromium, and -licxel in tne ¿iced ana Urine. Archives ot Environmental Health. Vol 6: 236-295. (H• Imbus, senior author.) Potential Hazard ot r.xposure to Lead. Archives of environmental Healtn. vol 6: 255: 272 . (R. Kehoe, senior autner.) Carcinogenic Effects of T131 Compared with X-Irraaiation - A Review. Health Physics. Vol 9: 1371-1364. (£. Saenger, senior author.) Automation cf Radiation Treatment Planning, 111: A Simplified Tystea of Digitizing Isodoses ana Direct Print-Out of Dose Distribution. British Journal of Radiology, vol 36: 522-527. Intravenous Methotrexate (Amethopterin) Therapy in the Treatment of Acute Leukemia. Pediatrics. Vol 31: e34-339. (J. Perrin, senior author.) 13041 Automation c£ Radiation Treatment Planning, II: Calculation ot Kon-Convercent Field Dose Distrinutions. British Journal ot Radiology. Vol 36(427): 63-67. Robot ireatr.ent Planning. Procedures ct t ne Hocnester Conierence on Data Acquisition ana Processinc in Biology and Medicine, New York, 1bb2. Peraamon Press, New Ycrit, pp. 299-319. Robot Data Screening. Proceedings ot tne Rochester Conference on Data Acquisition and Processing in Biology and Medicine, New York, 1962. Peraamon Tress, New York, pp. 231-242. 1962 Occupational Exposure to Organic Lean Compounds. Archives ot Environmental health. Vol 5: 532-536. (R• JeTriviile, senior author .) New Developments in Chronic Disease Epidemiology: Competing Risks ana Eligibility. American industrial hygiene Association Journal. Vci 23: U33-Ua6. Radiation rpideniiolcgy. Cancer. Vol 15: 4d9-5Q3. Comparative Studies of Certain ~ead Alkyls. Environmental Health. Vol 5: 525-326, 532-536. senior author.) Archives ot (E. Bingham, 1 9 r. 1 A Practical Procedure for Automating .¡aciation Treatment Planning. British Journal of Raaiology. Vol 34: 7^,6-733. Epidemiological Methods and Community Air Pollution. Arcr.ives ot Environmental health. Vol 3: 267-275. (J. Phair, senior author.) Competing Causes ot Deatn in Coal Tar Workers. Kettering Report. 1960 Cesium-137 Retention and Distribution in x - I m o i a t e a Rats. D.S. Army Medical Research Laboratory, fort Knox, Kentucky. Report No• 504 . (G. Keriakes, senior author.) Seasonal Variations in the Birth of the Mentally American Journal of Public Health. Vol 50: 955-965. Deficient? 1^ 0f ArO üjh The Leaa Content or the Atmosphere. Presented at the 53rd Annual Meeting or AFCA, May 1960, Cincinnati. (J. Cholaic, senior author.) Vhat is z c ie-culiar About Accepting Psychological Reports. Vol 7: 363-364. the Null Hypotnesis? Neoplasia Following Therapeutic Irradiation for Benign Conditions in ChilGhood. Radiology. Vol 74: 389-904. (E. Saencer, senior author.) 1959 Pualic Decisions ana Their PossiDle Effects on Inferences Drawn i rcm Tests of Significance - or Vice-Versa. Journal of the Aaerictn statistical Association. Vol 34: jo-3*. Pulmonary Function in Children, I ana II. Journal or Vol 30(0) : 51 4-533. (I. L. Bernstein, senior author.) Allergy. Tables of Pulmonary Function Values in Children Ages 6 to 14. Kreger Printing Co., Cincinnati, Dhio. (I. L. Bernstein, senior aatnor.) The Anorexigenic Action of Dextro-Araphetamine Sulfate upon Feeding Responses ot Differing Strength. Journal v.-r Comparative ana Physiological Psychology. v'ol 52: 179-1 82. (P. Siegel, senior author.) Sources of Contextual Constraint Upon words in sentences. Journal of Experimental Psychology, vol 57: 171-ihO. (ft. Adorn, senior author.) 19 57 Effect or Irrelevant Drive on Extinction Psychological Reports. Vol 3: ¿15-613. of Bar-Pressing. A Central Surveillance System Measurement Model, Part I, II. Project. Michigan Z345 , Z91U, jniversity of Micnigu«. A General Survey of Statistical Decision Michigan Z915, University of Michigan. Theory. Project 13043 Bio-Statistician/MathematicianThis witness will be identified in the near future. At that time a curriculum vitae will be supplied. This witness will describe the mathematical/statistical model which will be used in the presentation of the figures to which the witness will testify. The theory subserving the testi­ mony is that the multi-faceted presentation of symptoms and signs and test results in the same veteran makes a random compo­ sition of such an array extremely unlikely in view of the relative in-frequency of each facet of the array. As such, this testimony will be used in the generic and specific proximate causation areas. HENDERSON & GOLDBERG, P.C. 1 6’1 2 F r ic k B u ild in g P itt s b u r g h , P A 1 5 2 1 9 February 27, 1984 Thomas W. Henderson Theodore Goldberg Robert L. Jennings, Jr. Joel Persky Antonio D. Pyle Thomas W. White l/" Ms. Nancy Petrilla U.S. District Clerk U.S. District Courthouse 225 Cadman Plaza Brooklyn, New York 11201 Re: MDL No. //381, Agent Orange Product Liability Litigation Dear Ms. Petrilla: Please find enclosed for the Court file, Plaintiffs’ Compliance with Guideline No. 34 on Plaintiffs' Government Causation witnesses which are to begin being deposed on March 1, 1984 in Washington, D.C. Also Please f-lnd »njIngpH an a H rUf.-f on a 1 rnpy nf P 1 a-In t i f f 4 ' Expanded I Summaries on the following Plaintiffs' Cansatlnn Fvnp.rts which I promised Magistrate Shindlin she would receive before Wednesday, V February 7Q ...1Qft/i Apparently, the original court copies were missing some pages. I apologize for this inconvenience. Please be advised that by copy of this letter and the enclosed documents I have notified all parties on the attached service list of the filing of said documents with the Court and I have served the U.S. Department of Justice, Ms. Gretched Witt, on or before noon, February 27, 1984, with the enclosed documents as per our agreement. Thank you in advance for your kindness and cooperation in this matter. ✓-Very trul yours, Alison Pettiette 12045 cc: Enclosures Ms. Gretchen Witt See attached Service List Hand Delivery ■f PI•AI IT 1 FF '3 GOVSRKUEN? CAUSATIOi! WIT •!E;:S E S Ven.un 13. Kouk A. __ _ Center for T);jsea ce C e n t re! B. Both C. G o n e r d Events fact..'-:! ar.d expc-t " v c -1 >6 i : (CD C) A t l a n t a . GA test iw^ny is s o u g h t . Any fro v.ai knowledge of the history of lit . s i c J.dc y pr a ying in 'J.S. anu ;.l)roai!; f aciudin,g ; hut not limited to, (I industrial a p osar t y arc! -a:':pi'.'sions; (2; reg Lstratlon of .':;A-D, 2 . ,5-T v/ith the Department of Agrirultrve : nti r n y o t h e r riu /a at.. governmen . the L•ic a . g c n c i m by ittt’auLt- i ‘-■y -- etna" k::o 1 .?.-1.a 1- '7 * -f* -:dlng , bat r.•*t lie ;r n^e tr.c other phs . i* use of . the .ci1 '- in Vi rtu.n.. '2) char.yes ’ _J.c*r. rcqti rciccnt of her l .sldc3 wit' tli gov c.rament and it s agencies includin ^-EPAi and CJIIf ; and (3 J> .^/k3 .rdge of 71:T r>•• ;L a rjv i a l an-' other hum.-:n l J ,A ,3 -7 in the U 3 . and 0 / G,, 2 : r\: a k * ‘J y ¿z > Cr \\ \ ,,?r : ;.sntrl itswc .'.rawer of Plaintiffs1 to' <■1 •IiWCl‘ "nto " ?*. o%. r*^'*i j Ko. 19 attached ‘ .O -u v.- ar d incorper r.te■ isreia for all parre: event S 0 1' c■ i•• » *r*r-i vitnes ::ec tna; ectu;:1 info rmatioi lined : ab "' r See T", *' C* -at cf f: .pest:n s and any f■' u a. of . D. Eirpert Taetimciiy roug ht in v;11nc s: 2 ) ■ .uMect. Hr. DD ! and diorins; Agent Ora , 2 ,A >-••2’- rCDD’s blue, Pink, Greer,.' and 'Furp (air r k'hite » Alue r z c z i and related chi orophe-uols end human risk a a scssnentt rug::..rding enpo cure including butt not limited to, cue or more of the f ol loving subje et a r <•a s : a) Chemistry/E iochetnisttry b Manufacture c} T t i ■„i 1 7 d) Mcdes of I'nac.: Etto cure e c . . i d/or ) I t eduction Environment (Human 0 , i?1 -r. Animais) . S..;*.to ci Art/Etutù of Medical end ,e v; Lit eruttare !L L’p 1 ■ • .e \ 1 .) :; 1; V.1 "..ne PUy srirIogy /atud ies Pii'-:,io logy/Studi«:; K-Ü.:, Mt':y / ■;i o s£ a t i :.j lea Piantò j animals * huntns dancer Epidemiology i 2.pre-uct-va Epidomioiogy Ac. ,e-:-c EerltU Ef 3) v.vtrMss vii.. A; r.skid opinions about boti, puIliaUed ar.d/or on-go itt ; at ud 1 .-»■ 4) .Itattfi vi! 1 b. -..eked opinione about any studi or raccerta. vit nee s has personali;- performed or actually participated in. witness vili be cskod opinions about other governoantal studies . rittnecc is expected to review the following do culi:en ! r prier te giving testimony; lite, EIA, Research And Develop m e n t . He alth Asce»smani: Docum ent -on -Piò::: is for th 0-ffi-ce s of Air' u alit 7 »' P la uni::y 'and Standaie-c , pVepar ed by the Env ir Canetti, cl Criteria and ,1 3 secs C f !:i c e , C i .c Aa n a t i , Ohio 4 5148 ■( July 12048 } r^. ' f. ' • r A . . , . EPA, Research and Development, Health and Environmental Effects Profile f o r ; Tetra Pcnta, and Ilcnaehlarodibenr.o-p-dioxins, for the Office cf Solid Waste and Emer­ gency Response, by the Env..rcnBental Criteria and Assessment Office, Cineinnat Ohio 45243 (Jen. 1983). ) EPA, Research and Davc._opr.ieat, Ambient Water Quality Criteria for 2,3,7 *8 TCDD , pre­ pared far Office of Water Regulations and Standards, i. y the Environmental Criteria arc Asses.event Office, Cincinnati Ohio ••)52- i 8 (July 1903). R e c e i v e h a d D ec; lop n e n t , Dio t i n . . , Indentvial E n v i r o t a e n t a l R e s e a r c h <•»y \. Civ. ■■ i.nati -O / (J.cV*.v 'o A c o g . ' o.. there r'c;:n.ti:: ,n a t '. eh • l . H' i .1. 1 o? n a 1 «j u * J C=:lo*:} at hint: of \. lr.l to testify as to factual knowledge they nr..; have inclutdfng: 1: Kanc& Hand Personnel: there persons will testify tc their knowledge cl: the Stanch Hand Operatic::Hatch Kcndern* exposure to Agent Crane,- ¿’ .nc':/or kirvlsdgo relating to the spraying, testing, and effect.:: •:f Agent Ovivjo c.:i Inmans. t, Msnbars of lie V. ii. I-rmad Pcrceo: These persons ray testify tc the cirruinstrroe:: aid corro'.tions orcrounding the spraying of Agent Grange, 1. Persons present v. Vietnam d*or'ng the evpc.'ru.re period in question 1031-197?., ir.eludj.nc;. let rot limited h o, military and paramilirrary personnel of ■'■ho :!., Ife: Zealand and Australia,, v.ho have knewledge of the cpraying oparatiem of ■!dir herbicides, tho closure of the Plaintiffs* class, the lasar&c acccrripanyr,-.-; any such exposure, the Plaiiitiffs ’ thsoseives, aid tuie i")efenfant company rerprasentatives present ir. Vietnam to overt'.. the deliveries and spraying ebarations of the I. •bioidss the*/ mviufactcred. Persons together with -their drrrristrat; ve and docusasnfcary evidence who gave testiiiiony (which will forra vhe substance of their testimony herein)- at the ETA Cancellation Hearings of 2,4,5-T (1279-1911; ur ss: PITI'', including but not limited Dr. I'oy A.lbr-rtDr. K. Diana Courtney - 'bere Bauchmer .91 I Any current or previous employee, contractor, a;;bcontractrr, in-house >nr private consultant of each c f: the Defendants or any other person who has factual Icrcwj.edge of Ilew dioxins v/ori; uper. plants, animals, ar.d/or humans. Any icaarri.-jat or previous enpioyeo, contra:.tor, subcoivtrae'tr, iu-tteass car private consultant of each of the Defendants or any tidier person who has factual know.'lodge of any statist os concerning ‘ha effects of dioxins upon plants, animals, at Vor humans. Any crrr'st or previous employe..; ctnt.rr.ctor, subcontactor, in~lKFJEc or private cornu: tent of each of the Defendants or any ttìv:... perse including, but ret limited to, msnbers of ErA arti tether gower. .aanta.1 ace c.:.ensaticn claim/..its of the Defendants v;ho -'..sired relevant rcoupaiicnai onposures ana.'or xx •event c corpstiers! injuries and/ :r diseases and/or cymptcms r !iis reievent ylcut listed la Answer to lie. 19 (sub 171 above. Ci...1 .-. /t .. «. ,■ # q * H i ^ .U'e .w--« o - R e p r e s e n t a t i /o s ■-n ;t *“ o' •. • 1“hr. . r-.itj 1£?A a c t i o n s 115c3) •:.ind/o: 2T.C.C’a aocaT n;.-:ary an d d e c e n s t r a t i V3 w ith •—‘ct■;y :;';/ -Ì- lin e n y a l hoar:..up -w hich v / i l l form Js u b s ta n3.C3 c CiL 'CliC3J- t o s t : :. ::ny h a r e in ; o r >. t h e f a i l u r e tlie d ia n pr: o p t and ie f f e c ■live a c t i o n f : ' ban t h e p ro d u c ti.o n o f 2 .4 , f21 7. f -_1.1 i t s ae:it3ifli:ia:it d ie :u.ns. 1~ -Si Any and ail parsons bavinp 1 .crledge o... relevant facts regarding ■'.•-lie financial status of Use Defendants and -their ability to respond in punitivo dast.yer., including, but not limited, to, their past, present, and future pr “its and earnings in th:.. ''sited States and abroad since 1922 through and inciudiny the present frau Hie sale of die products made the basis of this lawsuit, .i.e., 2,4-D, 2,4,5- T, phenoxy herbicides aid the relevant herbicide market. Amy and ail persons, hiring iuiov.iedge of relevant facts regarding the ownership iv/-.erests of t b , Defendants ■id their ability/- to respou' in punitive car.ages. i.-.eluding, hr . ..at limited to, defend ;.nts: domes tin end foreign subsidiar.-.es, joiit /enturers, licensing :.grc2ser.tr., and/;::: other public or private corporate ons in the rJ, S. and breed, in ..-hioh those defendants cv/n a subst.ru.tial fir/ncial .biterc vt since 1925 t’* .lugh and including the present. -12 ■4 r-»* ■ ' ? -v - .1,, * b-\ ’W 2.:. Any and all persons listed by Plaintiffs1 in both original and ."c.r.idad witness lines, as e::part witness {medical, sciotific o:: causation*, , covcm.3;t witness, gcwernmoat causation witness, dsiendc.'-nts’ ei.ployees and/or related personnel and/or any witnesses li.sv.-d by all Defendants, may be called at time of trial to prcsr.t factual : ."o;.T.>:v-.ion as t ■ any issue involved in this c have kr,r.;:.cdg.?. of l\-..levant fasts,, including infe.-snation as any of the previously listed subjects in tils Answer, including,3ast ret limited to : c. David hriebel.. 1'irb. h. Dr. A i m Fclmc ■ Yx. ' .ml *• ’«jt;. ■ Dr, ■!.. Depps c. Dr. Cartel, ralF fDi.*. K. ‘1. ¡■’ ■t.Conn g. Dr, h. '.-hi ¿re. h. Alvin Air» i. Avrilvu iAuigrrr.ut 21 Arr/ and oil perrons \.hc r.i.v f_.ctv;.'l hnowlocgc ronceming the individr'l represented i.vo L-iaintiffrs dredges, including, but not 11 ; to, the 1 liewing: a. Any and 11 raed' r.l por.cr.ns who have exarairiscl, observed, treated and/';.:: tested the ?1ointiffc: for injuries disersss. and/or related '..ysirai n..d emotional conditions vi. ~h resulted from Plair.fi. -eh. ' ttipesure to Agent Orange, and/or pusnexy herbicides, their conctitr.en.tr, cstaandarv by-products, wastes, residua.’..- end r ~atamiaantn. b. Any and all hospital personnel *.-jhore Plaintiffs have been confined for treatment rolat'eg to their exposure to ¿hefsndants* products in Vietnam. o. Any .end ail p e r m s with knowledge of the economic losses, psychological and/or intangibi' da-r-Bysr: unstained Icy y u r dlaint* .'-f': as - rusu.l f: ••£ thei- :i.ne "ierj awl diseases r ■¡suiting rect their ■'•reo.'r.’.re to !.V:fenchants' pu d-.-.cts in Vietnam. h Any a '.d all parser; with ¡madedge of the past, present and/or future ec.r.e sir losses your lie: vtiffn have or will sustain in ¡die fut’re os resin '.•. of tlv.-.:•* ;srj of wage eaxsiings ¿rr.h'cr wagc.3 earn:.!».: capacity ros-iting from the injurious and di.sea.ses made the basis cf this ?. /suit vdiich'•■■ere caused by ■.intiffs e:;posure to Defevdants! p?r. dusts i" Vietnam. 13053 r \ Unitoti :$ia»ÄS ::rvMrof'.nií*fv ;i Protection rir; »• i■.trm» r.virtvimwUí r\ ■ . i-íu*ffcíoiv •.\nonrwt:■OH 45IÜ03 lUifii.-uien-ííf . -f? /-~J'X W'EJ 1.^- ^ i ^^ U ‘i S '■■/"'N z''"' PLAINi£F F ’S COVER ilE !:T CAUSATION WITNESSES Jab ¿¡s» M'ikerj e u A. El’A , IJ a h i n TV. E o tb fee ",uu.l and C. General E -,e at s sought. Any factual knowledge of the history of herbicide spraying in U.S. and abroad; including, but not limited to » (1 ) industr i. exposures and explosions; (2 ) registration 2,4 ~ D , 2,4.5-T vith the Department of Agricul..ure and any other government agencies b; a r y and/c r d l if t ::e i:efen clants ; o f the histsry of '*‘~/ *1 f;t u a 1 knewled ..b !C:i.ie ;pray iug in t 7 •-» U .S . and abroad; i n c._ ••n -*< ? but r.ct iimi ted t o v (1 ) D .S . mi ii C. C. Ay u;:e o ’ Agent 0 ran ge a n < other p h sr net:; Î C 2. J -* v letnan ; (2 ) ch r*"•rr-a.-5 -?*- ^:;»3 , -,3 t r-rtf' .or. L*C C” 2 rement k o f he ~1TD j.C 1v’l8 3 VJi.tl U .f . government and its agencies includin; u n owl cd of FIERA, F D A ,E P A , and C-SHA; aiu „ j --! and «-•* other hum. any o*./1 1:dge of indu;‘trial 0X P o 2 ii C_ Ï ±z: the U.3. and a broa di 'll See ..nsv-er ar.J. Supplr. tentai Answer of Plaintif fs 1 to Défendants : Int arregato ry No. 19 attachée' e t c avn .d n incorporâted 1 110 0 0 ra herciti for ail pures rc : events r r ccurrences vhicr. thés y be expectcd to give satior w icnessc-s i thev mav hâve reaarr fact t:a 1 informât sue Toct c 0 u 1 1 i n e Human L i. • As ses ornant of Exposure to 2,4-0, 2 :4,i;-T and d i<. .vins and any „actual knowledge in support t a e re o f . Expert Testimony 1' Te s time -.ay ir sc ;ght in witness' c a p ?,u i t y . personal and of fini o b u rO o c.t Matter 2,4- D 2,4,3 --T , TODD s and dioxins ; A g ont Nr I/._i (also White, Bi u S , Pink, C r e e n . and Pur tf W w* L A- !o D 0 5 and celate«' sh i o r o p h en o 1 o and h ubi an risk assassinar; regi, tding erpes^re , in,- tuding , but not; liritcd to. rue or aore c • the £ a 1 low \n g « -abject ar tan : a) C h e rai s t r y /B ic c h e u._s ■;r y b/ IIaaufacture and /or ?r :■duct :<. d) H o d t.c e) Fate in t h e "a vii onner. t (Hum,;a s, Plants, Animals) f> dedica" S t G t 1 of Art/State of : lit arature •7 n ^ o2 Human Fnpcsui and Scienti! Plant lays it'op 7 /Studies An... :-l Lhysiolcgy/Studies H ut „u Gtuli as Ep-.da.- ...0 1 c a ■ /2i 0 st at is-1.1X C. 3 ? 1ants . unti r Is. hunaas Gau-v.-; lìpide-..iclogy bap ..:di-c.:.ive Epidemiology n' •0s J7' ''ivr :*S Healtn E :£cats .e r , vrì-lin-'i-i/.s r i 1 be ac,kcd opinions ab-'ut both y"ib 1 1 ahed .;.r.J/ov ou -gc.ing studi..s. 41 Ya >J Y a s ; wii:nacr. will be asked opinions abc it other go-ornaent.il- studies. 6) Yen. vitaass :•!.s expected t ~ review the following docu.inn t s .1‘.Lor t« <•iv :i.vp t eo C im-;ny : v i m c c ;a vi 1 1 be aslce-d -pinions about any studies or resear ::h uitnees Las personally perf irmed o r ; at u a J.1y oa rt ici pated in. Sr«, E^A, Research a n d D e v e 1 o pme n t , H e a 1 t h At_ses sp e at ho cun ant, o n -Dioxin n__ o r t hy '•£ f:i c o e of Air Qua lity,' Planr.inr. 'and I-TcaiTda'rH*s , proparad by the Em* i 1,-ouEeD.al Criteria and L- oecstna C C f icf : Cincinnati , Ohio 45148 ( ,Julv 1- ^ 5»-» i.4y ’ 60 Úu -ii- ■ 15. Any person with factual knowledge tlirou-h any sur\ test??, epidemiological studies or otherwise undertaken by -ay state government, any private public or foreign corporat m , the u. Congress or the government c.f any nation ccncarnih- .tire chenacal compounds, 2,5-D, 2,4,5-T, dioxins, or related chii ttphonols relating to the creation of dioxins, the detection )f dioxin;1 ,, the c-.arpjers of die „ins' exposure, and/or the toxicity, arcincgeuicicy, fetotoxicity. teratogenicity, acute and/or cironic ffects on plants, animals and the hunan population. 16. toy and all person., listed in The Chemical Uovche ' Alastair fetevy, as having factual hnov.’le.! .ge regarding 2,4,5-T i,4-D, end its contaminant dioxins. 17. Ai.! 'worker compensation carriers for the Defendant and docu­ mentation cl all occupational exposures filed sine 1925 which evidence rndustnai injuries or diseases at the TC 2,4,5-T, 2 r4-D, Phenol, pari caging, and/or transpcratic;. pia- s of the Defendants, 1C. Any and all i r.-rant ■' : prior workers caroensation <. dinar. :s of tiie Defend?." f who claiif reievant occupational ex ■eures end/o relevar : oc-nr. :tio^ii ir T.trier. and/or disease::; and. : syirntcms a: the xx.l-r.vt-• /.inte ’... sb. .• j.n tr.ov.'or to No. 19 (aid: V, „:bcva. 19. Any and all members of ildlC;: ¡.J• . I~3• tlOoisc of Represent ives .983’' and/or any parson her with the:i documenfcarv and done trativo evidence giving testim xy at said hearing (which v/i form th substance of thei.r testimony herein! on the failure .: the EF‘ to take prompt and effective action to loan the prod: ;icn of 2,/--D- 2,4,5-T, and its contaminant dioxins. Carenittc a or. Gversinh":; Lcvicw of the T?A actions 20. Any and all persons having knowledge of relevant fat ■; regarding the financial status of the Defendants and their ab: sty to respond in punitive damages, including, but not lira: ed to, their past, present, and future profits and earnings in tl United States a:-d abroad since 192:" through and including the pres nt fran the sale of tiie products made the basis of this lawsuit, i.e., 2,4-D, 2,4.5,--T, phenoxy Iierbicides and: the relevant ' rrbicide market. Any and all persons hiring knowledge of relevant fac. ; regarding the ownership interests -.f the Defendant?-, and their -oility to rescond in punitive damar including, but not limi' d to, defendana s 1 domestic end •o.ign subsidiaries, joint nturexs, licansir.■j agreements, -nd ■ other public or private >.brporntions in the uf S. and abroad, which theca defendants own a subs:antia! financial intere: since IS If through and including the orasent. i o - 12 - g ft -i U0X • •*v e. f. Any and ail persons w?i.u knowledge of past, prc and/or future reasonable one necessary coots of doctors, hospitals, nursery care, medical equip drugs, and any other related medical services r or to be rendered in the future to Plaintiffs a: result of their injuries and disease resulting their exposure to Defendants' products in Vietrv .ed Any ana all persons with knowledge of tlie physii al present!, physical and ; an.l sent), physical pain (pi jh doh (past and pres- nt) v .d as a result of their f. osura in Vietnam and which in ) iaintiffs will continue .e time into the future i beyond the cate of thi Trie" . Respectfully sub .tted; _ 2 .'Ü_’ Themes ■W. Mender. n, Esqu.i Allison Pettiett' Esquire CERTIFICATE OF SERVICE I hereby certify that a true and correct copy of the aregoing Supplement to Plainti.fi!e Inf nrsrogatories wars mailed Federal Ex ress to Me. William ihrchloy, Valley, Drye ñ Warren. Kr. Gone Locks, Plai .tiffs’ ¡ysnagemeno Coned.tv.ee Agent Grange 'Office, with copies to personally servo die remaining Defendant:--;. at the Tuesday depositions and Ms. Nancy Petrilla n.S. District Clerk,-U.S. Courthouse, 225 '(¿.dman Plaza, Brooklyn, Hsw York 11201 this 20th dry of February, 1301. ■' 4 , ! 1 4 ..J.J__ . , Kr/'-Alii ?.on Pettiette # ** - 14 - Ur;-t>!i'i Slams í-nvirtn.Tiem.il Prr.if-.-Ton •*lerii'v '‘lustrisi tir. nt:>rv 'ifin.nl.. CiiKmn.iti t ■:«ttîBS -yj-c .. ^ •/*'" -t í'trj ,ù U O O /T' PLAINTIg? S GOVEIvNîlEN'. CAUSAT!'CM WITHES.:FS Janet Springer EPA, Washington, D.C. B. Both Iactual cad e::par: testimony is tough C„ General Events : u :y fa ctual know ledge of the h lì r*57 X c iue sprayi ng in Ü.U. and 2. 1'. C Iuc!ir.g j ¡.ut not liti;ited to, 0 ::po C V1res and e;:closio ns; <’2 ) : 9 /. c o ... ich tk 2 » ‘T - ’h e D coarti •- V r> i; V nr e and cr.y oth .r go vc rnmei au d/- r til ox the Defendant. y .':actual 1-UOW 1 dge o f th Ad o cp r ay An g in the Ü . U . i••.clud .'..., bat Uc '.: 1 in it ed to , W It ili U —*r ' use of Agent: Orange an s or*v T. 1 4. »4 ■n• x>~-. ry of road ; ) industrial istration of t of Agriagencies by uistory of 1 abroad; ) other pher.r orb I.r i-.as in Vi cinam; (2 ) chan .o in the 1 st •t*,r>tion re _ulrer.cn t s of herb ides w i th th i. j » «1 • j »5 - o * 3) u n cO ) v* Plant fhyriology/Studio Animal Physiology/Studies ilv.r.an Studies Ev ida niology/Biost atistAcs 1) 2' Cl y (Hr.uans, Plants, animals, hur :ns Cancer Epidemiology Repro-ductive Epidemiology Advcr n a r.Ic a 1th Effects •*.,* w .tness will be- asked opinions about both published and/or on-going .studies. 4) Tea, witness will be asked opinions about any chuc-ec or roservth witness has personally performed or actually participated in. 5) Yes, witness will be asked opinions governmental studies. 6) Yes, witness is expected to review, the following documents prior to giving testimony: See. about other E?A, Research and Development, Health A s se ssment Document- pit'-Dioxins for the Off Acas- of Air Q u a l i t y . P l a n n i n g 'and '"otart-darcs, pfeplared by the ."nviron :eni.al Criteria and Assessme Off is ^ir. icnati, Ohio 45243 ( July 19 r* r- n ** l C ' •J D 0 E'‘A, Research and Devalopment, Health and Env J.romaentàl Flf: ;ectfi Profile for; Te Penta, and Hexach.lorodibenzo-p-dioxin for the Office of Solid Waste ahi Eme gency Responso, by the Environn «tal Criteria and Assesaraent Office, Ciuci Ohio 4 5 8 (Juna 1983). EPA, Research and De\reloptnent » Ambìent Water f'nality Cri te ri a fot 2,3,7 , 8 TCDD, pr pai: .'.il for Office of 1-Jatar Regalar ions and Stendardo, by the Environmentai Cric cria and Aasescnent Office, Cinti Ohio 452AE (July 2983). EPA, P,crif’n"”.l and hovelopment, Dioicirn, ii i .i.l.'il inivirnn>i ini.al al. di . innati, Ohio (l‘ J78; . docuucnfcs is attnehed. ' jt*. **. 1*2 o d o ( "UPrLSMgra\L ANSWER TO INTERROGATORY NO. 19 Plaintiffs note preliminarily that the extant Grier on producing fact v Ventores etatec that fact witnesses are not due until March 2, 1984. However, Plaintiffs may call one or mere of the following parsons (or these from various categories listed beicrv) at time of trial, to testify as to fac'u.-ul knowledge tft-'-y may have, including: 1. Ranch Hand Personnel: These persons will testify to their knowledge of the Ranch lime. Operation.. Ranch Handers* exposure to Agent Crrngo, ar.d/cr leu .-/ledge relating to the spraying, testing;, and effects of Agent Grange on humane. 2, Maribsrs of the e. 3. Armed .'orcoc: There persons may testify to the circiruchaircef! end condition’:: surrounding the spraying of Agent, Ora: :;e. 1. Perse’ .is p::rcent in Vietnam during tile exposure period in question 1?6?/ 197/., i.nclt.tr:'ng.• !->ut not limited to, military and parmailitaiy peruonr. :•! cf the 3:, New Zealand and Austral:.;:, v.ho have hr.r-./j.cdgo of the spraying operations of tile herbicides, the exposure of the Plaintiffs’ class, the hazards Ecoanvconying any such exposure, the Plaintiffs’ themselves, and the .Defendant company representatives present in Vietnam to oversea the deliveries and spraying ■..peratiens of the herbicides they manufactured. 1. Parsons teg '.•her void, then:: dmacnntrative and documentary evidence who cave testimony (which v/ill form the substance of their testimony herein) at the VPA Cancailaticn Hearings of 7,4,5-T ’1979-1980) under FIFRA, including but not limited to.: Dr. Roy Albert: iv.G• K. Diane Courtnc; Rob;art K. Baughman, ] Din 01 av A:-:elson Or, Renatc I'JLr.'brcur'-'. Dr. O e m 'o. Gcodr': Dr. dirk T. latch,in Dr.. ,.V_n?.id Thome:' U.■ » O r . Rainer Frentcel--! r cnbClnv J' a. <-b. - c. d. e.. V• 3h. r- -• - 9 * ^ <7^ V 'l l ¡:. Ma ¡or Alvin Young I. Dr. Rodney Povey rr;. Kenneth V. Therein a. David Eutzelii 0 / Dr.. Michael Gross p. Dr. Ranee Stringham r. Dr. van' Miller Any current o:: previous employee, contractor, subcontractor, in-house or private consultant of each of the Defendants or any otrier person who lias knowledgs of the manufacturing grocesoes, chemistry, occupational eccpesure and/or toxicity cf snd/c- 2,4,5-T or related chlcr.,phenols; including, bat rot limited to, laborers;, operators; supervisors; entract administrators? quality control personnel; engineer- {process, dierdcal, reclianiavl and/or safety). fi. Any current or previous employee, contractor, subcontractor in-house cr private cnsultant of each of the Defendants or cry cd'sr perron who Ins Ixowledys of the possible means of ]yrcpliiacfci.c or hecticn from, the Lizards of cUoidns* exposure; inclining, k v net limited to, laborers, operator's, supervisors; contrart cdnvr.irtraters, q-.rlity control personnel, engineers {process, chemical, mscluoiical ond/cr safety';. 7. ?jny current or y.rcivicu..; c. .ployca, contractor, subcontractor, in-house or private consultant cf each of the Defendants or any ether person who has knowledge cf the means to v;am those who might be exposed to use of tiia herbicides in question, particularly -Agent Orange, including, but not limited to, laborers, operators, supervisors, contract administrators, quality control personnel, eng: .„acts (process, chemical, mechanics; 1 and/or safety). i. Any current cr previous employee, ■".ltractor, subcontractor, in-house or private consultant of each cf the Defendants cr any other person who has factual laicwledge of any ether manufacturing processes which could reduce the risks of exposure to Agent Grange and/or other phenoxy herbicides being contaminated with dioxins and further reduce the ri sk and hazard to human health cf ar.y such exposure. 9. Any current or previous employee, contractor, subcontractor, inrheizna cr private consultant of each of the Defendants or- any of tier person who has factual jmowledga of conspiratorial conduct of '...he Defendants, individually and/or duplicative efforts (acts which are parallel in nature) which tended to or did in fact result in misleading the public and the United States government from gaining knowledge of the dangers attendant fresa exposure to Agent Orange and ether phenoxy herbicides. .2068 -10- •'■.ïjnqzxgty, Any current or previous employee, contractor, subcontractor, in~h::>usa or private consultant of each of the Defendants or any other person who lias factual .cnowledga of hoi// dioxins work upon plants, animals, and/or humans. Any current car previous enploy.ae, contracter, sufccontractor, in-‘house or private consultant of each of -the' Defendants or any other parson who lv. a factual knowledge of any statistics ocwoerning the affects of dioxins' upon plants t animal's, and/or unmans. 12. Any current or previous employee., contractor, subcontactor, inr-lioii^e or private consultant of eadi of the Defendant:-: or any ether person i-r ludir.j, but not limited to, members of E2?A and other governmental agencies, who has factual knowledge of the followincr incidents; n. Love Cenar b. Tlares Beach. Kineouri c. Se-vesce, “taiy c. BASF (1951, lidi - Fcvfiisdie in Germany) c. Frcducticn rishapn end/c-r explctiers since 1325 at a. y cf the plants o" any of the afar, "ants lreruifacturing, T. 2,4~D, _2;>i,5-T phenol, cliorina, acetic acid, benzene, sodium hydroxide:, potassium ivciror-lde, ar-d/cr Agent Grange, including Irish', ps in the packaging, and tear-per ting of -the Defendants' products f-n the 0 ° * Armed Forcer. bases for eventual shipment U. t:„. Vietnam, f. berrying cf Viete .13. Any current or previous ea»loyeo, contractor, subcontractor, i-v-house or privata consultant of each of the Defendants or any ether person sin has factual knowledge of any surveys, tests, epidemiological studies of any kind relating to the effects of exposure to Agent Orange, 2,4-D, 2,4,1-0 or any constituent •thereof including the secondary by-product known as dioxins. 14. Any psrson with factual kr viledgs of how decisions are made within the United States goverrr.'.ent, particularly trie decision ■:o use and to continue to use piisnooty herbicides in Vietnam, particularly Agent Grange; any person with factual knowledge of y • cmmsiit procurement contracts and the invitation to bidders, . particularly those perrons who negotiated the government contracts far all pbenoxy herbicidfes. (agents white, blue, purple,, pink, green, o/.vnge I and II) with the individual defendants repre­ sentatives between 1961-1972. -1 15 Any perron with factual knowledge tJurough any surveys, tests,"" epicoi/uological studies or otherwise undertaken fcv any state gover-taent, any 'private public or foreign corpora"-ion, tine U. S. Congress or the government of any nation concerning the chemical compounds, 2,5-D, 2,4,5-?, dioxins, or related chioronhenolc relating to the creation of dioxins, the detection of dioxins, the dangers of dioxins1 exposure, and/or the toxicity, carcinogenicity, fetotoxicity, teratogenicity, acute and/or c.irciit . -feet: on plants, animals and tlie human papulation. 16. Ssrty and nil persons listed in The Chemical Scythe ? Alastair liny, a;., having factual knowledge regarding 2,4,5~'i 2,4-D, and its contaminant dioxins. 17. .'.11 worker cartelisation carriers for .tlie Defendant.; and dccumnitatien of all occupational exposures filed since 1925 which evidence, industrial injuries or diseases at the TCP, 2,4,5-T, 2,-i-D, Phenol, packaging, and/or Ltansporntion pl?*-'r.s ->£ >'• •, ryafond.in»,'-. 11. Any and all current or prior worker:' oenrpensation claimants cf the Defendants who claim.;../ relevant •-.coupational e-eoauren .--.idA C; .nr'.l : rolcvarh " ' ".’’' rC -. vVtCjJ..o ;‘r ]vries and/or diseases c.i syi.yt»~.is ]rnc.; . . jl-.. ■ t lents _au list .i iv. . *.w ,w .w w-^~ 1'’ »»v-««*- 19 r C.j.j. members ■;f ;-J-7T ; o -h Over si.ghtu Devi:on together with their i givrr.g tes'.:iivcuy at r.. ."’¿jst-rnce of ::heir test: many herein) on tlie failure cf the E-T. to take, preopt and effective action to can the production of 2,4-D, 2,4,5-T, and its oontraninanl dioxins. 20. Any and all persons havrV.g knowledge of relevant facts regarding the fhiancia?. status cf the Defendants and their ability to respond in pu.ftive damages, including, but not limi-bid to, their pas:-';., present, and future profits and-earnings in the United States and abroad since 1925 through and including 'the presen", from tlie os It of ike products made the basis of this lawsuit, i„e., 2, -B, i.,4,5-7, phenoxy herbicides and trie relevant herbicide nuu ret. 21. kv.y and all persans having knowledge cf relevant facts regarding the ownership interests o f the Defendants and their ability to r■.-pond ;n punitive damages, including, but rot limited to, defendants' domestic and foreign subsidiaries, joint venturers, licensing agreements, and/or other pu b li< : or private corporal:err in the U. n. and abroad, in v.\ ;.l financial ;nto;. ist s uresent1# y J T 1- **3 ;U i u ,/v. %#' -1 r~ \ e. Pay and all persons with knowledge of past, present and/or future reaccna- ue and necessary costs of doctors,, hospitals, nursery care, medical equipment, drugs, and any other related -medical se: ocas rendered or to be rendered iu the future to Plaintiffs as <_ result of their injuries and disease resulting iron their exposure to Defendants' products in Vietnam. f. hr.y and all parsons with knowledge of the physical disfigurement (past and present), physical and mental rmpairrvsrt (past and present), physical pain (past ana present/ raid mental anguish (past and present) whies Plaintiffs iiave sustained as a result of their eupouure to Defendants' products in Vietnam aid which in reasonable probability Plaintiffs wall continue to sustidr: for an indefinite: time into tire future far beyond tha data of this trial.. idrpectfi :1hy suhnitted, A Jj_______ fiO .in:. W. tenctv m, Esq uu.ro iUliscn Pettiet of isouire sfivics ¡. hereby’ certify that u Larue and correct- ropy of the foregoing Suprleraer.t to Plaintiff's “nterregat-rres were mailed Federal Express to Mr. f/illiam Krohlcy, Kelley, Drya C- ¿ferrt n> Mr. Gene Leeks, Plaintiffs' Man?c ument Co.rrit.t.ee Agent '"range Office- with copies to personally servo the remaining Defendants at ■ j .:.. n Ohrestay depositions and Mu. Nancy Petriila, icirict •l.euk, U.S. Court c u g o , 121 Csd-van: Plaza, Brooklyn, New York 11201 this 20th day of February, l % f . \ h u til Allison Pcttiette 13071 P’.ATNTI FF ’S G O V E R N M E N T CAUSATION WITNESSES / Peter Infante A. National Institu.ce tor Occupational Safety & Health, Wa 3 h I>. Both factual and expert testimony is sought. C. .General Events ?re-1961: «il Any factual knowlod c of the history of herbicide spraying in U.S. and abroad; including, but not limited to, (i) industrial e::po£urss and explosions; (2 ) registration o 2,4-0 , 2 , ,5-T with the Department of Agri­ culture and any other government agencies by any and/or all of the Defendants; 1961 --presort: : ¿lay 1a....tu-.1 knowledge of the history of herbicide spraying in the U.S. and abroad; including, but net limited to, (1) U.S. n i 1 i t or y v.::■2 cf Age;t C r ar.y n u n ?. o th <...r p h cr tie -h ‘ ' ‘ ■ ; j "> V *et-v-.m: (2 ' changes in t.•u gistra _on ;;.:y; romen t a herbici tea v i Uli V- .S . g r n m a n t and its agcncie- including knowledge o' FI E R A , FDA,ERA, and OCHA; and (3) •ray knowledge of Industrie? and ether human exposures tc 2 , -D , .?,4 ;5~T in the U.S. and abroad See Answer and Supplemental Answer of Plaintiffs 1 to Defendruts’ Interrogatory No. IS attached hereto a incorporated herein fer all pur­ poses re.. events or occurrences which these causation: witnesses may be expected to ,lvs any factu.nl information they may have m,garden, the subjects outlined in said Answer. Human Rick Assessment cf Exposure tc 2,4-D, 2,4. 5-T and diox.nr and any factual knowledge in support thereof D. Expert Testimony 1) Testimony in sought in. witness’ personal and official capacity. ?.) Subject Matter 2,4-D, 2,4,5-T, TCD D’e and dioxins; Agent Oran Z i’ l l (also White, Blu.e, Pink, Green, a m ’ Furpl «V and related c h 1 o r o p he no 1 s and human risk assessment regarding exposure, ** «eluding, but not limited to, one or more of the following subject areas: V •f a) Chemist ry /Bloch ami".::r- b) Manufacture and/or Production c) Toxicity d; Modes of Human Exposure c) Pate in the Environment Animals) O State cl Art/State of Medical and Sclent L it ovati: ve ? r r ‘i o / ... 1) :.) Plan-': Physiology/Sti lies Animal Physiology/Studies :■; lia ir. a n Studies Er.idrc.:iclogy/Bio.* tatisticc 1) ... J '( (Ilutans, Plants, > - / I-lent c , animal s , humans Cancer Epidemiology Reproductivo Epidemiology Advcrro Health Elfeats 2} 'res j witness will be ashed opinions about both published and/or on-going studies. 4; Vcs; witi:cso will be asked opinions about any c udie or research witness has personally performed or actually participated in. 5) Jos, witness will be asked opinions about other governmental studies. 6) V e s , witness is expected to review the following documents prior to riving testimony: f!a e , PiP A 5 Pc sc r. rc h N 10. Any currant or previous employee, contractor, subcontractor, in-lîTura c r private consultant of each of the '.defendants or any ther perron who has Tactual knowledge of how dioxi: i work upon plr.nts, animals, and/or humans. 11. Any currant or previous employee, contractor, suboontra'-fcor, iii-house or private consultant of each of the Defendant, or any other perron who lias factual knowledge of any stat.i les i/or concerni..g the effects of dioxins upon plants, animals, humans. Any current or previous employee, contractor, subcontac in-heuse or private consultant of each of the Defendant other person including,- but rot limited to, mentors of other governmental agencies, vv.s has- .Tactual itncwledge c following incident: ■: x, or any ?A and the a. Love Canal. b. Timas '.-each, Missouri c. Sevasco, Italy d. BAS?' (1353 - 19H4 • ¡iadi.ooha. in Gerrsir/:e. Prcdu-etion td.shr.ps and/or: explosions since 1315 at aa of the plants of any of tile Defendants manufacturing, if ‘, 2,4-D, 2,4,5- T phenol, chi. rite, acetic acid, benzene, sodium hydroxide: potassium hydrttide, and/or Agent Orange, including mishaps it:, the packaging, art tv«2ispcrfcing of die Defend nits’ product.s' to the V. S. Armed Forces bases for eventual shipment to Vietnam.' f- Spraying of Vietnam frtsn ISS1~1.972. Any current or previous employee, contractor, subcontractor, in-house or private consultant of each of the Defendants ir any ether person -who has factual knowledge of any surveys, tests, epidemiological, studies of any kind relating to the effects of exposure to Agent. Orange, 2,4-D, 2,4,5-T or any constituent thereof including the secondary by-product kner.-.n as diox'- is. Any parson with factual Iznovledge of ho; decisions are made -within the inited States government, particularly the decisi . to use ar.d to continue to use phenoxy herbicides in Vietnam, particularly Ago h Orange; any person with factual knowledge of government procurement contracts and the invitation to bidders, particularly those persons who negotiated the government ■toutracts for all phsncxy herbicicitg (agents white, blue., purple, pink, u.scn: orange 1 and “i; with the individual defendants repre­ sentatives between 1961-197... . -li- 0 78 Day person with factual knowledge through any surveys, tests, epidemiologies 1 studies or otherwise- undertaken by any state government, any private public or foreign corporation, the U. S. Congress or the government of any nation oonseming the chemical ocaqpounds, 2,5-D, 2,4,5--?, dioxins, or related chic phenols relating to die creation of dioxins, the detection < : dioxins, tiie dangers of dioxins' exposure, and/cr die toxicity, carcinogenicity. fetofcoxicity, teratogenicity, acute and/or chronic <:. Any and all rr:smbsj's f the ■'* k • _■ re Cerai-ittiie an fversichus Re > ■i'rtt7 ■ any pan.. u t. needier ’ thei..u dc evideu :--, givi: -j ban. : vjy at said substa. -go fyp 'heir t :»:r:.;tiray !c.rn to take premp a and cffactive r-\?r ' r Representative:: ■ id denser,strative (which will form the 153T—■V*^r knowledge of relevant facts regarding Any and air parser the financial status of the Defendants and their at •lity to respond in punitive damages, including, but not. limited to, their past, present, and future profits and earnings in the united States and abroad rinoe 1921 through and including the present fresi the sale of the products inaia the basis of this lawsuit, i.e., 2,4-C, 2,4,5-i'. phc-no::y herbicide:- and the relevant herbicide marker Jury and ail person.1: havii g iciowledge of relevant facto rec.-rdi.ng the ownership interests cf the Defendants and their ability to respond in punitive damages, including, but not limited to, ;:cr.dants: dccactio and foreign subsidiaries, joint venturers, Ircenr'.ng agreements, and/or other publ.-.c or private co.rporations : . fho U. C . and abroad, .in which these defendants our.ni a subp'-ential financial interest since 1925 through and including the present 1 o n >?a .1kj u / ri -12™ >v Any and ail persens listed by Plaintiffs1 in both original and amended witness lists, as expert v/itness (medical, scientific or causation), gcVermont witness,, covermsnt causation witness, c&iiendants’ employees and./cr related personnel and/or any witnesses listed by all Dsfandarhmay be called at time of trial to ¡present factual information as to any issue involved in tins caseT- Sctt ¿rod all msiaberc of the scientific and/or medical oonraanit. wfen have hmowledge of relevant facts, including inforoatian ••¡sx..iy of -the previously Listed subjects ii. this Answer, including, '¿at :ot Limited ‘no.’ » 1 b^.*- Scvid *t;iebsi, bh•. e > rv L. A..C.' Polarr '5 .** ■Det.. vcul Colder y ..jt*—f.r. T) 3r. C. Par~t£ G. Dr. Cette1, liitA it Dr. E 3. AzDc-.vaii Dr. U. id &.v..jir.'.i Alvin Aim i. sfarilyn 1ingarhut / Anj• and all ecu no who hm irkb'.viduai ierrrnent \"j.i rot limiter! fr... lew: ’a'.vc.f..;dc.., concer.iing the. s daoiaces, including, but a. Any end. • i-:e-'i-~.--l penoc:>n why have examined, observed, treated .one..' o: rented the .Avintiffs * fer injuries, diseases and/or related cirri cl and i- t-A A r^ . I-LAIMTI F" S GCVERUHENT CAUSATION WITf’SSSES D. D ian e Coui'tnoy ^_ EI-À, Washington, D-C. A.. !ì®ih- fastaci m:d oxpert testiaony ia snii; C. Gen c.-Tal 1ven tc ? r c - 1 S 61 : Any al knowl- d g • cf thè Lir..rory of h 0 r b i c it!e sprayir.g in U.S. and aaroad; includi n ; , b ut no'- 1 i .¡’ .ad C o , (1) indù e x p 0 s u r n a and c x p ’. o s io . ■; ( 2 ) r e g i ; t r a c 2-,4~D, 1,4,3-T r;i.:h th j D ripartine;: of '.¡»ri- cultura and any othcr gr.vevnmcnt agencies Ir: a n y a n d / r r a l i c : t h è De?avi da *£3 ; ? 981-prcse-. /.cy ^ c r u c l ha a:.»" ■ ’ gr o f t h è h r e r e r y o f ..orbici:r r r r y i r g i n ...he U . 3 . and ...' r e c o ; ir .c i u .; i t b a r not l i m i t a i C o , ( 1 ) "4.7. ¿v:.1 Cary ca ; ,:ra 1 ■ ;.n iic::n:-u. ; (1) cfcaogaa In thè 1 A3 eni: Grange ov.d rrre r pii v *., U . S . gC73Vi»:. ;cat enei L i •'« *• hno-rledge cf FI72.A , Fi-A, EPA, aad t'.'.of; c 1 1 n c v.s t r i a i a 0 d c can : 0• ,4 ,5~ Y in i rb o r.cT Sa A v ..:r. a n i b u p p lr .- a evitai Ansio Delencnnts in t c rr 0 3 a >. crete- e: d incorporar rosee re: everrà -r causar fon ■ i r :: o z reo t ... -7'- m a ti any factus thè sub; ce­ 01:•-line' i des V„ t i n d ù diti. OS MA; and ano .1 OSHA; òhe r 1 urne . C U .b . and 1 fi" 3 ' tc s . r r a e hed jf c: i. .. cu rw h i c h th e s n 2 d t 0 crj_V Q hav c telare Hr.if.an ri Hi.sic .h'^erse n t of E mp0 :o 2 ,4—i>, 7-,4,5-T ano o sera sur ài errino and ;■ factral hciowletige i r s u p p o r t r 1: e r a r f . x p e : L. T e s t ime rsv 1) l ’ e 3 i irne n y s c u . '.11 i n capacity. *•\ / »•ri r ri ile t i s : v. / i l wi r." TCi'D *1 ( n i no Uhi f . i •» /, # * »*\?■*)r} 1 4 A »1 and related chloaophenols and i: r,ian riskassessment, regarding exposure, ncluding, but not limited to, one or more of the following subject areas: a) Chemistry/Biochemi3 try b) Manufacture and/or Product!- a c) Tor. icity d) Modes of daman Exposure c) Fat e n the Environment (Hu. cr :, Plants, An '.maIs) of Art/State of Medical .end Scientif i r) L erasure Plant Physiology/Studies .nimal Physiology/3t dies --ni u nudi aa g) •»id ami o logy /Biostatistics 1) 2) 3) h‘ Plants, animals, humans Cancer Epidemiology Reproductive Epidemiology Adverse Health Effects 2) Yes, witness wil. . be asked opinions about both published and/or on-going studies. 4) Ye s, witness will be asked op inions about any studies or research witness has personally performed or actually participated in. 5) Yes, witness will be asked opinions about other governmental studies. 6) Yes, witness is expected to review the. followingd ocumenr. r. prior to giving testimony: See, EPA, Research and_Development ,__Hea 1th Assessment Document on Dioxins for the 0 ffice s_of A i r Quality , Plan ni tip, 'and "Standards, "^nfeparad by the Environment, al Criteria and Assessment Of fine, Cincinnati, Ohio 45243 ( July -'-981: a J,njv W>«--J ( ( SUlTI M-iBITAL ANSWER T ) IN reRROGATORY NO. 19 Plaintiffs note preliminarily that the extant. Older on proiucing fact witnesses states that fact witnesses are not due until March 2. 1984. However, Plaintiffs may call one oi more of the following persons (c those from various categories listed belav) at time of trial to testify a.* to factual knowledge they ray have, including: 1. Ranch Hand Personnel: These persons will testify to t. air iarxtfLedgc of the Ranch Hand Operation., Ranch Handers* :,rposure to Agent Orange, ar.d/or kncw.ledgt relating to the sort : tenting, and iffects of Agent Grange on himsns. tersbers c:. tun IK S. Armed Forces: These persons may .entifv to the circrostanceo and conditions rurrounding the sp aying of Agent Crauge. 3. Perr.ci'is prerant an Vietnam during the exposure period i question 1961-1972, includ-ung, out not limited to, ail'tary and paramilitar1 / personnel of the U. 5., New Zealand a i Australia, who have icr.owledge of the spraying operatic? c of the herbicides, the exposure of the Plaintiffs’ class, :he hazards accompanying any such exposure, the Plaintiffs themselves r and the Defendant ccr.pany representatives present in "ietnam to oversee tlie deliveries and spray ng operations of the herbicides they manufactured. 4. Persons together wi' h their demonstrative and docisaenti ry evidence who gave testimony (which will form tlie substance of their testimony herein) at the EPA Cancellation Hearincs of 2,4,5-T (1973-1980) "nde:; 7IFRA, including but not limited to: a. b. Dr. Rov Albert-Dr. K. Diane Courtney C. Robert K. Baughman. Ph.D. d. Dr. 01 av Axelsen e. Dr. Renate Kimbrough f • Dr. Dawn G. Goodman a. Dr. Kirk T. Kite'in h. Dr. Donald Thomas i. ry*-^ R?iner Krentzei-Boyrne j - Dr. ’•rifctl'iew Meselcon, Hnrvax _Q.. ic n$4 ( f k. Major Alvin Young l . Dr. Rodney Eovey m. Kenneth V. Themein n. David T. Buzzelli o. Dr. Michael Gross p. Dr. Renee Stringham r. Dr. Van Miller 5_ Any current or previous employee, contractor, subcontr ictor, in-house or private consultant cf each of the Defendaj cs or any cther person who lias knowledge of the manufacturing processes, chemistry, occupational! exposure ant-/or to: icity of 2,/.~D and/or 2,4,5-T or related chlorcphenols; including, but mot liiruted to, laborers?. operators; supervisors; con-jract administrators; .uiality control personnel; engineers process, chemical, mechanical and/or safety). 6. current or previous employee, contractor, subcontractor, iu-bnuse or private consultant of each cf the Defendants or any otivr: perron who lias knowledge of the possible means of prigl-jL. .ic protection frem tho harards of dioxins1' exposure? i&riui but not 1ir.utec. '-o, laborarc, operators, supervisor:;, -rontraet adminirc.rators, quality con.trol personnel, engineers (process, chemical, niechanioal and/or safety) . 7. Any current or previous employee, contractor, subcontractorir>*house or private consultant of each of the Defendants or any other person who bus knowledge cf the means to warn those who might be exposed to use of the herbicides in question, particularly Agent Grange, including, but not limited ;-o, laborers, operators, supervisors, contract administrators, quality control personnel, engineers (process, chasical, mechanical and/or safety). 8. Any current or previous employee, contractor, subcontractor, in-house or private consultant of each of the Defendants or any other person who has factual knowledge of any other manufacturing processes which could reduce the risks of exposure to Agent Orange and/or other phenoxy herbicides being contaminated with dioxins and further reduce the rink and hazard to human health of any such'exposure. 9. Any current or previous snployee, contractor, subcontractor, in-house or private consultant of each of the Defendants or any other person who has factual knowledge of conspiratorial conduct of the Defendants, individually and/-;:; duplicative efforts (acts which are parallel in native) which tended to or did in fact, result in misleading the public and the united States government from gaining knowledge cf the dangers attendant from exposure to Agent Grange and other phenoxy herbicides. $ f* l -3.0- 5*J 10. Any current or previous enployeo, contractor, subcontractor, in-house or private consultant of each of the Defendant:.'; or any oLuar person ulio has factual knowledge of how diox.vs work upon plants, animals, and/or humans. 11. Any current or previous employee, contractor, subcontraccc.:, int-touse or private consultant of each of the Defendants or fiwf other person who has factual knowledge of any statistics concerning the effects of dioxins upon plants, animal's, and/or InfflmaBis12. toy current or previous c.nployea, crntrr.otor, subcontactor, irHhcuse or private c r.nsultant of each of the Defendants or any other person „nciuding. but net limited to, members of EPA and other governmental agencies, wiio has factual knowledge of the following incidents: a. Love Canal b„ Times Beach, Missouri c. Sevesco, Italv d. BASF (1953, i.,54 - Badisch a in Germany) e. Production mishap:, and/or explosion:; since 1925 at any c.I the plants of any :.f the Defendants manufacturing, TCP, 2,4-D, 24, 5--T phenol., chlorine, acetic acid, benzene, sodium hydroxide - potassium hydroxide, and/or Agent Orange, including mishaps in the packaging, and transporting of the Defendants' product.; to the U. S. Armed Forces bases for eventual shipment to Vietnam. f. Spraying of Vietnam from 196]-1972. 13. Any current or previous employee, contractor, subcontractor,, in-house or private consultant of each of the Defendants or any other person who has factual knowledge of any surveys, tests, epidemiological studies of any kind relating to the effects of exposure to Agent Orange, 2,4-D, 2,4,5-T or any constituent thereof including the :.ccondaxy by-product known as dioxins. 14. Any person with factual knowledge of how decisions are made within the United States government, particularly the decision to use and to continue to use phenoxy herbicides in Vietnam, particularly Agent Orange; any person with factual knowledge c p government prccursn&nt contracts and the invitation to bidders, particularly those persons who negotiated the government contracts for all phenoxy herbicicts (agents white, blue, purple, pink, green, orange I and 11} v;ith the individual, defendants repi.eser.fatives between 1961-1372. - 11 - 13038 Anv person win i t'actua knowledge through a m surveys, tests, epidemiological studies or otherwise undertaken by. any stace government, any privy« public or foreign corporation, the U. S. Congress or the government of ary nation concerning the chemical cavpcunds, 2,5-D, 2,4,5-T, dioxins, or related chloroyhenols relating to the creation of dioxins, the detection of dioxins, the dangers of dioxins' exposure, ard/cr the toxicity, carcinogenicity fetotoxicity, teratogenicity, acute arc/or chronic effects on plants, animals and the human population. Any and all parsons .listed in The Chemical Scythe by Alastair Siay, as having factual knowledge regarding 2,4,5--T, 2,4-0, and its contaminant dioxins. Ail worker compensation carriers for the Defendants and docu­ mentation of all occupational exposures filed since 1925 which evidence industrial injuries or diseases at the TCP, 2,4,5-T, 2.4- D, Phenol, packaging, and/or transy.oration plants of the Defendants. Any and all or rent or prior workers compensation claimants of the Defendants who claimed relevant occupational exposures and/or relevant occupational injuries .and/or diseases and/or symptoms the relevant plants listed in Answer to No. 19 (sub 17) above. Any tnd .11 tu'-irfce.vs <■.£ the G. House of Representatives Caixnittee on Oversights Review of the EPA actions (19G3) and/c any person tcgather with flier: dccurrentary and demonstrative evidence giving testimony at said hearing (which will form the substance of their testimony heroin) cn the failure of the EPA to tak .prompt aui effective action to ban the production of 2.4- D , 2,4,5-T, and iis ccntaainant dioxins. Any and ail persons having knowledge of relevant facts regarding the financial status of the Defendants and their ability to respond in punitive damages, including, but not limited to, their past, present, and future profits and earnings in tile United States and abroad since 1925 through and including the present frcr.i die sale of the products made the basis of this lawsuit, i.e., 2.4- D, 2,4,5-T, ;-heroxy herbicides and the relevant herbicide market. Any and all persons having knowledge of relevant facts regarding the ownership interests cf the Defendants and tlseir ability to respond in punitive damages, including,■but not limited to, defendants* domestic and foreign subsidiaries, joint venturers, licensing agreements, and/or cuter public or private corporations in the U. C. and abroad, in which these defendants own a subs'-uitial financi.a.l interest since 1925 through and includin.;: the present. \ 15. Any person with factual knowledge through any survc j , tests, epidfcmiological studies or otherwise undertaken by ry state government, any private public or foreign aoi.por.at , the U. S. Congress or the government of any nation concemi n '■the chemical compounds, 2,5-D, 2,4,5-T, dioxins, or related chi ■ohenols relating to the creation of dioxins, the detect.'tor dioxins, .the dangers of dioxins' exposure, and/or the toxicity, • rcinogenicity fetotoxicity, teratogenicity, acute and/or droni. c fects on plants, animals and the human papulation. M. Any and all persons listed in The Chemical Scythe b; Alaetair Heyc as having factual knowledge regarding 2,4,5-T, -,4-0, and its contaminant dioxins. 17- M i worker' compensation carriers for the Defendants and documentation of all occupational exposures filed since 1925 which evidence industrial, injuries or diseases ¿-.t the TCI-. 2,4,5-T, 2.1-D, Phenol, packaging, and/or trensporatien plan of the IDfefe. -'ants. 18. iliy and oil current or refor v;cri:ers•conpenration claimants of the Defendants who claimed relevant occupational exposures and/or relevant occupational in1uric:.: and/or diseases er. './ :: symptoms a< the relevant plants listed in i.nswcv to Mo. 19 (sub 1.7) above. 19. Any and ail members of tine U. S. House c': Representatives Committee on Oversights Review of the EPA actions '(1S83) and/or a.ny person together with thoir documentary aid demonstrative evidence giving testimony at said hearing (v-nich will form the substance of their testimony heroin) on the failure of the ETA to take prompt and effective action to ban 'tine production of 2.4- D, 2,4,5-T, and its contaminant dioxins. 20. Any and all persans having knowledge of relevant facts regarding the financial status of the Defendants and their ability to respond is: punitive damages, including, but not limited to, their past, present, and future profits and earnings in the United State and abroad since 1.925 through and including the present fron the sale of the products made the basis of this lawsuit, i.e., 2 .4- D, 2.4 ,5~T, pheiioxy herbicides and the relevant herbicide roarxet. 21. Any and all ¡persons having knowledge of relevant facts regarding the ownership interests of the Defendants and thoir ability to respond in punitive damages, including, but not limited to, defendants' domestic and foreign subsidiaries, joint venturers, licensin'“ agreements, and/or other public or private corporation in the n, 3. and abroad.. in which these defendants own -• sub­ stantial ncnci.il interest since 1925 through and including the present. -12- :088 !' <■ 22. Any ¿rid all persons listed by Plaintiffs' in both erf inal and ¿¡mended! witness lists, as expert witness (medical, sc entific or cauisation) , goverriment witness, government causati witness, defiendamts' lanuloyees and/or related personi.el and/or any witnesses .DiifBSod by all Defendants, may be called ¿it time of trial to ¡jassent factual information as to any issue involved n this ca: 2. 23- «fy and all members cf the scientific and/or medical -mnunity whan have knowLedge of relevant facts, including infer .tion cm any of 'due previous;// listed subjects in this Answer, including, ¡bat not limited to: a. David Kriebel, Ph.D. Ib. Dr- AJLan Poland c_ Dr. Paul Goldmann, PAS? di. Dr- C. Kuppe e. Dr. OottuI, BASF f. Dr. E. e . McDonnell g- Dr. K. S. Khiera ir. Alvin Ain: i- Marilyn Fingorhut 24. Any and ¿ill persons who have factual knowledge conce. Ing the individual representative Plaintiff's carnages, inciuc ng, be: not limited to, t! ; fcilc.;ing: a. Any and all medical persons vino have examined, observed, treated and/or tested the Plaintiffs' for injuries. diseases aod/or related physical and emotional conditions vn ch resulted from Plaintiffs1 exposure to Agent Orange, and/or phenoxy herbicides, their constituents.- secondary Ly-products, wastes, residuals and contaminants. b. Any and ail hospital personnel where Plaintiffs have been confined for treatment relating to 'there exposure to Defendant!' products in Vietnam. c. Any and all persons with knowledge of the economic losses, psychological and/or intangible damages sustained by your Plaintiffs as a result of their injuries and .diseases resulting from their exposure to Defendants' products .In Vietnam. d. Any and ¿¡11 personr with knowledge of the past, present and/or future economic losses your Plaintiffs have or will sustain in the future as ? result of their loss of wage earnings and/or wages earning capacity resulting from the injuries and disou.ses made the basis of this lawsuit which were caused by Plaintiffs exposure to Defendants’ products in Vietnam. < -.13- ^ f LA¿ N T I F ? 'S G O V E R N M E N T G A U G AT IOI? W I T N E L S E o A* ii• Center fo hi sea:e Control ( CDC"> - Nat 1 Inst. 0ecu net S l e t y and Health, Cincinnati, Ohio He lib f••'.ahi■ .a1 arc c::pert testimony is sought. c. Genera1 EV 'x: '* id: : Any f a c t u a l k n o j l c d ge c f t he h i s t o ry of • . > abr ,;a¿ i herbieide spraying in U.S. •i. ' ' ni ineu in i l a d i n g , h a t n e t d i m i t e d to, \ .::cpos-. res and exp lonions; (2) registrar ion 2- í--D; .¿i,5-T with the Department -f Agri .cultura i any cuan” government agencies •-.r. y un? / o r all cf the Defendants j 19 61 y : 'r.e n t : ' 1 . ; t u a . ’. k n o w l e d g e c f t h e h i s t o r y .. h : r b ’ . .da •: p r e y i n g i n t-i:- TJ . d . end e l r o a . ' . ; Ircdadi. but net U n i t e d t o , (1) U -S . 11 .. . y 2 ' Apart .nngo and other pie .a _ iaide o lv. Ac"tt:’ ) .changas in the .is;:ratio a rer.uirfúauhs cf herbicides v;ifh 1.3. g -v . -1 ~.t ■and its agencies _neluding •■.ns-rdedge of .IPP.A, FIA,EPA, and QSKA; cud f.ay lactic Ipc cf industrial and other Vv.usr '■¡tpcj-iroc to 1, t-D, h. A, 5-T it the u.L. ;.n;' <•?.ú «1 * S^o .'.aewer and St•yple­ nentr.1 Answer cf Plaintiffs' to Cef end ant r 8 Interrogatory H e . 19 attached h cret' ai:f incorpcrated herein for all vu oses ..•a : events o:. occurrences which rh causation witness as nay be expected to give cry factual infernatien they nay have regar f'.u sul’-'octo outlined iu said Answer. •.iv.r.n Vi.:!'. Asses f;:.lvl;ií: of ^:;:)r;:ro to 2,4-D, 2 ,t ,5-T an „li, fC _il.-. r. t ,t., ;z M x.. i.•. 1 .-. knowledge in supper d i. the - l r . j .. . pert 'lastimón-. t Testirvny it ü'■ught in witness : personal and offic ca pac *i•'*v * ) Subiccv. Matt C:T A .4--: r•1: Bia.r¡: r 1 c::pc : ■a . 3 ..acli;.:;; P L0 * r--" C . <>!' . the .te • .... I i.„ 1 3; cir .vt. ..ci:.'. '3.-.. ■'.lev. c/\i /3 ' nr.:. -'-'¿i!. :d e.'.'.i both ’.lb 3. c. V. :; .r.. ■ •i. w :V .:<• .rr... - u '. t: . : v '__ >; .;rv: r .r 0 o .r pc je■a ■ "i i . !.y < . ..' r :. c:... .r.'c -h ■ i: the 3 1.. ; : i • , ■v c. i .1■::;.r rr :<• re.:: o . : : ; : i e c e ■" t _ / ¿ i c , 3 -’. c l i r 7 I-' r t t i r ; ■•■ti .0 » ; b o n r 0 d 'b ,r .:’ •••,i dn' ~'rio:r -.3. Crider: eri A 1 Q H Q & 9 UO jL .XW .. > .\i * : if •• .. -•-• : . •.•' . •.:.:-„,>i'■■; ;.ii;'^r ^'\';'•■:•■..^,'I EPA, Research and Development*^Health and ^ Environmental\EiTiecti^ProEild^for; Te Penta,. f 03 ga C r i t e r i a ; add:;: Ohio 45248 EPA, R e s - a r c h a n d ; 0 e v .d l d p m e n t- s lf e a b i^ Qua 1 i t y f C r& pei^^ n ared- f o t . O f f i c e : o f ‘¿hie ie^ kRe gu la iiio n s a n d S t a n d a r d s ¿ ^ b j ^ t S d l ’E ^ / C r i t e r i a a n d A e s e s s m e n tS .O f f I c e ,;, C i n c i O h i o A5 24S $ J u l y cV * EPA, R e s e a r c h a n d D e v e l o p m e n t ^ D i o x i n s In cu strial Ci.acinnat A copy of th e s e d o c u m e n t s i i; a t t a c E n v iro n m en tal R eseari 1' \ .jL'?PL£M£NTA7j ANSWER TO INTERROG ATORY No. 10 Plaintiffi'i notes preliminarily that. the extant Order on yrod icing feet witnesses states that fart witnesses are nc/ •. due unt-.il March 2, 1984. Towever, Plaintiffc nay call one or more of the following persons (or those freni various categories listed belo'-/) JC.* -siine of felci to testify as to rual kncxdedbe they may have, including: 1. Ranch Hand Personnel: Ttasa »persons v.lll testify to their tern-ledge c .: he Rani:!' Hand ' aeration.- Ranch Handers’ exposurcto Agent Orange, ard/cr b*.sr.iici.e-e relating to the spray- .j. testing, and effects of Age:.:L*. Orange on ’vjniar.c. 2. Uzitoaxs of the S. fened f . rrces: These persons may testify to the ci rcjrasfencfi3 and cerrfifeens s-rcroundmig tha spraying of Agent Grange.. 1. Persons present i . V5.at- 'am dm..; t.g the eoeposure period in question 19CI-1?'/ i, incluiln-j, hut not liraited to, military and parami:J.tary • rsonnel of Lha d., S., New Zealand and Australia,- who ha a icncv/ledge of the rpraying operations of the herb .das, the exposure of ;±:-. Plaintiffs' class, the hazards nrpanyir.g ary such 33:00.jure,’the Plaintiffs’ thcmsel and the Defend representatives present in Vietnam to oversee .die deliveries and spraying operations of tifa herbicides ■ hav manufactured. bosons t-.c.other --/iti. -'.'¡sir dsoonstrative and documentary evidence v:hc gave iesiirmvy fehich will form the substance of their testimony herein? a.t ti:e ERA Cancellation Keatings of 2,4,5-Y /1 i960) unde;. EZRA, including but not limit ■-, to: a. ■-b. - c. d. e. f. i 1. i 1M 'll • , • ■ iM.y obhM 11.•, • |.U ' W i ' l . .11 . .||| I , .-n.,>1 V'UU; li. l i UHO-/J , '.iliiMiM im , i-4lit i 1 is>,.-«il,f j r M!, ent|^*r-vi r;n r r , , ■ ■ rv ilv .'tu s li «ultvi-i.slJLriI- 1'ilfc m ' , q-'-uliir; control personnel, engin<. jtu (process, chemical, mechr.i-d.cai and/or safety). Any currant cr previous eiployee, contractor, subcontractor, .i.rt-hau.ee or private consultant of each of the Defendants or any other person ■■ho has factual inowiedge of any other manufacturi.' pirocesses which ci-uid reduce the risks of exposure to Agent Orange and/or other phc..ioxy herbicides being contaminated with dioxins end further reduce the- risk and lr.uard to human health of ■:iy su exoosure. ISC Inv OUT¥V'+" 0 *- ^ 15.. A ny p e r s o n w it h f a c t u a l k n o w le d g e id iroug h a n y c u r e p i le m io lc g ic a l s t u d io s o r o t h e r w is e u n d e rta k e n h g o v e rn m e n t, a n y p r i v a t e p u .b l.ic o r f o r e i g n cr. p o r t C o n g r e s s o r tin s g o v e rn m e n t o f .any n a t io n c o u e e m i. co m p o u n d s, 2 ,5 - D , 2 , 4 , 5 - T , d i o x i n s , o r r e l a t e d c iv r e l a t i n g t o t h e c r e a t i o n o f d i o x i n s , t h e c i e t e c t io : d a r g e r t o f d io K ir .s * e x p o s u r e , a n d / c r t h e t o x i c i t y f e t o t o . ; i c i i : y , t e r c t o g e - i c i l y , a c u t e a n d / o r c h r o n i* p l a n t s , anim a.'.a an d t h e human p o p u ..a t io n . ■ys, t e s t s , any s t a t e o r., t h e U i S . t h e c l lent, c a l r o n h e n o lr o f d i o x i n s , tine c a r c in o g e n ic it y , e ffe c ts .;i 16 A n y and a l l p e r s o n s l i s t e d y A la s t a ir . 2 ,4 - D , d id H e r/, i t s V ). i n T h e C h e m ic a l S c y t h e £3 h a v in g . f a c t u a l Jcncfr.’l&dcfe r e g a r d in g 2 , 4 . ! ; ' c o n ta m in a n t d i e i n s . nun p -ctv• A3;» worJ. e - e x : , 'i >•—i f v it' c : r ! r r ^ ,>'!• t' - r>*,]v-v,xlartf 1925 w h ic h .i'Ciital.j/.,;*. o f i i . - . j . ^.oci.v’V'. - torso.. . .pobi .ccc f l l c a s i n : 2 ; 4 , 5-T , e v id e n c e in d u ;c t r i a r i n g ■ .ries o r d i s e a s e s a t t h e T . 2 , 4 - D , P h e n o l , p u c k a g i: y . a n d / c r t r a :is g o r a t i o n p ic . .c s o f t h e D e fe n d a n ts. d a l l o ■ r u r d o r ...ic>: w orJur.'s c c r t o a i s h t i a n '■ ■ he b rid a n t:r. who c d :.' cd r e l a v a n t o c c u p a t i o n a l e r e l e v a n t '.c..;.!, ja t io * ,1 : r u r i c r a r c , ' o r d i s e a s e s a ru -," - • >.,. ' .* ,, d .in A n s w - r ) U o . 19 (s*. thr- ; - r y e v e n t '■ ..a r n n n t s •.!: X ) c u r e s .. i f 1 j f symptoms 1 7 ) above. 18. Ar.y 19 Airy an d a l l . mambo.rs o f t h e ü . S . H-.uea c f For :r e s e n t , t f i v e s u r r m it r o e on O v e r s i g h t s R e v ie w o f t i n E FA n o t i o n s 11933} a n d / o r a n y p e r s o n t o g e t h e r w i t h t h e : r d o c u m e n ta ry a n d d c . r n s t r a t i v e e v id e n c e g l.v.’n g L e r .t i:;o n y a t s a i d h e a rin g * (w liic h w i l l fo rm t h e s u b s t a n c e ci f t h e i r t e s t im o n y h e r e in ) or. t h e f a i l u r o f th e r t o t a k a prom pt an d a f f e c t i v ^ a c t i o n to b a n t h e p re r a c t io n o f 2 , 4 - D , 7 : , 4 . 5 - T , an d i t s c o n ta m in a n t d i o x i n s . 20. Any and. a l l p e r r o n s h ■ r - . 'ir j k n o w le d g e o f r e l e v a n t i a c t s r e g a r d in g t h e f i n a n c i a l s t a t u s o f t h e D e fe n d a n ts and t h e i r a b i l i t y t o r e s p o n d i n p u n i t i v o d am ag es, i n c l u d i n g , b u t n o t l i m i t e d t o , t h e i r p a s t ., p r e s e n t , and f u t u r e p r o f i t s an d e a r n i n g s i n t h e U n it e d S t a t e s •••nd a b ro a d s i n c e 1925 th r o u g h an d i n c l u d i n g t h e p r e s e n t fro m th e s o l e o f t h e p r o d u c t s made t h e b a s i s o f t h i s l a w s u i t , i . e . , 2 , 4 - D , 2 , 4 , 5 - T , p h e n o y * h e r b i c i d e s an d t iia r e l e v a n t h e r b i c i d e m a rk e t- 21. A n y an d a l l p e r s o n s h a v in g Icnow ledge o f r e l e v a n t f a c t s r e g a r d in g t h e o w n e rs h ip i n t e r e s t s o f t h e D e fe n d a n t s a n d t h e i r s '- i i i t y t o re s p o n d i n p u n i t i v e d a m a g e s, i n c l u d i n g , b u t n o t l i m i t e d t o , d e f e n d a n t s 1 d a n .-.o tic and. f o r e i g n s u b s i d i a r i e s , j o i n t v e n t u r e r : : , l i c e n s i n g a g r e e m e n ts , a n d / o r o t h e r p u b l i c o r p r i v a t e c o r p o r a t i o n s .'n t± i. s . an d .-¿broad, i n 'w hich t h e s e d e f e n d a n t s own a s u b sta n t.-..a i f i n a n c i a l i n t e r e s t s i n c e 1925. th r o u g h an d i n c l u d i n g t h e p re se n t. r *3 ft t ÙUi0 y /TV 22. Any and ail persons listed by Plaintiffs' in both original av.d amended witness lists, as escort witness (medical, scientific or causation) , government witness, government causation witness, defendants' employees and/or related personnel and/or any vlhncsses listed by all Defendants, may be called at time of trial to present factual inCotraafcicn as to any issue involved in this case. 23. Any and all members of ¡die scientific and/or medical car»tunity oho have knowledge of reliant, facts, including information cn aiy*of ¡/he previously 1.later' subjects but net limited to: David Kriebel, Ph.IJ. b. Dr. Alan Pcrend c.. Dr. Paul Gcldmanr., EAtf d. Dr. C. Rar-po e. Dr. Oettal, FA2? f. Dr. E. E.. MoDc:.nol.l g- Dr. K. S. Khiora u Alvin Pû j Mar:ilyu Pingerhut At:Y anf3 all persons wiio 1- r> factual irtc individuel representative Plaintiff's -la. r limited to, the folic/,-:Lng: a. Any end all medical persens who have treated and/or tested tee Plaintiffs’ for injuries, diseases a n d ./ cr related physical arc scestional tiers which resulted freer. Plaintiffs’ errpesure to Agent Orange, and/c phenoxy herbicides, their constituents, secondary by-products, wastes,residuals and. co-:hrnirs.:-::3. b. Any and all hospital personr el where Plaintiffs have been confined for 'treatment relating to their exposure to Defendants’ products in Vietnam. c. Any and all persons with knowledge of the eccnanic losses, psychological and/or intangible damages sustained by your Plai-ntiffs as a result of their injuries and diseases resulting from tl.eir exposure to Defendants' products in Vietnam. d. Any and all perrons -with knowledge of the past, present and/or future economic losses your Plaintiffs have or will sustain in the future as r. result of their loss of wage earnings ana or wages earning capacity resulting from the injuries and diseases made the basis of this lawsuit vbich were caused by Plaintiffs exposure to Defendants' product,s in Vietnam. Off i, U >7 -13- g. Any end all persons with krewledge of pact, present nd/or future reasonable and necessary costs of doctors, hospitals, nursery care, medical equipment, drugs, and any other related medical services rendered or to he rendered in the future to Plaintiffs as a result of their injuries aid disease resisting from their exposure to Defendants1 products in Vietnam. fey and all persons with knowledge of the physical i'isfinurement (past and present), ph.ysical and méritai ïrrrpairmint (past and present), physical pain (past and present) art* mental anguish (pest an present) which Plaintiffs have sustained as a result ci their e:qposure to Defendants * products in ‘'letnam and which in reasonable probability Plaintiffs will continue to oust:'.in for an indefinite time into the future far beyond the date of inis trial. respect!rily submitted, 1r.c.t.to lv. Henderson, Esquire Allison Pettiette. Esquire iEErlFIOVLE 0? SEhvtAi hereby certify that a true or.d correct copy of the foregoing Supylsnert to Plaintiff’s interrogatories were mailed Federal Express to hr. Wii.-iun Krohley, Kelley, D::yc & Warner., ifr. Gene Locks, Plaintiffs1 Haragement Ccexr.ittse Agent Orange Office, wuth copies to personally serve the remaining Defendants at the vir.esday depositions and ¿Ms. Nancy Petrillr., j.f. District Clerk, tf.S. Courtitou.ee, 225 Cadmun Plaza, Brooklyn, New York 11201 :±iis 2u’di day of February, ISC i. ^ ) i :Alison Pettiette l.i:> 1 C n CJg A P hAIN T ZF F 1S GOVERNMENT CAUSATITI! WITNESSES I Donald Earne3 A. _____ EP A a U n . si h .1ngt on , D . l - . B. Beth factual and expert testimony is sought. C. General Events Fre-lDül: Any factual knowledge of the history h e r bicidc spraying in U.S . and abroad including, but not limited to, C D indust:-; exposures and explosions; (2) •registration 2,4-L, 2,4,5-T with the Department of Agri culture and any other government agencies any and/or all of the Defendants; 13 Si-present: Any factual knowledge of the history o herbicide spraying ir. the U .S . and abr.au; including, but not limited to, (1) U.S. military use of Agent Orange and other pie herbicides i- Vietnam; ( 2 ) changes in f. e gi3traticn requirements of herbicides w t i U.S. government and its agencies including knowledge of FIFE A, FDA.EPA, and 0S1IA; and an}- knowledge industrial and other hum a: exposures to 2,4-h, 2,4,5-T in the U.S. ana r o ae ; See Answer and Supplemental Answer of Plaintiffs' im Tea end ant s ’ Interrogatory No. 19 at-f ached he-.•etc and incorporated herein for all pur­ poses j o : o v a ::.c s c.r occurrences which ther causation witner ico may be expected to givo any factual information they may have regar the subjects outlined in said Answer. Human disk Assessment of Exposure to 2,4-D, 2,4,5-T at dioxins and any factual knowledge ir supper thereof. E t ' err: T e s t i m o n y 1; 2 ) Tes t i r any i n sough:; rap a c i t y . Subject in witr.LSs 1 p e r s o n a l and offi M atter -',4-^, 2 ,'■ ,5•-T , TCnr,'s nnd dioxins; Agc-c 0 L/17 (a-.ro Whitt, Blue, Pink, Greta, and Pu 1ST - fz y and related chloroplienols and human risk assessment regarding exposure, including, but not limited to, one or more of the following sub set areas: a) Chora .stry, Biochemistry b' l-ieuufactvre and/or 'Production c) Toxicity d) Modes of Human Exposure e) Fate in the Environment (Humans, Plants, Animals) f) .State of Art/State of Medical and Gcienti literature 2} 1} 20 g) Epidemiol"gy/Brostatisties 1) 1, 3) h) Plant Physiology/Studies Animal Physiology/Studios Er.m.tn Stedies rlento, animals, humans Cancer II idemiolog-; Reproductive Epidemiology Adverse Health Eff :cts wi t n s o c w i 11 be aske.d opinions about both published an d /o• o u- going studies. wi tne: will bo asked opinions about any studie or rosearch w it n e s s has personally performs d or r. ctuclly pert ’tip cted in. w i . less will 2 • ' asked opinions about other governmental studies. witness i a expected to review the following documents prior to giving testimony: Coe, ETA, Jleccaroh ad Development , Ur.al»*h )i ox ir.s for tv: ■-Lr 'IS. r ■ ■■ A-ir’0 u ..lity , Planning 'and. "Ctanl.ar? _r Df e r e d b the Env i.5. ?.na L r.c e s sm Office, > 4 5 2 4 o ( July i 9 4 O X o 101 EPA, Research and development, il alti; arici Environmental Effects 1' le for; Tot Penta, and Hexaclilorodi je.izo-p-dio/.ins for the Office of Eolio Waste and Emer­ gency Response, by the En .irontieV tai Criteria and Assessment C .'fice, Cincin Ohio 45248 (June 1983). EPA, Research and Development, /..'.bient Water Quality Criteria for 2,3 ,3 TODD, pre pared for Office of Watc Regu Ratio-.s and Standards, by the Er .rönnen: to *. Criteria and Assessment Tice, Cincin Ohio 4524C (July 1933) . T7 copy of th Ressac ch and Development, eicxins, Inclusi ial Environmental Research Cr.sir.ncti , Ohio (19 7 8). dnenroontr ?.s n t t n ah ad . 1S102 c f expose; contaminated human ‘ciC'COiT ; .ts or any ai conduct arts (acts n fact Tovemment rcosure to <3 1 A. ^ 0 4 -L0- ■'Irs; r Any current or previous employee, contractor, s’abcontractor, in-house or private consultant of each of the Defendants or arty other person who has factual knowledge of how dioxins work upon plants, animals, and/or humans. Any current or previous employee, contractor, subcontract o r , in-house or private consultant of each of the Deft ■\dants or ear other person who has factoal knowledge of any static ics concerning the effects of dioxins upon plants , animal's, .id/or numans. Any current or previous ernpiovea, contractor, su.bcontactor, in-house or private consul tar of each of the Defendant? or any other person including, but ¿. c limited to, ma;ibers of .2PA and other governmental agencies, who has factual knowledge of the • following incidents: a. Love Canal b. Times Beach, iMissouii c. Sevesco, Italy BASF {1551, l.) 1 - DadiscliC: in derrnany) o Product.' tn ¡.iisbans and/or explosions since 1925 at ary of tils pLv .to of ary c:i the Defendants manufacturing, TC". 2,4~D, 2,4,5-? phenol, chlorine, acetic acid, benzene, sodium hydroxide, .potassium 1.ydrc3d.de, and/or Agent Orange, including mishaps in the packagilrg, and transporting of the Defendants5 products to the U. S. Armed. Forces bases for eventual, shipment to Vietnam. Spraying of Vietnam frcr.i 1961-1972. Any current or previous employee, contractor, subcontractor, in-home cr private consultant of each of the Defendants or any other person rhc has factual knowledge of any surveys, tests, epidemiological studies of any kind relating to the effects of exposure to Agent Grange, 2,4-D, 2,4,5-T cr any constituent thereof including -the secondary by-prcduct known as dioxins. Ary person with factual knowledge of hew decisions are made within the United States government, particularly the decision to use and to continue to use phenoxy herbicides in Vietnam, particularly agent Grange; any person with, factual knowledge of government procurement co: bracts and tlr. invitation to bidder?:, particularly those persons who negotiated tine government contracts for all phenoxy herbicio'..: {agents white, blue, :uirplr, pin!;, green, orange I and II’ with the individual defendants repre­ sentatives between 1961-1972. ■f o * Jl ^ JL -11- 22 . Any and all persons listed by Plaintiffs' in both original and amended witness lists, as expert witness (metical, scientific or causation) , government witness, government causation witness, defendants; employees and/or related personr l and/or any witnesse listed by all Defendants, may L.e called at time of trial to present factual information as to any issue involved in this care. ;3. toy and all members of the scientific and/or medical conmunity wiio iiave knowledge of relevant facts, including information on any of the previously 1. sted subjects in this Answer, including buiL no't limited to: a. David Kriebsi, Ph.D. b. Dr. Alan Po..me c. Dr. Pau.' Goldnsito., BASF d. Dr. C. huppe e. Dr. Oettel, EfiSF c. Dr. B. S. McDonnell X g- Dr. K . C . Khiere h. Alv.in Ain i. Marilyn Fingerhut 24. ( Any and all percent w h h a v e iactu; 1 Icnowledge.concerning the 's damages, including, ¡out individual representative P.l .\intif: • not limited to, die following: a. Any and oil méditai persons who nave examined, observed, treattd ard/or tasted the Plaintiffs' for injuries, diseases and/or related physical and emotional conditions which resulted from Plaintiffs"' exposure to Agent Orange, and/or phanoxy herbicides, their constituents, secondary by-products, wastes, residuals and cor-tsininants. b. Any and air hospital personnel where Plaintiffs have been confined for treatment relating to their exposure to Defendants products in Vietnam. c. Any and all persons with hxcwledge of the economic losses, psychological and/or intangible damages sustained by your Plaintiffs as ¿: iasu.lt of their injuries and diseases resui from, their e:qposure tc Defendants' products in Vietnam. d. t o y and all persons with, knowledge of the past, present and /-syfuture scenario losses your Plaintiffs have or will sustain in the future m a result of. their loss of wage earnings and./or* wages earning capacity resulting from the injuries and dice, made the basis cf thi:: lawsuit which were caused by Plaint! y.i eoxesura to Defendants' products in Vietnam. 13106 -13- r e. f. Any and ail persons with iuiowledge of past prand/or future reasonable and necessary cos' s o doctors, hospitals, nursery care, medical 'jui drugs, and any c ther related medical serv. ;s or to La rendered in the future to Plaint: _.is result of their injuries and disease resulting their exposure to Defendants1 products in Viet red t Any and ail persons with knowledge of the pays, disfigurement (past and present), physical and impairment (past and present;, physical p .in (■ present) and mental anguish (past and present) Plaintiffs have sustained as a result of their to Defendants' products in Vietnam and which i: reasonable probability Plaintiffs will continue sustain for an indefinite time into the fnoire beyond the date of this trial. jsure Respectfully sv ted, T o m a s Vi. Hende:: Allison Pettiett n, Esquire Esquire al and .h CERTIFICATE OF SERVICE I hereby certify that a true and correct copy of the re ring Supplement to Plaintiff he Interrogatories were mailed Federal E ess to Mr. William Krchiey, Kell. '/, Drye & Warren, Mr. Gene locks, Pia. :iff.- ' Imagement Ccranittes Agor t Orange Office, with ropiv. .3 to persona ,.y serve the remai'•ling Defendants at the Tuesday depositions end Ms. Nane PctrilL: TJ.S. District Clerk, U.S. Courthouse, 225 Cabman Plaza, Brooklyn New York 11201 this 20tli day of February, 1904 Allison Pettiette 13107 -14- »'í ■v?v '■■v/fcvM: ¡usinai rl'V/ironiMenia! r!n ).-.rniorv OH *•'5? ‘:;»vtronm. :t«ii Pm^jcfion •iqcncv i*=0'TB8N •?tíS-ir:fiA “pee*. a •* Ü10X3J1 r <* 1 J /■ N .<0 , * PLAINTIFF'S Gt'VERNMJiK” CAUSATION WITNESSES I Umberto Saffiotti National Cancar Institute, Washington, D.C. B. Both factual and expert testimony is sought. C. General Event.; Pro-1961: Any factual knowledge of the history of herbicide spraying in U.S. and abroad; including, but not United to, (1) industrial exposures and explosions; (2 ) registration oi 2,4-D, 2,4,5"? with the Department of Agri­ culture end «any other government agencies by any and/cr all of the Defendants; 19 C1-; .as ent: ..my fat tuc?. knowledge of the history of herbicide -ryraying in the U.S. and abro;-. 1; including. Luc tot limited to : •(!) U.S. military vis ’ of Agent Orange and ether when herbicides in Vietnam; 2*. changes ia the r ._ gist-ration requirements of herbicides with the U.S. government and it a agencies including knowledge of FI FRA, VDA, EPA, and OS HA; and (.3) any knowledge •f industrial and other human exposures t ; 2,4-D, 2,4,5-T in the U.S. end abree ; See Answer and Supplemental Answer of Plaintiffs' t o Defendants' Interrogatory No. 19 attached hereto ._nd incorporated herein for all pur­ poses re: events or occurrences which these causation witnesses may be expected to give any factual information they may have regarding the cub;] secs outlined in said Answer. I nan Risk Assessment of Exposure to 2,4-D, 2,4,5-7 and d ioxinr, and any factual knowledge in support thereoi. D. Expert Testimony 1.) Testimony is sought in wit no o s ’ personal and official opacity. 2) Subject M a t c.:: , 2,4-D, 2,4,:"-?, TCDD’s and dioxins; Agent Crang I/II (also White, Blue, Pink, Green, an. Purple 13109 t. •\v:*- .<**■ ■ and related chlorophenole and huaan risk assessment regarding exposure, including, but not Unit ed to, one cr more of the following subject areas: a) Chemistry ¿’ 'Biochemistry b Manufacture and/or Productitm •'/ Toxicity A) Modes of Human Exposure e} i?ace in the Environment (Humans. Plants, Animals) r\ State of Art/State of Medical and Sclent if Literature 1) 2) 3; Plant Physiology/Studies inAn.a! Physiology/Studies Hu an b ::abio s Epidemiology /Bis at ati st ics 3.) 2) 1) Plants, ani: sis, humane Cancer Epidemiology Reproductive Epidemiology Adverse Health Affects 3) / "os, witness will be ashed opinions about both published and/or on-going studies. ') Yes, witness will be asked opinions-about any studio; or research witness '.'.as porsrnally pa rformod or actually participated in. 5) Yes, witness will be asked opinions about other go'.’ernmeutcl studi 6) Yes, witness is expected to review the following documents prior to giving testimony^ See, EPA, Research and Development, Health Assessment Do cum ent on- 'Dio >rins for the Offices of Air Duality, Planning ‘and iiandcirdr. ,’*r"pVepare¿Pby the Environmental Criteria and As sensei Office, Cincinnati, Ohio 45248 ( j-.-.lv -- •V*. .A®., 10 I ! •••~ / T \ •• v , EPA Research and Development, Health and Environmental Effects Profile for; Tet Renta, and .Ucxacli ‘orodibenzo-p-dioxins for the Office of Solid Waste and Ever gency Response, by the Environmental Criteria and Assessment Office, Cincin Ohio 45248 (June. 1983). Research and Development, Ambient Water Quality Criteria for 2,3,7,3 TCiiD, are pared for Office of Water Regulations and S ta nd ar ds , by the Environmental Criteria and Assessment Office, Cincir. Ohio A 5248 (July 1583). iZPAj Research and Development, Dioxi. s , lad \strial Duvironr-antal Research Cincinnati, Ohio (1573). A copy o f •throe documents is attached. -; V ... * >A "-r.-y Wi- #1 },:-i •.r ;• '.Air- ¿Vv, ■ ':: i i.Z'A ,jt \,:yr: SUPPLEMENTS!- ANSWER TO DTrERTOGATORY KO. IS Plaintiffs note preliminarily th-.t the extant Order cn producing fact witnesses states diet fact witnesses are not due ur.til Ms :ch 2, 1984. However, Plaintiffs may call one or more of the following parsons (or there frou varieus categories listed ixûow) at time of trial to testify as to factual -knewiadge they may have, including: 1. Ranch Hand Personnel: Tiieta persons will testify to their knowledge of the Ranch K a m Operation, Rancii Harders* exposure to Agent Orange, and/or knowledge relating to the spraying, testing, and effects of Agent Orange on humane, 2 Marker.’ of the G, S. A:me«d heroes; These persons may testify ho the circumstances and conditions surrounding tiie spraying of Agent Orange. 3. Person:; prenant in Vietnam daring tire exposure period in question 1S61-1D72, including, but rut limited to, military and paramilitary perr rnnel cf t::e U. S., New Zealand and Australia, who have jmowledgo cf the spraying operations of the herbicides, the exposure of tlie Plaintiffs‘ class, the hazards accompanying any such exposure, the Plaintiffs’ themselves, and the te fendant cnmcrr.y representatives present in Vietnam to oversee the deliveries and spraying operations of the herbicides they manufactured. i. ::arsons together wit!-: their demonstrative and docunentary evidence who gave testimony (which will form the substance cf their testimony herein) at the EPA Cancellation Hearings o¿ 2,4,5-T (1979-1980) under F1THA, including but not limited to: a. Dr. Roy Albert; i- 'v. Dr-. K . Diane Courtney _ c. Robert K. Baughman, Fh.D. d. Dr. Oi av Axeleon e. Dr. Reuate Kimbrough f D r . Dawn G. Goodman g. Dr. Kirk T. Kitchi.ii h. Dr. Ronald Thanos i. Dr. Rainer Prentzel-Beyma j. Dr. Matthew Pfccslson, Harvard .3 -9- 1. K- Major iJLvin Young 1. D r . Itocbiev Bcvey in. Kenneth V. Themein n. David T. ifazzelli o. Dr. Michael Gross p. Dr. Renee Stringiiam r. Dr. Van Miller o. Any current cr previous employee, contractor, subcontractor, in-house cr private consultant of each of" the Defendants or any other person who lias knowledge of the manufacturing processes, chem.ic._ry, occupational expo.sure and/or toxi ity of 2,4~D and/or 2,4,5-T or related chlorcphenols; including, but not limited to, laborers?. operators; supervisors; contract administrators; quality control personnel; engineers {process, chemical, ¡nscnanical and/or safety) . G. Any current cr previous employeef contractor, subcontractor, in-house or private consultant of each of the Defendants or any other person who has knowledge cf the possihf means of prephiaciis protection frem the hazards of exposure; includin';, ;.rt not limited to, laborers, operators, supervisor: contract administrators, quality control personnel, engineers (process, chemical, rechanical and/or safety). Any cur;.ant or previous employee, contractor, subcontractor, in-house or private consultant cf each of the Defendants or any other person who has knowledge of'the means to warn those wiio might he e:xo.?cc to use cf the herbicides in question, particularly Agent Orange, ’deluding, but not limited to, laborers, operators, supcrvr.scrs, contract administrators, quality control personnel, engineers (process, chemical, mechanical and/or safety}. 8. Any current or provi.u.s employe.';, contractor, subcontractor, irr-house or private consultant cf each of the Defendants or any other person who has factual Ijxwledge of any other manufacturing processes which could reduce the risks of exposure to Agent Orange and/or othr.r pher.oxy herbicides being contaminated with dioxins and further reduce the risk and hazard to human i valth of any such exposure., 9. Any current or previous employee, contractor, subcontractor, in-heuse or private consultant of each of the Defendants or any other person who has factual knowledge of conspiratorial conduct of the Defendants, individually and/or duplicative efforts (acts which ;-ro parallel in nature) which tended to or did in fact result In misleading the public and the United States government frezn gaining knew)edge of the dangers .attendant frem exposure to Agent Orange and other phenony herbicides. 13113 -10- 'r~^. 15. Any person with factual knowledge through any surveys., ter/ epidemiological studies or otherwise undertaken by any stato government, any private public or foreign oo. poration, the U. 5. Congress or the g. /eminent of any nation concerning the chemical compounds, 2,5-D, 2,4,5-T, dioxins, or related chlorcnhenols relating tc the creation of dioxins, the detection of dioxins, the dangers of dioxins* exposure, and/or tint's toxicity, carcinogenicity, fetctoxicity, teratcgcrdc.ity, acute and/or chronic effect./ on 10. fny current c..: previous erployco, contractor, sufcccntractor, inr-housa or private consultant of each of the Defendants or . any other person who has factual knowledge of how dic:cins work upon plants, animals, ¿nd/or humane. 11. Any current or previous arnplcyea, contractor, subcontractor, in-house or private conruitant of each of the Defendants or any other person cho lias factual knowledge of any statistic/ concerning the effects of dioxins upon plants, animals, and/or humans... 12. Any current or previous cr"-loyea. contractor, suocontactor, in-licuse or private consultant o'- each of the Defendants or any other parser, inaiming, but not .inited tc, members of SPA and ot'or government.?r agencies v/h^ h?.r; factual knowledge of the a. Love tanal . fc. Times Beach, Missouri c. Sevesco, Italy d. BASF {1953, ?.954 Badir-;ha in Genrar. . v . Production rnisbarn ar.d/or explosions since 1925 at any of the plants of any cf the Defendants mam-factiiring, TCP, 2,4-D, 2,4,5-T phenol, chlorine, acetic .cid, ben2 ena, sodium hydroxide, potassium hydroxide, and/or Agent Orar.ge, including mishaps ir. the packaging, and trar porting of the Defendants' products to tl:-i U. .c. Armed Faroe; bacon for eventual shipment to Vietnam. f. Spraying o.': Vietnam from 1SQ-1972. 13 Any current or previous onployee, contractor, svboor.tractor, in-hc'.ise cr private consultant of each of the Defendants or any other perron who has factual knowledge of any surveys, tests, epideadolcgical studies of any kind relating to the effects of exposure to Agent Orange, 2,4-D, 2,4,5-T or any constituent thereof including the secc./dary by-product known as dioxins. o •« ' . 14. Any parson with factual Imowlcdge cf how decisions are made id.thin the United States government, particularly the decision to use and to continue to use phenoxv herbicides ir Vietnam: : ■ , ft ‘ ■ 22. Any and all perse.is listed by Plaintiffs* in both original and amended witness lists, as expert witness (medical, scientific or causation), government witness, government causation witness, defendants1 employees and/or related personam . and/or any witnesses • listed by all Defendants, may be called at tuna of trial to present factual information as to any issue involved in tliis case. 23. Any and all members of the scientific and/or medical carenuuity who have Imowledge of relevant facts,, including information on any f t h e previously listed subjects in this Answer, including, but not limited to: a. David Kriebel, Fh.D. b. Dr. Alan Poland c. Dr. Paul Goldmann, BASF d. 'Dr. C. Eappo e. Dr. Gettel, BASF f. Dr. E. E. McDonnell g. Dr. K. S. Khiera h. Alvin Aim i. Marilyn Fingeriet 24. Any and all persorn woo ha i f. ..rtu; 1 knowledge concerning the individual representative Plaintiff' •s carnages, including, but not limited to, the following: a. Any and all medical persons who have examined, observed, treated and/or tested the Plaintiffs’ for injuries, diseases erd/or related physical and ecaticnai ’conditions which recited from Plaintiffs • exposure to Agent Grange, and/or phenoxy herbicides, their constituents, secondary by-products, wastes,, residuals and contaminants. b. Any and all hospital personnel where Plaintiffs have been confined for treatment relating to their exposure to Defendants’ products in Vietnan. c. Any 'and all terrors with knowledge of -the economic losses, psychological and/or intangible damages sustained by your Plaintiffs as a result of tlieir injuries and diseases resulting from their exposure to Defendants’ products in Vietnam. d. Any and all persons with knowledge of the past, present and/or future economic losses your Plaintiffs have or will sustain in the future as a result of their loss of wage earnings ancl'or wages earning capacity resulting from tin injuries and diseases made the basin of this lawsuit which were caused by Plaintiffs exposure to Defendants' products in Vietnam. ’rv ^ 1 -1 -13- Industrial Environmental i:. Unitoci St.'tfii; Enviromnor.mi Protect:» .1 A'jijncv Landratruy Cinc.r-n;.:i O H -JE2GS Hccmrch & Doviiinamon; ■yíTJirp¡ *fa Y ■■'A i-Srf'-? S . ’ V. ' ' • ’■ir'""■»■ -1 í ^•>:V\í£^’ ; *3*1' • • •*t*«r ./VA. „ ^ •/-'v X. \ j•* •• i 1/ . 1 _ ^ •?^ ^ 'y * ¿ r 1^ ->W ■-ÿ»»*.«•>•' '% * • ,V . ‘i Î\ ■í ! •^j \ ? • * ■, '■* • * T. ■'■'tip* Tf*\ ; W ; J À i \ V.. r 13116 o b o i•¿ ■■alat.od c 1 e r api on o 3.s •T.ti' •yV:;úo n v i n o.-Co.asmer.t ro.j-ar ú in£ e;:po :.\ire > i.uclv. JlV . ” noc 1 luíi i c l o , o Tito r e o £ -.i»i~i íi,'J.'.oraiz¡g s a b \ och a? a r c a r :; Jlienin ir- /Eiachor.ir,trv on liar.:: Jactrurc: a n d / o r »t o::ácií;-'T ;cs ■jr .iv.ir. a ti .. y. v c ~ :cc ae ir. íiho Ji-.vircnacnC (i'asnar.s . Áni.r'.lc) c1 ■ :j £ .r. i/ .:1 ¿ c £ y,~^/eaj. v.r■ dlant rV.yciology/3tud:lcs jt.r. i . - , ?h*- ¿ o *a£~ /¿tu. ±cs? •■‘ .Civlí.oo i, o- i o c á o p ll animáis . hit- c :r.:;;c” :p±¿ asiioicgy ..e 1:.- .lv\. 1.>ida1 .o..^C'/ 1/ 1. .: ..».* 'd Y :' . ■;: :•* .1.1. ¿i o < “ i ’ ; t 'd ..h /:! v 1 /*'■V OI. -¿o •• •a *- -k "X y -p ■• ; 'a s e a :.- ,:, . r; .ijJ i ;•• v ? i: . h » oprnuons a vout “■a ■■’ neo o har; ja r s o n a .il ~ -te n e d .va. be í:pin lorie ;■■ j. x.. i. i;i ‘ f. :ne: r:e~.■"•. :1 strudíe-; . ..•i re rj?T 77 ’ZO ^ ::e \-: o» t i l a f c l l c v l : : ^ -'.I'. *11 ¡i J\J.7t¿C..l"-- , hcs.'-.c.rch ord _ D a 1optaant-¿ 'lertl'd: A .i'r. c .t e i o a i - ¡ic c .u r r . e n t - - o r í 7) x o : : z n s o r r C lfrlc-cr;- o:'l__Air' d O á -litiy -, T 3. a n .n l n y 'an¡ " S E c .ú c T r . 'T d o ; nhc Env: p r e p a ra d by " ...................... '.aerial Críteria and AoS'-.c <•-•'"icini. -.trO Ohio 4 5 2 id 1£117 ? r. î ’. r y . v : i C c r.t av f i c v E : y fo r : ” v .w r .iv : i : n T . . „ n w : : t ; ; s ^ s D i s *;i.« •: C o n t r o .’. (CDC) s A t l a n t a , Gi o t f 1'■i y 1 o o o u 'ro o « .3 . r... -. cr*n 1 c A r -• ,-s * ••-*•. e I: ii3 . -1«1L 1*. >;; ■j i “î "ü i n 0 . : ; . a r d a .0. i 1»C r ■ »... no.i: liiuited i o , ; *•£ . .mil .'.ad « " V ' i o s i o n s ( ! . ) r é g i r .::: e t i o ; ■■ 11: t'io i;ej..a .: i<:■. c A g r 5V vu r . 1 \::y o.:ae:: gcvernr.cnr. 'r -?: icc 3 sii ci thn Défendant s ; î ’;• ' • ..... )Vjlr g . ;•:: r îi; •.::î:■ y . 1 ■ .b :'o a-d : oi .'.laite ; ;; ---; &: 0' y 1 .''l < .’. il V.e-'ir.;.-i ; (2 ) " ,!;:r.j,e s in. ch cl i_ _. OJ._ CS g v e r • rnj • r r . ; l ; , . ; L - -î: l.IT A A , FDA , Z P.;’. , and CSHA ; o u i 7 •end a c h e r hur.ar. - t rî s* ^ * r\ -* ^î ' • '*’ ì l"5 •' * v * ^ i - TC ' c l ” ir; !;ho U - ano ih::f;u *: .. • ;o •.r. .en. t*-Tr- \fs •'■ >î” • 0 S3 H ..- o *-*-^ ... V-L1im _• T o j . ?.:1Ca. ,z.vi î".U; :.ua 'ne W /T V J inr*.—.•- Cf Er■ ■orra ! }•..:.r:le /. flrlcx: *.> < ■ .1 1 7 . '.atv.a ;V' X*Clf)}T. 'O ■ ?C ^LJ».4t; i f f : 7 Ce .. ... i i 0 -> J. . a 11 a c n e c r e in f . a i l _ .1 r e n n e s o h i ■ C il £ Il t) £ Ct e d CG f; 'L' ny r.;ay iiav a. - c:z ■id A>.:.a e r . —i. /. ;. -Y— U , c •/ J. e d .9:c; i n c Eroert: Tosti:. ■.• . La ji :' l»*.»«!IXÎw. m es a ’ nn e n - il and î Irà, Green, o ff c a r ■o i t r ; ...." ..î, . . TC. i .:. . h i t n , JM1.il® , nn .1 .? a r ? . 13118 iJ '0 o o o o T-! \J vf ■»X .-4 X f'J rj rj sU ‘••i •. i T i f ; r -, r"> r*r 4 ! '* í-r C r’ < N ■J 0) O r i, •M 4J : ^ «:-; < ÍO •. 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P Pi ■>p J - i: - ■ ■ r.; r. £ • • v -.y ■ÿj O ; 1 r) :■ ! t., t:. r-1 .. i:P , c : :■■'■ i■ i . v¡ •< 4 . :j •) fin a a > f ■¡J■ Jrf ■ ' P! B ri -h ij fd. I ¿jJ ’a} r; h i¡ -3' ? s‘ •■'j-i- i!g t!Ei óí rc».:\ : O ’ f.' < -Î-* Æî -*» u > :J H >s. : -i\è ÍU V r: -<-! u,'.: ;i Uu'Hz, M ^ ii .r; r !’r-l il! Oy ' O. «-Ì fi fi ri c.' .. (■< (•j ,d o-i VJ . y r (■ ;-; •h: •■ ■! cl ; J g C-. S, B.• * M ï.| r-: 3î • i> U': n n a a k . i-îaj*::x il Lvie ? f o r r g i.- C-r,. ' -jûdr.oy i -/ v\Sy Iw'ùoL V . j f i c r e i r il. D e rid T . E t ' r \\ ' j. On L e. Kéciiac'' G'-O:;:'. V>- Dr.. Rencí: Z:tria ri-c .*# D r. Vax* M i l l e r Any corren!; c r c r o v i et»pic g or., r é f r a c t e r . 3Ucccntrr.cfcor, :jr„-i.:aj£s or p r ív e t e co-ncult/rr-: o f corn o f tir . D éfendants c r cïïi/ •'-•fcSiü-.rr carsou v;àc l«:s îitow led ça o f fh e ruerrfacuuriug y v 'c c ir x : -, d ie r f.o tr y . '••ccup^ûioru.il expcsrrsa a n ú /o r t c x i c i t y ri 2 , . - 1 ar..i,c:r ;:. -\, !1 '.: c. relaL ed ••àtloriyjdisrcln; iro.lrdiricj, ?.vit. ivj-t lim ite i! ~ -, 'ri: o . . y y : y c ;e ra fv .r o ; s r o s r tfUsors; cxrotraci a d d id s t r u lc r r , r r l l .y < .d r o i çarocnnr 1 ; engin-.:, jr s (prccnrt-;, Civroaical, ms;--iç. -al or ".or c a r f y ’ . nny cssci :vi. ; : n -•;. . roufr-to-Loi-. cvle" i..txacu cr, in ~ b c u se e r r e r ;i: c r. l u l f r i o. ' a a .il c £ t h e d ife u d a v é o c r any otbe.r y i - Los I t... led;:- -.r£ tu e ç c c c :d ln ireau.- o f :rrcrLÿ o r f i r c o c i _ l i e r •; . c c e o r d i c r r v : e x p o iu re ; :'n o ir c i .ry , voi v.-•i j.i ■r.r -, c.- .c.fo r a r r ;, -para ture.. ru p c ry f.o o rr, c o n t r a e > - '.ni i ce o r . • - u v r iity c e . i t r e l f.o re v u n o i, originaire» •p ro c s r ç c/::- : " r - ;rr .1 r. *.,Vt s a f e ty ) . Any cv-.r r _ . . çrr r. , o; ■ cia oint r or ;>:r. oufcorîfror..:or *. c .. vii' * c. ;-ho .1amendants cr i l Xvv.ro: ' o ; :"lrr'-' <: V /.rey • .¡r fl i r .•’ foc va qucctior., r ie l . p e r t ie f r .1 * .. !. -f.’. lir.g, but :.ci: 11" itsd fo , 'f- •». . V.. ve;orre., conorrct adm inisfrators, 1: forero q u elite/ c.; . ■..2. rl.î:::na1 •.- gir.sors fococ C . ¿ '9¡ O.rrTTljLC"^j. :,-'.iv< ;.ief :anj.cri. eriG • in y cu rt nu cr y . „vi e s erg ' o y c r , r: ./.rrr .c r, sabrr/utr* c i c c , in-Loro;a c : r -fo n t v rr'orrltcn': e t r-;icii r i ti a D e fe r ía n te or any r ib e r ci-vscr. r'-.; car; fo c f r a i r o e r i r i r e £ any o tb e r ¡-.vr.v.ufcrc-- \r g or. •;or" ; . . . c i <*o M r o i . :c. •' :r r i vs o f or- ov . i.o ' ~e. f. r ' c c io rr : c i a r •; no .c: •• Ir-v.b-' .cio-'; io.i.Dg .jontesai"weed ‘i l i ' :c ' lo : ¿r. '. .'. " . ’- : ....i..... ■ tir: :.r rîr c.r •" Iv o crd t e héron hc o f or-- s ' i •• v r or . . Any e r r e r r . . - ; re v i eue et: o lc . r i r , c o n t r a - : t e r , s u b c o n tr a c f o r f i n - f o u e e ?•>.' .orirrvor r . : r t . i ;yy •*•£ e e - f c i f i e D o fe o d a n fr c :: ■ ofl'or : — ■-,;h' c o n c n ir a fo r io .f -:ond :r:f. ci the . i'..ipiicahrvo offerfs ',:.rt.: v£ :£.■" ro.j/: a;: ■ r o r a ii.o i i; .r' - '..:. "■'.ici - r r.' t o o r cij.d i n f o r t i ' ■ icicr-f.::./ • v Le " r i f e d S i r t e s e o v r m o e u t v,;l Í ;■f,i g fr. . ..ce o f ■' ; ' r ; ' :"•• ••vffc.i lr c l: frem ;yxcc .r : : •:/, (. *r. : C Ç.r.d O..’c .... ■ ' o rb J :1: oc. 13121 tey .nrrcnt or c>" > o-ìv.pleyeo, oocrircctory subcontrect*: r, in-hcrro or priant:: co eui ;ino of o-rii of ih* bedrrdants or c-ny ocrer persevi v;ììo io forbo;! h.^iadgc of how òL?::ins vrork unc.o plc/ocs, zrJx iC ls, ard/or 'amena.. hivy c m r e n i or prend.',un acployes, cor:Portar, sufcccntraotor, 3iv-V:.ouii3 c.: oriveto rs;:ltr.v:c or eco;', of òhe Défendants or ry ofiher oerrcn v;l:o hoc lacerai ¡y.rfo:..nègo of any r.tati.st.ica coRCGming tire offerte of dicrios i:pon niants, aniir-als, r.v:i/or bimano. hny carrent or previe ■ 3;;i viso, contraetor, n-i-acnteotc-r, in-hcuco or privatr c:.r:rtil" .t f cren of dio Dcfoni-uiits or . .7 irvi’:vè ..or ».vcìrioLr; of; EFi\ r 1 ether perse.. iùcruôh'Vî. 'or other gevarnnenfal r jorréo,, re òro ÓY^iix . '.ocvlnch-e .-f tho foilo/i ’¿a ór rieten?;:;; a. Leva e m i b, 'fret He:17 e. re. birw X ly ,. ’*ì^ .**•* • •*'. 1e-;..;. ■"-‘l C? O** f o r ■i r r v. .7Ó..morng, ad?, i... r’.f .ri..r, tic Culaco. tediu» lvte feto, cnd/or : jrrt Jronge, inci'adirg ring., rei rmrpcriin;; cf tha Défendants' . .frac ’ orco- rare:; f;r eventual nhipssnt ir,e. Möi,~iT.: ilnv .serrar:'*. er previe*.-s arploy-eo, e w;tr..,ctor.. cube ;ntre ter.. ;r irosa rv p;;r;-.fo n ;7Ì':=v.t of croi: cf tre iteferfarvtr or eny ni '7 -'crccv. vivo i ; ferirei irrefeeder of r: y evzvoys, tests.. fole-":'.■••’I r: udir : eh ••■ • ;•■'■•. , riur-le. oivi-i, ■:io: . oraree ï ¡.. : r"i f '•'•ho irli- '":*ol *'.ofend:'nt;; rep*--•.....7 ;.7"er 'leteroen.óih .: 7; Any person with factual h..owlcdga thrtu nu surveys.- tests, ó*pidc.iiioic gical cfco: :vr;v . c i :nr-h :;■ undertaken by ur.y state govar-.rant, y.u/ gii :topublic or ieroigu v-orpc-iati.cn, ite a. S, ;iangress or the govov eri: or m y nr lien concerning òlio clerical eanpeunds, 2,L*-Q, dir:¿no, or related vhion: yheuoi s relating to tho dr.s> dia detection c. dioxin:.;, the dangers of dlo:v■ ; . r* 1 .sub -7; .i.OV. Any .end '* 3 .jcaari '.'.toe c. y ;. '••:■■: ;o y ± •. evict...'.: r.4-r- ' . . .. r. .. -r : ; ; !'••irasentrrtives it "a . ’ ...f 'he h .nhicns (1933' and/or' t tt d n inerii■ ■•• rise, dororstrati 1 : an • si unit d 1 .., '.which will .re..: te :td„in • herein' v..n ita failure of die Evi: devivi, a*.tier, ns tiri dia productleu of r; cantari nani ir- •.*jr •:t id nil rerscss •±:. iinov: /; :.: ■inenioi sa. or relevant facts rasarring d d.c rirrend e*in si r rheir abilitv '0 .urge:.., including, hut nut limited te, 'si: pact. present, end t u t m profits ~:*.d eatai’ncs in the United! tints:, ■and itread s i m :i,r::”.:;h and lard ding the present fn.-m the aals of the arc'rots rarin ;te r“C.is cf this lawsuit, i.c. ■ 2.4-D, 2,4,C-T, th-'.rn ;* !*.■:... rei ves end tie relevant herticrir roaricet„ iry ri al", per: ens 'rj 0. i& or relevant factr *. regard'e s/r !■: . efor. Vent,s :ivi their obiirtv to 'he ’neridiip rnt■■■:.••. respere in puiiifivv: *'l^rrt'yr• . ir- •->■ • : ’ri net limited to,. defender!ts: demerit and io*.*■'*'' e: hrldio ries, joint vsnrurars, Ì'C 'ut-lic or pv;.:.vate corporatio licenr?vy ag'""Gir'*ni:.;. erdt 7 ...•m .... .* "% < .. ._ .■■■'., ; -\; .!■•h in thè . r are defendants ever a -substanti :1 li.rsr rial ' i l .A. trough and inni .-ding v... s-rssert. A ...» » Dry are. rli pero.'ir* 'ioted Ly * *'n r-oth crigi-oal a'";! cii.c:-.dcà ’ tir:::;.-.; .< no corperC .■’.‘ ¡■.no.- ; •Unii, :.ori ‘ .tii:u; cr '•’ausatisi-;i . gc......:t .. b i.-Ltncsjyovu..r::-«v.nfc cuuscv'J.« i '.iitnesa, defiridanto: 1r.pI0ye.cs mid/or mlrvi.vi porsor.rjel ;nd/or uny vinr/tàses iicted by all ¡icfenòcoitr, rt«y be C£J..;o.Ì at fciirt of tr:'il to prcser.t laotiani i; fcrcuatirn as to au.u larve involvcd ~ i chic casa. Any ao 1 all ooobcoo of Ilo sciertifi-. snd/er radicai ■ .umunity wbo ’:iov;lacge of relevant facis. iucludirig Infoio otion on m y o vile a \2v :‘-o.sly l'.olci r-fbjeotn in tbis Anne ixciudi-15, :-..i noi . vit:.: 1 t- /.... David 1:;:' d., J« 0:0 l.- .. . f ... c. Do. laui Coll.. .. J1• ... «t • •• --- „■ * — 6* Lv.w* ' j;.ww.'. ; ..ni... o. Do. !.. tt ’oliera h. Alvi-... Ab,. L. '71.... '•’. ’■ ‘.17. « ■c At Any 0.1 rvf o m e r o • ni i o l e ' ■. :...-.co..'::!: no lù:. - o .ny >io c:.un incDid- nqr L .1 ■ccuo.. itrcr.ecrje ceno •n.i t i f i . rhc •; *V1..’ •it y.rreiene vbo !¡rivo e?Kr'TTC- ^ Any oc y’’ * ....7 “. •.-.re­..7’. vie-; <":.o i ¡.aiil:.info1 f-:r :nj . 7;v’ .-nne;'Vm : ¿•r.d e net.lonol conciti: óre i. r;Ibll.l’.iV'..'-Ili'* n .-.b.»...-L'Y.y to ir t Crenee ; or.’ ¡'.or •‘i* ; ntucrìtt, on ■'o d?.ry •yv; • • *f.l1:.du:io ni or ■ u« C..i .-r.“ b. :..ocp;.''- vr.nour ri viir -a Plaéntilfs have been confined, : Craaicvni boti,:.;; te .thsir copoturG te Defendants’ ero ¡voto : vieti:--:..n t. ;• / ì .t.; C -. aj. pcyrholcci e ..1 arre o r r. ...... -•riola cciiaagas orci, n lo in tif f n a s o reru f t e r t b o ir in i u rico «2nd ’*’j * ' ~ C J? V '" 7 * ’. r ' frcr.i tl*. t i r eypoouro to nei r • .io.,/ nr.:' ni 1 ' .r: ■..t- ; nwloun : on 4-ì.ie os " ’>n P l a i n t i f f .rat.2 « /i'y - . / j f o t--.■•': ■ : -■• v-7. ' ■’ " •■^ i?' *i ■-f tim i;: lo s s o f wage v ie futi- will suri •coges e.r-:.ìing cooo-'-ity lt:.oy Irrora tiic injuries e-d disse: r rada thè boer e cf thic „cv/suit \fr.'eh were caused by '¡tan-tifir cort'o. to Defemntn' -croi’uofcr; Vietnrr. 3124 vy". es« Any and ail par so '.-.dta kv;-- r.e ho of ik./ trial. Peep ectirtl.r;* ryabr.ittud, ‘„..rsnts W. Henderson, Esqui..n VJL'J non fettietta- loauire 1C ■ rare ;■ oo ■ . a •‘rr-.r; L.'oplomm... to . l.oh. olff1s hr. .hr. -ator; ", :oo ..at aug_ cf the fcreg..ir«p tore mailed Federal Express to . liic„a. Krc-hlc/. Kell'“- , t o-; ?. f-tr .ran, *lr. done locks, Plaintiffs*. ifin.o'cr.sr/. Ccavovt .or. hcro-at Irr-rop.; hfoioo, with espies tor personally servo r 'st.—'. ■ r.t. a vie v sdey 1 .T/ccrti-ons red M e tfenuy Ictrilla, . oils rot-1:dry of r'eho;.o..,, lloh I ts iz e , n:-aco?clyn, Nr-; York ,o 111:; :.on :'stti.ette 1 th e re m a in in .; taLuvakor I UNITED STATES DISTRICT C O U R T EASTERN DISTRICT OF NEW Y O R K --- ------------------------------- X In Re "AGENT ORANGE" MDLNO.381^ PRODUCT LIABILITY LITIGATION ■X o. „ /> "/* //■k DEFENDANTS LIST OF FACT WITNESSES SUBMITTED PURSUANT TO THE SCHEDULING ORDER FOR THE COMPLETION OF DISCOVERY ____ i "V r; kj> o BUDD, LARNER, KENT, GROSS, PICILLO & ROSENBAUM, P.C. 33 Washington Street Newark, New Jersey 07102 (201) 622-7400 I 1. !^ \ UNITED STATES DISTRICT COURT EASTERN DISTRICT OF NEW YORK ---------------------------------- X In Re "AGENT ORANGE" MDL NO. 381 PRODUCT LIABILITY LITIGATION ■X DEFENDANTS LIST OF FACT WITNESSES SUBMITTED PURSUANT TO THE SCHEDULING ORDER FOR THE COMPLETION OF DISCOVERY BUDD, LARNER, KENT, GROSS, PICILLO & ROSENBAUM, P.C. 33 Washington Street Newark, New Jersey 07102 (201) 622-7400 DEFENDANTS LIST OF FACT WITNESSES SUBMITTED PURSUANT TO THE SCHEDULING ORDER FOR THE COMPLETION OF DISCOVERY On behalf of all defendants, and pursuant to the Scheduling Order For The Completion Of Discovery dated January 10, 1984, counsel for Thompson Chemical Company hereby submits the following list of potential witnesses to be called at trial, attached hereto as Schedule A. These witnesses shall be called to testify as to the issue of the government contract defense. Furthermore, attached hereto as Schedule B, defendants hereby submit a list of witnesses presently scheduled to be deposed at a future date. Therefore, defendants reserve the right, after these witnesses are deposed to determine whether or not these individuals shall be called upon at trial. Each individual defendant also reserves the right to submit an additional list of witnesses on their own behalf which they may choose to call upon to testify . Dated February 29, 1984 R espectfully submitted, BUDD, LARNER, KENT, GROSS, PICILLO & ROSENBAUM, P.C. Newark, New Jersey 07102 (201)622-7400 Attorneys for Defendant Thompson Chemical Company RIVKIN, LEFF, SHERMAN & RADLER 100 Garden City Plaza Garden City, New York 11530 Attorneys for Defendant The Dow Chemical Company*^? 1 Q> I a TOWNLEY & UPDIKE.. 405 Lexington Avenue New York, New York 10174 (212)682-4567 Attorneys for Defendant Monsanto Company ARTHUR, DRY & KALISH, P.C. 1230 Avenue of the Americas New York, New York 10020 (212) 841-9300 Attorneys for Defendant Uniroyal, Incorporated KELLEY, DRYE & WARREN 101 Park Avenue New York, New York 10178 (212)808-7800 Attorneys for Defendant Hercules Incorporated SHEA & GOULD 330 Madison Avenue New York, New York 10017 Attorneys for Defendant Uniroyal, Incorporated CLARK, GAGLIARDI & MILLER 99 Court Street White Plains, New York 10601 (914) 946-8900 Attorneys for Defendant T H Agriculture & Nutrition Company, Inc. Schedule A Andrew W. Anderson 1311 Thomas Run Road Belaire, Maryland 21014 Richard R. Bates 2810 Pheasant Lane Clarksburg, Maryland Gordon A. Anderson 102 Hickory Lane Naugatuck, Connecticut Frank L . Bauer 600 Grant Street Pittsburgh, Pennsylvania Robert J. Anderson 3624 North 36th Road Arlington, Virginia 22207 ♦Russell H. Betts Robert L. Andreoli 25 Eighth Avenue Iron River, Michigan ♦Weldon Bills John Angel Box 78 Yellville, Arkansas Peter S. Bing, M.D. 7900 W. Pico Boulevard Los Angeles, California Kenneth Arndt, M.D. 330 Brookline Avenue Boston, Massachusetts Donald J. Birmingham 19811 Wedgewood Drive Gross Point Woods, Michigan Louis B. Arnoldi 512 North Overlook Drive Alexandria, Virginia Warren R. Bontoyan 3910 Meeting House Road Perry Hall, Maryland 21228 John C. Atkinson 1222 Merchant Lane McLean, Virginia 22101 Rodney William Bovey Dept, of Range Science Texas A&M University College Station, Texas Dr. Joseph D. Avellino 2219 South Broad Street Philadelphia, Pennsylvania 19148 Carl Gwin Baker 19408 Charline Manor Road 0 lney, Mary1and John D. Baldeschwieler 619 South Hill Avenue Pasadena, California William F. Barthel Route 2 Mount Vernon, Iowa 77343 Lester Boyer Edgewood Church Road Frederick, Maryland Harold Brown 101530 Third Street, N.W. Washington, D. C. Major William Andrew Buckingham,Jr Department of Political Science U. S. Air Force Academy Colorado ♦At the present time, addresses on these witnesses are unavailable; however, they will be supplied as soon as possible. ^ „ X & 3 jl 9 Schedule A - Page 2 John L. Buckley P. 0. Box 263 Whitnes Point, New York George W. Connell Route 2, Box 626 Warrenton, Virginia Levi T . Burcham 4701 Crestwood Way Sacramento, California Katherine D. Courtney, Ph.D. Environmental Biology Division EPA Environmental Research Center Research Triangle Park, N.C. 27711 Dr. Edward James Burger, Jr. 2233 Wisconsin Avenue, Suite 324 Washington, D. C. 20007 Jack E. Burton 204 Vivian Lane San Antonio, Texas Charles E. Bushey 374 South Peoria Circle Aurora, Colorado 80012 Dohrman H. Byers 12060 Lawnview Avenue Cincinnati, Ohio Theodore Carroll Byerly 6J Ridge Road . Greenbelt, Maryland John F. Callahan, Sr. 2612 Green Road Baldwin, Maryland David M. Cawthorne P. 0. Box 293 Forest Hill, Maryland Milton K. Christensen 1089 Clubhouse Boulevard New Smyrna Beach, Florida Joseph F. Coates 3738 Kanawaha St., N.W. Washington, D.C. Nicholas H. Cox 2516 East Cass St. Joliet, Illinois Robert E. Cox 203 East Belerest Rd. Bel Air, Maryland William J. Crawford 524 Margaret Dr. Fairborn, Ohio William Murlin Creasy 3910 Molly Rd. Pine Bluff, Arkansas 71603 Eugene Cutright 1474 Maplewood Dr. Macon, Georgia 31210 Roswell G. Daniels 226 West Edgewood St. Morton, Illinois 61550 Robert A. Darrow 7613 Baltimore-National Pike Frederick, Maryland 21701 Thomas R. Dashiell 304 Thomas Ave. Frederick, Maryland 21701 Delmore, BG Fred J. 1600 S. Eads Arlington, Va. *George ^Collins* Joseph Amadeo DiPaolo 6605 Melody Lane Bethesda, Maryland 20034 *At the present time, addresses on these witnesses are unavailable; however, they will be supplied as soon as possible. IC'OO i. . Ox, Schedule A - Page 3 William W. Dorrell 8600 Pine Cliff Drive Frederick, Maryland *Dr. Hans Falk Paul Doty 4 Kirkland Place Cambridge, Mass. William A. Fenner 2713 Roffin Road Hopewell, Virginia 23860 Francis Gene Douglas 3101 South 54th St. Kansas City, Kansas David Firestone HFF 426 200 C. Street S.W. Washington, D.C. 20204 Henry N. Doyla 5303 Augusta St. Bethesda, MD. Lee A. DuEridge 1730 Hornet Rd. Pasadena, California Robert H. Duguid 107 South Lyndbrook Rd. Bel Air, Maryland Sigmund R. Eckhaus 4208 Colonial Rd. Pikesville, Maryland Fred I. Edwards 5206 Worthington Drive Bethesda, Maryland Dr. Kenneth Endicott . 11317 Broad Green Drive Potomac, Maryland William B. Ennis, Jr. 1131 S.W. 74 Terrace Plantation, Fla. 33317 Graydon Casper Essman 11 Holcomb Drive Williamsburg, Virginia Donald W. Falconer 115 Kline Blvd. Frederick, Maryland 21701* Henry Fischbach. 5627 Bradley Blvd. Alexandria, Virginia Lawrence Fishbein 3203 Misty Lane Littlerock, Arkansas 72207 Oscar G. Fitzhugh 4208 Dresden St. Kensington, Maryland John Stewart Foster 2737 Sinton Place Pepper Pike, 44124 *John Frawley Herbert G. Fredericks 2414 Diana Road Baltimore, Maryland Seymour L. Friess 6522 Lone Oak Court Bethesda, Maryland Verne C. Fryklund, Jr. 6805 Broyhill St. McLean, Virginia 22101 Donald W.. Fuhlhage Rural Route 1 Tonganoxie, Kansas * At the present time, addresses on these witnesses are unavailable however, they will be supplied as soon as possible. Schedule A - Page 4 James Gardner 1616 Arlington Drive Salt Lake City, Utah 84103 Benjamin Harris 11323 Glenarm Road Glenarm, Maryland ' Major Robert M. Gastineau, M.D. 2381 Rexford Drive Pittsburgh, Pennsylvania 15241 E. Ross Hart 1160 Chain Bridge Road McLean, Virginia 22101 *Perry Gehring Wayland J. Hayes 2317 Gold Club Lane Nashville, Tennesse John H. Gerety, Jr. North Entrance Friendhsip Inn P.0. Box 1885 Klamath Falls, Oregon Harry W. Hays 3900 Watson Place, N.W., Apt. 2G Building A Washington, D.C. 20016 *Thomas Gervason Albert E. Hayward. 5716 Jefferson Blvd. Braddock Heights, Maryland 21714 William Godel 711 Ledo Park Dr. Newport Beach, Ca. 92660 *John Gordon Robert J. Heaston 8231 Stonewall Drive Vienna, Virginia 22180 James A. Hebbeler 821 Park Court Palm Harbor, Florida *Harry Heimann Nathan Gordon 4990 Sentinel Drive Apartment 301 Bethesda, Maryland 20816 Dr. Herschel E. Griffin 11274 Pabellón Court San Diego, California 92124 Brunildo Antonio Herrero 616 Lake Hollingsworth Drive Lakeland, Florida *David Henry Groth Garnett Higginbotham Division of Food and Color Additi FDA 200 C Street, S.W. Washington, D.C. 20204 General Paul Donal Harkins 65104 Northport Drive Dallas, Texas 75230 Donald F. Hornig 16 Longfellow Park Cambridge, Mas s. *At the present time, addresses on these witnesses, are unavailable; however, they will be supplied as soon as possible. 13134 Schedule A - Page 5 Richard G. Horton 208 East Ring Factory Road Bel Air, Maryland 21014 Philip Charles Kearney Building 050 BARC-West Beltsville, Maryland William Horwitz 9830 Cherry Tree Lane Silver Spring, Maryland 20901 Surgeon M. Keeny, Jr. 3600 Albermarle St., N.W., Washington, D.C. Riley D. Housewright 147 Fairview Avenue Frederick, Maryland Dr. Marcus M. Key University of Texas Health Science Center. at Houston P.O. Box 20186 Houston, Texas 77025 Harry Otto Huss Route 1 Box 352 Uhrichsville, Ohio 44683 Kent R. Irish 1604 Rock Creek Drive Frederick, Maryland Keith H. Jacobson 740 Beall Avenue Rockville, Maryland Dr. Bernard J. Jandorf 6017 Baywood Avenue Baltimore, Maryland 21209 Marc Jeffries 2108 Hyden Ct. Fallston, Maryland 21067 Dr. Henry A. Kissinger 435 East 52nd St. New York, New York Michael Klein 1800 South East St. Lucie Blvd. Building 10-306 Stuart, Florida Dayton L. Klingman 2028 Forest Hill Drive Silver Spring, Maryland 20903 Albert Christian Kolbye 4802 Fort Summer Drive Bethesda, Maryland Wesley Rudolph Koster Dr. William Jurgelski 105 Northlake Dr., Apt, 215A Office of Health Hazard Assessment Orange City, Florida 32763 National Institute of Environmental Health Science William George Kratz Research Triangle Park, N.C. 27709 985 North Capitol Many, Louisiana 71449 *Abram Saul Kaplan George M. Lawton 1388 Almond Ave. Livermore, California Ronald Joseph Kassel 222 East Belcrest Road Bel Air, Maryland * At the present time, addresses on these witnesses are unavailable; however, they will be supplied as soon as possible. 13135 Schedule A - Page 6 John S. Leary, Jr. 2002 Sea Cove Court Nassau Bay, Texas Ian Alastair Mitchell, M.D. 110 Parmele Blvd. ( Wrightsville Beach, N.C. Douglas H.K. Lee 421 Wood DUck Drive Sarasota, Florida Francis W. Morthland 5602 Garrett Rd. Durham, North Carolina Jane Lewis 5125 Temple Hills Road Temple Hills, Maryland 20748 Donald W. Norberg 9153 East Stanford Ave. Englewood, Colorado 80111 Dr. Douglas Lindsey 1501 North Campbell St. Tuscon, Arizona Dr. Harold T. Magnuson 12305 Fernando Drive San Diego, Cal. 92128 Gordon J. MacDonald 20 Occom Ridge Hanover, New Hampshire Dr. Arthur H. McCreesh 1317 Saratoga Drive Bel Air, Maryland 21014 Harold Noble MacFarland 2320 Harrah Manner Drive Pittsburgh, Pennsylvania 15238 William D. McElroy 9651 Black Gold Road LaJolla, Cal. 92037 Dr. Arthur H. McCreesh 1317 Saratoga Drive Bel Air, Maryland 21014 Robert S. McNamara 2419 Tracy Place Washington, D.C. Harold Joseph Magnuson, M.D. 12305 Fernando Drive San Diego, California 92128 Vincent McRae 12000 Old Georgetown Rd. Rockville, Maryland Walter W. Melvin 413 Bobolink Court Fort Collins, Colorado 80526 John F . O' Leary Route 1, Box 213 Queenstown, Maryland 21658 Edward A. Metcalf 906 Wellington Rd. Baltimore, Maryland 21212 Peter G. Olenchuk 6801 Baron Rd. McLean, Virginia 22101 Lester L. Miller 437 Blueridge Drive York, Pennsylvania Normand E. Olivier 31 Mosher St. South Dartmouth, Mass. Charles E. Minarik P.O. Box 682 West Harwich, Mass. Boris J. Osheroff 13102 Camellia Drive Silver Spring, Maryland 20906 Hi J ,. * J J. d o Schedule A - Page 7 Arthur Joseph Pallotta 601 Abbott Lane Falls Church, Virginia Maj. Gen. Jacquard H. Rothschild 2323 N. Central Ave. Phoenix, Az. 85004 Laverne A. Parks 322 E. Garden Green Port Hueneme, Cal. 93041 Dr. Jack Phillip Ruina 28 Hawthorne St. Cambridge, Mass. 02138 *Vernon Perone Umberto Saffiotti 5114 Wissioming Road Bethesda, Maryland Lawrence M. Petrucelli 5600 Cedar Parkway Chevy Chase, Maryland Samuel Sass 17 North Read Street Bel Air, Maryland 21014 Alan P. Poland 2918 Nottingham Way Madison, Wisconsin Bernard Schwetz 1101 30th Street, N.W. Suite 205 Washington, D.C. 20007 Paul Aaron Possick 46 Winding Way Woodcliff Lake, N.J. Melvin M. Rabstein 4401 Gulf of Mexico Drive Long Boat Key, Florida Eberhardt Rechtin 1665 Cataluna Palos Verdes Estates, Cal. Kennard A. Reynard 2496 Cedarwood Drive Adrian, Michigan Merl Ringenberg 612 Rock Spring Road Bel Air, Maryland Ralph T. Ross Room 330A Administration Building U.S. Department of Agriculture Robert A. Shade 199 Rooster Drive Eagle, Indiana Warren C. Shaw 1907 Edgewater Parkway Silver Springs, Maryland Carleton G. Shead 1406 Flying W. Trail Helotes, Texas 78023 *John R. Shoemaker Seymour D. Silver 2920 Strathmore Ave. Baltimore, Maryland Dr. Van Murray Sim 1615 Toll Gate Road Bel Air, Maryland Washington, D.C. *At the present time, addresses on these witnesses are unavailable; however, they will be supplied as soon as possible. Schedule A - Page 8 Dr. Thomas C. Simmons 2706 Bynum Hill Circle Bel Air, Maryland Charles H. Townes 1988 San AnLonio Ave. Berkeley, California Anthony N. Sinclitico 1800 Willann Road Baltimore, Maryland 21237 John L. Traub 610 West Baker Ave. Abingdon, Maryland Marshall Steinberg 927 Jaysmith Street Great Falls, Virginia ♦Thomas A. Treglia *Dr. Jesse L. Steinfeld John Wilder Tukey 115 Arreton Rd. Princeton, N.J. ♦Herbert E. Stokinger William Martin Upholt 525 East Indian Drive Silver Springs, Maryland William W.. Stone 434 Sanahelena Drive Solana Beach, California Cyrus Robert Vance One Battery Park Plaza New York City Marshall Stubbs 2001 Columbia Turnpike Arlington, Virginia ♦Wayne E . Vandeventer Walter Edward Sultan 1203 Springwoods Terrace Fallston, Maryland 21047 Filiberto Vargas 6165 East I Lift Ave. Apartment 308 B Denver, Colorado 80222 William H. Summerson 5108 Brittany Drive South Stu Petersburg, Florida Steve S. Szabo 20 Milrose Lane Monsey, New York General Maxwell D. Taylor 2500 Massachusetts Ave. N.W. Washington, D.C.* Henry L. Verhulst 5917 Walton Rd. Bethesda, Maryland Frank J. Vocci 6009 Winthrope Ave. Baltimore, Maryland 21206 Dorothy M. Ward 345 Homeland South Way Baltimore, Maryland 21212 *At the present time, addresses on these witnesses are unavailable; however, they will be supplied as soon as possible. *■ *; t Schedule A - Page 9 Paul C. Warnke Cummings, Burlington, Rubier, Acheson & Shaw Washington, D .C . ^ John T. Weimer 1500 South View Rd. Bel Air, Maryland 21014 Frank H. Westheimer 3 Berkeley St. Cambridge, Mass. 02138 William Childs Westmoreland Box 1059 Charleston, S.C. 29402 Jerome B. Wiesner 61 Shattuck Rd. Watertown, Mass. Jerome Wilkenfeld 5757 Owensmouth Ave. Woodland Hills, California Donald Whittam 10308 Brookmoor Drive Silver Spring, Maryland 20901 James H. Wills 9706 Bellevue Dr. Bethesda, Maryland Herbert F. York 6110 Camino De LaCosta LaJolla, California Dr. Mitchell Zavon Occidental Chemical Corp. P.0. Box 728 Niagara Falls, New York 14302 Walter Leo Zielinski, Jr. 12705 Darnestown Rd. Gaithersburgh, Maryland 20878 13139 SCHEDULE B DEPOSITIONS SCHEDULED AFTER FEBRUARY 29, 19-84: 1. Donald Barnes 2. General Stanzwick Hay 3. Julius Johnson 4. Harold Kinney 5. Debdas Mukerjee 6- Elmer Wheeler 140 UNITED STATES DISTRICT COURT EASTERN DISTRICT OF NEW YORK In Re "AGENT ORANGE" PRODUCT LIABILITY LITIGATION MDL NO. 381 DEFENDANTS LIST OF FACT WITNESSES SUBMITTED PURSUANT TO THE SCHEDULING ORDER FOR THE COMPLETION OF DISCOERY BUDD, LARNER, KENT, GROSS, PICILLO & ROSENBAUM, P.C. 33 Washington Streert Newark, New Jersey 07102 (201)622-7400 Attorneys for Defendant Thompson Chemical Company UNITED STATES DISTRICT COURT EASTERN DISTRICT OF NEW YORK x In re "AGENT ORANGE" Product Liability Litigation x DEFENDANT DIAMOND SHAMROCK CHEMICALS COMPANY'S PRELIMINARY LISTING OF FACT WITNESSES___ Pursuant to the Special Master's Final Amended Recommended Scheduling Order, approved by the Court on January 10, 1984, defendant Diamond Shamrock Chemicals Company ("Diamond Shamrock") sets forth below its preliminary listing of fact witnesses who may give live testimony at trial in support of Diamond Shamrock's claims and defenses. This listing does not address deposition testimony that may be used at trial, which will be identified as part of preparation of the pretrial order. In accordance with the Scheduling Order and the Magistrate's Pretrial Order No. 9, Diamond Shamrock reserves the right to supplement and amend this preliminary listing. 42 Name and ■Etegent Address Description of General Nature.of Testimony Dr. Donald J. Birmingham 19811 Wedgewood Drive Gross Point Woods, Michigan Testimony concerning research and investigation of chloracne by U.S. Public Health Service in the 1950's and 1960's, including visits to Diamond Shamrock's former Newark plant. Robert L. Chonoles Diamond Shamrock Chemicals Company Berry Avenue at Route 17 North Carlstadt, New Jersey 07072 Testimony concerning manufacturing operations at Diamond Shamrock's former Newark plant, including: the removal of dioxin from trichlorophenol; and the U.S. Public Health Service study of the Newark workers in 1968-69. Sigmund R. Eckhaus 4208 Colonial Road Pikesville, Maryland Testimony concerning United States' program for the construction of an Agent Orange manufacturing facil­ ity, and communications with pro­ ducers of Agent Orange in connec­ tion with that program. Dr. Marcus M. Key University of Texas Health Science Center P.O. Box 20186 Houston, Texas 77025 Testimony concerning research and investigation of chloracne by U.S. Public Health Service in the 1960's, including visit to Diamond Sham­ rock's former Newark plant. Jane Lewis 5125 Temple Hills Road Temple Hills, Maryland 20748 Testimony concerning the procure­ ment and production of Agent Orange pursuant to the Defense Production Act, including directives and priority ratings issued by the United States. Dr. Alan P. Poland 2918 Nottingham Way Madison, Wisconsin Testimony concerning medical study of the workers at Diamond Shamock's former Newark plant in 196869, and research and investigation of trichlorophenol, 2,4,5-T and dioxin at. National Communicable Disease Center in the 1960's. Dr. Paul A. Possick 46 Winding Way Woodcliff Lake, New Jersey Testimony concerning medical study of the workers at Diamond Sham­ rock's former Newark plant in 196869. - 2- 1 ^>; M - 3 Name and Eresent Address Description of General Nature of Testimony___ Warren C. Shaw 1907 Edgewater Parkway Silver Spring, Maryland Testimony concerning DSDA regula­ tion of 2,4,5-T under FIFRA in 1950's and 1960's, and USDA research and investigation con­ cerning health effects and efficacy of 2,4,5-T. F. Gordon Steward Diamond Shamrock Agricul­ tural Chemicals Inc. P.O. Box H Tuscaloosa, Alabama 35404 Testimony concerning manufacturing operations at Diamond Shamrock's former Newark plant, including: the development, installation and operation of a method for removing dioxin from trichlorophenol; the U.S. Public Health Service study of the Newark workers in 1968-69; and the production and shipment of Agent Orange pursuant to contracts with the United States. Dated: New York, New York February 29, 1984 Respectfully submitted, CADWALADER, WICKERSHAM & TAFT y J ly A Member of the Firm Attorneys for Defendant Diamond Shamrock Chemicals Company One Wall Street New York, New York 10005 (212) 908-7000 B -3- •>: 1ù -• ä i \ AFFIDAVIT OF SERVICE STATE OF NEW YORK ) SS. : COUNTY OF NEW YORK ) MICHAEL M. GORDON, being duly sworn, deposes and says: 1. I am not a party to this action, am over 18 years of age and reside in New York County, New York. 3. On February 29, 1984, I served the annexed dant Diamond Shamrock Chemicals Company's Preliminary Listing of Fact Witnesses on each of the persons named on the annexed list by depositing a true copy of same enclosed in a postpaid properly addressed wrapper, in an official depository under the exclusive care and custody of the United States Postal Service within the State of New York. Federal Express. The copy to David J. Dean, Esq. was sent by A copy was also sent by Federal Express to the Agent Orange Plaintiffs' Management Committee, Suite 905, Brooklyn, New York. Sworn to before me this z r day of February, 1984 No.'«391« * S S SEÄÄreh'SJras^ S x .^ Co™»«» 26 Court Street, «avia list roa defendants Leonard L. Rivkin Rivkin, Leff, Sherman 4 Radler (for DOW CHEMICAL) 100 Cardan City Plasa Cardan City» Saw York 11530 Morton C. Silbarman Clark, Gagliardi 4 Millar (for T H AGRICULTURE 4 NUTRITION COMPANY, INC.) The Inna of Court 99 Court Street White Plaina, New York 10601 John C. Sabetta Townley & Updike (for MONSANTO) 405 Lexington Avenue New York, New York 10174 William Krohley Xelley Drye 4 Warren (for HERCULES, INC.) 101 Park Avenue New York, New York 10178 John M. Fitzpatrick Dilworth, Paxton, Kalith 4 L e w (for HOOKER PLASTICS 4 CHEMICALS CORP.) 2600 The Fidelity Building Philadelphia, Pennsylvania 19109 Biehard Goldstein Shea 4 Gould 330 Madison Avenue New York, New York 10017 Thomas Beck Arthur, Dry 4 Xalish, P.C. (for UNIROYAL) 1230 Avenue of the Americas New York, New Yozk 10020 David X. Cross Budd, Larner, Kent, Gross, Pieillo 4 Rosenbaum (for THOMPSON CHEMICALS) 33 Washington Street Newark, New Jersey 07102 Arvin Maskin Department of Justice (for THIRD PARTY DEFENDANT USA) Safeway Building 521 12th Street, S.W. Washington, D.C. 20530 L. Kevin Sheridan Executive Assistant U.S. Attorney Eastern District of New York United States Courthouse 225 Cadman Plaza East Brooklyn, New York 11201 COPIES OF ALL DOCUMENTS MUST BE SENT TO:__________________ Clerk of the Panel Judicial Panel on Multidistrict Litigation 1120 Vermont Avenue, N.W. Suite 1002 Washington, D.C. 20005 FOR PLAINTIFFS Victor J. Yannaeone, Jr. Yannaeone 4 Yannaeone Post Office Drawer 4109 Patchogue, New York 11772 Stephen J. Sehlegel Schlegel 4 Trafelet, Ltd. One North LaSalle Street Suite 3900 Chicago, Illinois 60602 Benton Musselwhite Law Offices of Benton Musselwhite, Inc. Suite 517 609 Fannin Houston, Texas 77002 Thomas Henderson Baskin 4 Sears Frick Building - 10th Floor Pittsburgh, Pennsylvania 15219 David J. Dean, Esq. Dean, Falanga 4 Rose 1 Old Country Road Carla Place, New.York 11514' ' ' k' y 'ft-- •';v‘' ' '" (ftEASTERN -DISTRICT OP NEWC0"'! YORK 'ft/; ;/ »DL ÿiVi::i;. .. ■ • ,. .-. ‘î’iw r - - . . .-•' •,'• • : *-*■'’' 1ft \ •*»<'. •'-r ’--.ft. 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UNITED STATES DISTRICT COURT EASTERN DISTRICT OF NEW YORK ------------------------------------------------------------- - In re : "AGENTORANGE" Product LiabilityLitigation MDLNo. 381 : : ----------------------------------x DEFENDANT DIAMOND SHAMROCK'S OBJECTIONS TO PLAINTIFFS' PRELIMINARY LIST OF POTENTIAL DEPONENTS PRESENTLY OR FORMERLY _____ ___________________________________ Pursuant to the direction of Magistrate Scheindlin at the February 9, 1984 pre-trial conference, defendant Diamond Shamrock Chemicals Company ("Diamond Shamrock") sets forth below its objections to plaintiffs' preliminary list of present or former Diamond Shamrock employees who may be deposed by plain­ tiffs, served on February 9, 1984 ("Plaintiffs' List"). Diamond Shamrock requests, however, that consideration of its objections by the Magistrate be deferred pending receipt and review of plaintiffs' "priority" deposition list. Since the commencement of deposition discovery in the "Agent Orange" litigation in 1982, plaintiffs have deposed nine present or former Diamond Shamrock employees on substantive rr - AW issues. An additional three employees have been examined pursuant to Pretrial Order No. 57. On December 12, 1983, counsel for plaintiffs confirmed in writing that their deposition discovery of Diamond Shamrock would be completed by the examination of five additional former employees: Richard Marrese, Donald Purdy, Cy Perkins, James King and Stanley Honour. M. See letter from Edward J. Gorman to Michael Gordon dated December 12, 1983 (Exhibit A hereto). Dr. Marrese and Mr. Purdy were examined on December 13, 1983 and January 5, 1984, respectively. The depositions of Mr. Perkins and Mr. King were both tentatively scheduled, and then postponed at plaintiffs' request for various reasons, including ill health of plaintiffs' counsel. The deposition of Mr. Honour remains unscheduled. I Now, only 12 weeks before trial, plaintiffs have identified ten former Diamond Shamrock employees that they may wish to depose, the three witnesses previously requested and remaining to be scheduled. Thus, if their List is accepted at face value, plaintiffs seek at the last minute to double the number of Diamond Shamrock depositions taken in this litigation. Their List similarly more than triples the number of outstanding depositions to be scheduled, in total repudiation of plaintiffs' most recent assurances to Diamond Shamrock. Plaintiffs' unannounced new "wave" of Diamond Shamrock depositions, in the face of recent representations to the con­ trary, would seriously and unfairly prejudice Diamond Shamrock's own pre-trial preparations. Instead of the three remaining ’2’ iZ lid j depositions agreed to in December, Diamond Shamrock would now be compelled to locate and prepare for depositions of 13 former employees, most of whom reside far from New York and are unlikely to agree to travel here for their examinations. The strain on the resources of Diamond Shamrock's counsel that would result at i this critical stage of the proceedings is obvious. Absent a compelling explanation for plaintiffs' failure to apprise Diamond . Shamrock of their intentions and to pursue scheduling of Diamond ; Shamrock depositions during the past several months, plaintiffs j should not be permitted to sidetrack Diamond Shamrock's trial preparations in the few precious weeks remaining before jury selection. In fairness to plaintiffs, Diamond Shamrock recognizes that plaintiffs themselves estimate that only a fraction of the deponents they have listed will actually be examined. Plaintiffs have also stated their intention to submit by February 15, 1984 a "priority list" that is expected to contain only one-half to onequarter of the names set forth in their original list, at 9214-15. ¿ss tr. Accordingly, Diamond Shamrock requests that con­ sideration of its objections to the number of former Diamond Shamrock employees identified as deponents in Plaintiffs' List be deferred to permit receipt and review of plaintiffs' priority pl -3- 1 ^0 U list, and discussion of that list between counsel for Diamond Shamrock and plaintiffs. Dated: New York, New York February 14, 1984 Respectfully submitted, ’T Diamond Shamrock Chemicals Company One Wall Street New York, New York 10005 (212) 908-7000 -4- / l LA W O F F I C E S O ’H a o a n , R e i l l y & G o r m a n , P.G. JA M A IC A O F F IC E 9 0 - 2 4 S U T P H IN B L V D . JA M A IC A . N .Y . I 1 4 0 6 (2 1 2 ) 6 6 8 - 4 1 1 4 P E T E R M. J . R E IL L Y E D W A R D J . O O RM A N P E T E R M. J . R E IL L Y . J R . N E W Y O R K O F F IC E I 2 2 BA ST 42N D S T R E E T N EW Y O R K . N E W Y O R K 1 0 0 1 7 R E IL L Y B U IL D IN G .4 4 4 MAIN S T R E E T P . O . BOX 73 (2 1 2 ) 6 9 7 - 4 2 7 0 IS L IP , N. Y . 1 I 7 6 1 (6 1 6 ) 6 8 1 - 8 6 6 7 M ARK O . S O K O L O F F R IC H A R D E . C H E S N E Y D O N A L D E . L A M PSO N E L IZ A B E T H M. O 'N E IL L O F COUNSEL H E N R Y J . O ’H A OAN - D E C ’D 1 9 7 8 ED W A R D O . D O U G H E R T Y - D E C ’D 1 9 7 7 O E O R O E W . KELLY ALLAN M. K A PLA N R IC H A R D F . P O H L (ADM . P E N N . B A R ) E D W A R D F . H A Y E S . I ll December 12, 1983 Cadwalder, Wickersham § Taft, Esqs. One Wall Street New York, New York 10005 Attention of Michael M. Gordon, Esq. RE: In re "Agent Orange" Product Liability Litigation MDL No. 381 Dear Mr. Gordon: This will confirm our telephone conversation of December 8, 1983 wherein you advised that Mr. S. S. Savage is deceased and Mr. S. B. Honour, still shares this earth with us although his exact whereabouts are unknown. Presently scheduled for depositions are Mr. Marrese, Perdy, Perkins and King. As you know Mr. Fiorella has written to Mr. Lex Creamer regarding his deposition but to date we have not heard from this gentleman. What we are looking for is a witness with knowledge of the various South American episodes involving chloracne and the use of 2, 4, 5,T. I doubt if we will hear from Mr. Creamer. If you will be kind enough therefore to arrange to have Mr. Honour presented for deposition, he, in addition to those gentlemen mentioned above,will complete our discovery. Thank you for your cooperation, I remain Very truly yours, O'HAGAN , REILLY S GORMAN, P.C. 5 < V EDWARD J. GORMAN CC: Albert Fiorella, Esq. D. Russo, Esq. ■Á.M 52 AFFIDAVIT OF SERVICE STATE OF NEW. YORK: 1. : ss.: COUNTY OF NEW YORK ) JEFFREY SAPER, being duly sworn, deposes and says: 1. I am not a party to this action, am over 18 years of age and reside in Queens County, New York. 2. On February 14, 1984, Diamond Shamrock's Objections to Plaintiffs' I served the annexed De Preliminary List of Potential Deponents Presently or Formerly Employed by Diamond Shamrock on each of the persons named on the annexed list by depositing a true copy of same enclosed in a postpaid properly addressed wrapper, in an official depository under the exclusive care and custody of the United State Postal Service within the State of New York. Express Mail. The copy to David J. Dean, Esq. was sent by A copy was also sent by hand to the Agent Orange Plaintiffs' Management Committee, 26 Court Street, Suite 905, Brooklyn, New York. Sworn to before me this 1984. MICHAEL MACKIN GORDON W otaiy Public, S tate of New York rv.«« I*0,»-««985 *«*. ro T tt.& a iT C a t i o n E x * « ; Marth SERVICI LIST FOR DEFENDANTS Leonard L. Rivkin Rivkin, Leff, Sherman t Radier (for DOW CHEMICAL) 100 Garden City Plaza Garden City« New York 11530 Morton G. Silbernen Clark, Gagliardi t Miller (for T H AGRICULTURE fc NUTRITION COMPANY, INC.) The Inna of Court 99 Court Street White Plains, New York 10601 John C. Sabetta Townley 4 Updike (for MONSANTO) 405 Lexington Avenue New York, New York 10174 William Krohley Xelley Drye 4 Warren (for HERCULES, INC.) 101 Park Avenue New York, New York 10178 John M. Fit 2 patrick Dilworth, Paxson, Xalish 4 L e w (for HOOXER PLASTICS 4 CHEMICALS CORP.) 2600 The Fidelity Building Philadelphia, Pennsylvania 19109 Richard Goldstein Shea 4 Gould 330 Madison Avenue New York, New York 10017 Thomas Beck Arthur, Dry 4 Xalish, P.C. (for UNIROYAL) 1230 Avenue of the Americas New York, New York 10020 David R. Gross Budd, Larner, Kent, Gross, Picillo 6 Rosenbaum (for THOMPSON CHEMICALS) 33 Washington Street Newark, New Jersey 07102 Arvin Maskin Department of Justice (for THIRD PARTY DEFENDANT USA) Safeway Building 521 12th Street, N.W. Washington, D.C. 20530 L. Xevin Sheridan Executive Assistant U.S. Attorney Eastern District of New York United States Courthouse 225 Cadman Plaza East Brooklyn, New York 11201 COPIES OF ALL DOCUMENTS MUST BE SENT TO:__________________ Clerk of the Panel Judicial Panel on Multidistrict Litigation 1120 Vermont Avenue, N.W. Suite 1002 Washington, D.C. 20005 FOR PLAINTIFFS Victor J. Yannacone, Jr. Yannacone 6 Yannacone Post Office Drawer <109 Patchogue, New York 11772 Stephen J. Schlegel Schlegel 6 Trafelet, Ltd. One North LaSalle Street Suite 3900 Chicago, Illinois 60602 Benton Musselwhite Law Offices of Benton Musselwhite, Inc. Suite 517 609 Fannin Houston, Texas 77002 Thomas Henderson Baskin 6 Sears Frick Building - 10th Floor Pittsburgh, Pennsylvania 15219 David J. Dean, Esq. Dean, Falanga 6 Rose 1 Old Country Road Carle Place, New York 11514' fr 2 A P A R T N E R S H I P I N C L U O IN G P R O F E S S I O N A L C O R P O R A T I O N S 1333 N EW H A M P S H I R E A V E ., N .W . 249 J fW ./ Û Û Û S W A S H I N G T O N , O .C . 2 0 0 3 6 R O Y A L P A L M WAY PA LM B E A C H , F L A . 3 3 4 6 0 (3 0 9 ) (2 0 2 ) 2 9 3 - 6 3 0 0 6 8 8*9 8 0 0 TW X! 8 1 0 * 9 8 2 * 7 6 2 8 TW X: 7 1 0 « 6 2 2 “ 1 9 3 A ( 2 S 2 ) CA B LE S O S - 7 O O 0 a d d r e s s : l a b e l l u m T E L E X : 12 9 1 4 6 / B 0 7 4 6 S R A P I P A X : (2 1 2 ) 269*2321 X E R O X *. (2 1 2 ) 76 5*1 6 3 0 February 14, 1984 Honorable Shira A. Scheindlin United States Magistrate United States District Court Eastern District of New York United States Courthouse 225 Cadman Plaza East Brooklyn, New York 11201 Re: In re "Agent Orange" Product Liability Litigation, MDL No. 381 Dear Magistrate Scheindlin: Pursuant to your direction at the February 9, 1984 pre-trial conference, I enclose Defendant Diamond Shamrock's Objections to Plaintiffs' Preliminary List of Potential De­ ponents Presently or Formerly Employed by Diamond Shamrock. Very truly yours MMG/mam Enclosure BY HAND cc(w/encl.): Clerk of the Court1''" Service List £il f O -r UNITED STATES DISTRICT COURT EASTERN DISTRICT OF NEW YORK -------------------------------------------------- X In re \ 1 . Charles Baron, M.D. Exhibit "A" 2 . Deborah Anne Barsotti, Ph.D. Exhibit ”B' 3. Ronald Codario, M.D. 4. Arthur W. Galston, Ph.D. Exhibit "Cr 5. John Garofalo, M.D. Exhibit "E" 6 . Lennart Hardell, M.D. Exhibit "pi 7. Maureen C. Hatch, Ph.D. 8 . Alastair W.M. Hay, Ph.D. Exhibit "G ' Exhibit „H' 9. Herbert Kay, Ph.D. 10. Ronald H. Kerman, Ph.D. 11 . Marvin S. Legator, Ph.D. Exhibit 'T Exhibit MJ' Exhibit "K* 12. Alan Scott Levin, M.D. Exhibit ML' 13. Peter Orris, M.D., M.P.H. 14. Marvin A. Schneiderman, Ph.D. 15. Ellen K. Silbergeld, Ph.D. Exhibit "M' Exhibit "N' ■16. Raymond Singer, Ph.D. 17. Theodor D. Sterling, Ph.D. 18. Biostatistician/Mathematician (Additional) Exhibit Exhibit "pi Exhibit "Rl Exhibit "D' Exhibit "O' "Q . PLAINTIFFS' MANAGEMENT COMMITTEE Thomas W. Henderson, Esquire I S 15 6 Dr. Charles M. Baron, M.D., is a physiatrist practicing in Philadelphia, Pennsylvania. His curriculum vitae will be supplied. Dr. Baron will testify as to the performance and interpretation of various tests in the veterans. These will include an eltroencephalogram on both sleep and waking states with nasopharyngeal leads. He will also perfrom electromyograms, nerve conduction velocity tests, and somato sensory evoked potentials of the upper and lower extemities. Dr. Baron will then testify as to the mechanisms by which toxins produce the changes noted in the tests and what the various tests are capable of determining as to the medical status of the patient. Then he will relate the results obtained in the testing of each plaintiff examined, give opinions as to the causation of those results where possible from the evidence revealed by the tests, and state the prognosis for the individual plaintiff for further deterioration in test results and/or for the individual's condition as a whole. 13157 Dr. Deborah Anne Barsotti is an Assistant Professor of Toxicology in the Department of Pharmacology and Toxicology of the Philadelphia College of Pharmacy and Science in Phila­ delphia, Pennsylvania. Her curriculum vitae is attached. Dr. Barsotti is a toxicologist who has done substantial personal investigative work with halogenated aromatic hydrocarbons. This category of chemicals includes various biphenyls and dioxins, and specifically includes tetrachlorodibenzo-prdioxin (TCDD). She will testify as to the relative chemical stability and lipophilicity of these chemicals as well as their resistance to degradation, and will testify that these qualities are what account for the perceived and documented bioaccumulation of the chemicals in the human system. Dr. Barsotti will emphasize the difference in results between chron­ ic and acute exposures to these chemicals, testifying as to the varying types of responses to acute and chronic exposures. Dr. Barsotti will discuss her own work as well as review the literature in these areas, noting differences in routes of administration, and in the species and genetic strain of the animals involved. She will explain these variations and where they permit extrapolation of results from animals to humans. In particular, Dr. Barsotti will also testify as to the similarities in response to these chemicals by rhesus monkeys and by humans, and will explain how the similarities permit extrapolation in this instance. Dr. Barsotti will also discuss reproductive toxicity, teratology and post-natal toxicity, including instances where no gross or clinical signes of maternal toxicity could be detected. OJ O. CURRICULUM VITAE DEBORAH ANNE BARSOTTI ADDRESS: Home - 4818 T r in it y Place P h il a. , PA 19143 215-724-5387 Business - P h il a. College o f Pharmacy & Science Dept, o f Pharmacology & Toxicology 43rd & Kingsessing Mall P h il a. , PA 19104 215-596-8978 CITIZENSHIP: USA BIRTHDATE: September 14, 1949 MARITAL STATUS: M arried; no ch ild re n EDUCATION: Humboldt S ta te U n iv e rs ity A re a ta , C a lif o r n ia - 1967-1972 Bachelor o f A rts Biology-M edical Technology Humboldt S tate U n iv e rs ity A re a ta , C a lif o r n ia - 1972-1973 Graduate School Coursework: Ele ctro n microscopy Endocrinology Instrum entation U n iv e rs ity o f Wisconsin Madison, Wisconsin - 1973-1980 Doctor o f Philosophy Pathology T h esis T i t l e : G ro ss, C lin ic a l & Reproductive E ffe c ts o f P o ly ch lo rin a te d Biphenyls (PCBs) in the Rhesus Monkey EXPERIENCE: P h il a. College o f Pharmacy & Science Phi l a . , PA - Ja n u a ry, 1983 to Present A s s t. P ro fe s s o r, Dept, of Pharm acology/Toxicology In s tru c t B io lo g ic a l Methods in T o x ic o lo g y , To xico lo g y I I I & Techniques in Ele ctro n Microscopy Advise undergraduate students F a cu lty a d v iso r fo r Tox Club Member, A d viso ry Committe fo r fo u r graduate students Conduct independent research 13160 A s s is ta n t S c ie n t is t - J u ly , 1982 to Ja n u a ry , 1983 P ro je c t A sso cia te - June, 1980 to June, 1982 U n iv e rs ity o f Wisconsin Dept, o f Pathology Madison, Wisconsin Coordinated m u ltifa c e te d research p ro je c ts in v o lv in g over 120 rhesus monkeys exposed to low le v e ls o f to x in s (h a lo genated arom atic hydrocarbons) and in te g rate d the c lin ic a l data and o b se rvatio n s w ith the residue analyses o f t is s u e s and f lu id s obtained by gas chromatography (GC) and con­ firm ed by mass spectrom etry (MS). Supervised the c lin ic a l and reproductive e v a lu a tio n s as w ell as the care o f lab o rato ry anim als. Developed d ata management and word processing systems u t i l ­ iz in g o n - s ite computers and t ie - in s to a Sperry Uni vac 1100 to s o r t , c o lla t e and s t a t i s t i c a l l y e va lu a te d ata. Conducted gross necro psies and m icroscopic e v a lu a tio n s and prepared necropsy re p o rts. Research A s s is t a n t - 1976-1980 U n iv e rs ity o f Wisconsin Dept, o f Pathology Madison, W isconsin Conducted radioimmunoassays fo r serum progesterone and e s t r a ­ d io l f o r use in e va lu a tin g the repro d uctive param eters in rhesus monkeys. Performed c l i n i c a l assessments on la b . anim als in clu d in g hematology and c lin ic a l ch e m istrie s. Supervised and evaluated data and prepared re p o rts f o r cont r a c t u r a l work. Separated c e llu la r fra c tio n s of t is s u e homogenates by u l t r a ­ c e n trifu g a tio n and assayed homogenates and re s u lta n t f r a c ­ tio n s fo r content o f vario u s components. Provided animal husbandry fo r rhesus monkey and r a t c o lo n ie s. Supervised u n it members on protocols f o r experim entation and proper methods o f conducting b asic la b o ra to ry a n a ly se s. Pre-D octoral Fello w - 1974-1976 U n iv e rs ity o f Wisconsin Dept, o f Pathology Madison, W isconsin Stocked and organized a la b o ra to ry fo r the c l i n i c a l and re p ro ­ d u ctive a n a lyse s o f la b o ra to ry anim als. - 2 - 13161 Prepared protocols fo r long-term feeding stu d ie s in the lab o ra to ry animals in clud in g those f o r g ro s s , c lin ic a l and repro d uctive assessments. Developed radioimmunoassay procedures f o r serum proges­ terone and e s t r a d io l. Conducted metabolism and d is trib u tio n stu d ie s in ra ts and rhesus monkeys using rad io lab e le d isomers o f halogenated arom atic hydrocarbons and other chem icals. Laboratory A s s is ta n t - 1970-1972 Humboldt S tate U n iv e rs ity Student Health Center A re a ta , C a lif o r n ia Duties included a s s is t in g in ro u tin e c lin ic a l la b o ra to ry p ra c tic e s involved in u r in a ly s is , gonococcal sc re e n in g , VDRLs, h e te ro p h ile s fo r m ononucleosis, th ro a t c u ltu re s and pregnancy t e s t s . AWARDS/HONORS: National Sea Grant Graduate Student o f the Year - 1976. PROFESSIONAL SO CIETIES: American S o cie ty f o r P rim a to lo g ists M id -A tla n tic C h ap ter, S o cie ty o f To xico lo g y SEMINARS/MEETINGS: P a r tic ip a n t - Federation o f American S o c ie tie s f o r E x p e ri­ mental Biology (FA S EB ), A t la n t ic C i t y , N J, A p r i l , 1976. T o p ic : " E ffe c ts o f p o lych lo rin a te d biphenyls on repro ­ duction in the p rim ate". P a r tic ip a n t - American A sso cia tio n o f P a th o lo g ists and B a c t e r io lo g is t s , Boston, MA, March, 1976. T o p ic : "The A sso cia tio n o f T ra n sp la ce n ta l and Mammary Movement of PCBs w ith In fa n t M orbidity and M o r ta lit y " . In v ite d Speaker - 9th Annual Sea Grant A ss o c ia tio n M eeting, Los A n g e le s, CA, November, 1976. T o p ic : "Toxico lo g y o f PCBs in the Adult and In fa n t Rhesus Monkey". P a r tic ip a n t - FASEB, Chicago, I L , A p r il, 1977. T o p ic: " E ffe c t s o f p o lych lo rin a te d biphenyls in nonhuman p rim a te s". P a r tic ip a n t - American Chemical S o c ie ty , 11th Great Lakes Regional M eeting, Stevens P o in t, WI, Ju n e , 1977. T o p ic: "Responses o f in fa n t prim ates to in te r u t e r in e and neonatal exposure to p o lych lo rin a te d b ip h e n y ls". In v ite d Speaker - Community Meeting on PCBs, U n iv e r s it y of W isco n sin , P a rk sid e , March, 1977. -3 1 f> * 62 P a rtic ip a n t - In te rn a tio n a l Symposium on Pathobiology of Environmental P o llu ta n ts , S t o r r s , CT, June, 1977. T o p ic s: "Pathology or rhesus macaques (Macaca m ulatta) exposed to ■tetrachlorodibenzo-jD -dioxin (TCDD)" and "Exposure o f p o ly­ ch lo rin a te d biphenyl (PCB) to in fa n t rhesus macaques (Macaca m u la tta )". In v ite d Speaker - Community Meeting on PCBs, Door County, WI, September, 1977. In v ite d Speaker - 45th Annual Convention of A sso cia tio n of Midwest Fish and W ild life A gencies, Milwaukee, W I, J u l y , 1978. To p ic: "Consequences o f d ie ta ry PCB consumption in rhesus monkeys". In v ite d Consultant - Symposium on PBB L it ig a t io n , T ra ve rse C it y , M I, J u ly , 1978. T o p ic: "PBB t o x ic it y in the rhesus monkey". In v ite d Speaker - Smerkee's Conservation C lu b , Sheboygan, WI, Feb ru ary, 1979. T o p ic: "PCBs and t h e ir e f f e c t s on rhesus monkeys". P a rtic ip a n t - FASEB, D a lla s , TX , A p r il, 1979. T o p ic: "Residual e ffe c t s o f p o lych lo rin ate d biphenyls on ad u lt nonhuman prim ates and t h e ir o ffs p rin g " . Expert Witness - S ta te o f North C a ro lin a , H a lifa x County, testim ony on t o x ic it y o f PCBs, Ju n e , 1979. P a rtic ip a n t - Sea Grant Symposium on T o xic M a te ria ls and t h e ir E ffe c t s on Marine Resources, Madison, W I, J u l y , 1979. PUBLICATIONS: B a r s o t t i, D. A. and Van M ille r , J . P .: Reproductive assessments o f rhesus monkeys housed in clim ate co n tro lle d c o n d itio n s. Amer. J . P r im a t o l., submitted 1983. B a r s o t t i, D. A .: Long term repro d uctive assessment o f rhesus monkeys exposed to ch lo rin a te d biphenyls (A ro clo r 1248). Fd. Cosmet. T o x ic o l., submitted 1983. B a r s o t t i, D. A. and Van M ille r , J . P . : Accumulation o f a commercial p o ly ­ ch lo rin a te d biphenyl m ixture (A ro c lo r 1010) in adult rhesus monkeys and t h e ir n ursin g o ffs p rin g . To xico lo g y. In p re ss. Bowman, R. E. , Heironim us, M. P. and B a r s o t t i, D. A .: Locomotor h yp e ra ct­ i v i t y in PCB-exposed rhesus monkeys. N e u ro to xico l. 2:251-268, 1981. B a r s o t t i, D. A. , Abrahamson, L. J . , M a rla r, R. J . and A lle n , J . R . : The e ffe c t o f clim ate c o n tro lle d housing on the repro d uctive p o te n tia l o f the rhesus monkey. J . Reprod. F e r t i l . 5 9 :1 5 -2 0 , 1980. . a. - 13163 B a r s o t t i, D. A. and A lle n , J . R . : nursing rhesus monkey infants. (A b s tra c t). Health im p lica tio n s o f A ro c lo r 1016 on T o x ic o l. Appl. Pharmacol. 5 2 :1 3 5 , 1980 A lle n , J . R . , B a r s o t t i, D. A. and C a rste n s, L. A .: Residual e f f e c t s o f po ly­ ch lo rin ated biphenyls on adult nonhuman prim ates and t h e ir o ffs p r in g . J . T o x ic o l. En viro n . H lth . 6 :5 5 -6 6 , 1980. A lle n , J . R . , B a r s o t t i, D. A. and Van M ille r , J . P . : T o x ic o lo g ic a l e ffe c t s o f A ro c lo r 1016 on nonhuman prim ates. EPA Report #68-02:2464, 1980. B a r s o t t i, D. A . , Abrahamson, L . J . and A lle n , J . R . : Hormonal a lt e ra t io n s in female rhesus monkeys fed d ie ts containing 2 ,3 ,7 ,8 -te tra c h lo ro d ib e n z o £ - d io x in . B u ll. Enviro n. Contam. T o x ic o l. 21:46 3 -46 9, 1979. B a r s o t t i, D. A . , C a rste n s, L . A. and A lle n , J . R . : Residual e f f e c t s o f poly­ ch lo rin a te d biphenyls on ad u lt nonhuman prim ates and t h e ir o ffs p r in g . Fed. Proc. 38:1119, 1979 (A b s tra c t). A lle n , J . R . , B a r s o t t i, D. A. and Lambrecht, L . K . : Reproductive e f f e c t s of halogenated arom atic hydrocarbons on nonhuman p rim a te s. New York Academy o f S c ie n c e s, 320:419-427, 1979. A lle n , J . R . , B a r s o t t i, D. A. and Van M ille r , J . P . : Pathology o f rhesus macaqques (Macaca m u latta) exposed to te tra ch lo ro d ib e n zo -£ -d io x in (TCDD). In te rn a tio n a l Symposium on Pathology o f Environm ental P o llu t a n t s , National Research C o u n c il, 346-355, 1979. ( A lle n , J . R . , Van M ille r , J . P. and B a r s o t t i, D. A . : T o x ic o lo g ic a l responses o f nonhuman prim ates to 1 , 2 , 4 , 6 , 7 ,8-h exach lo ro d ib en zo -£-d io xin (HCDD). T o x ic o l. Appl. Pharmacol. 4 7 :1 7 9 , 1979 (A b s t r a c t). C a rste n s, L . A . , B a r s o t t i, D. A. and A lle n , J . R . : Exposure o f p o ly c h lo rin ­ ated biphenyl (PCB) to in fa n t rhesus macaques (Macaca m u la tta ). In t e r ­ n atio n al Symposium on Pathobiology o f Environm ental P o llu t a n t s , .N ational Research C o u n c il, 339-345, 1979. S ch an tz, S. L . , B a r s o t t i, D. A. and A lle n , J . R . : T o x ic o lo g ic a l e f f e c t s pro­ duced in nonhuman prim ates c h r o n ic a lly exposed to f i f t y p a rts per t r i l l i o n 2 ,3 ,7 ,8 -te tra c h lo ro d ib e n zo -£ -d io x in (TCDD). T o x ic o l. A ppl. Pharmacol. 4 6 :1 8 0 , 1979 (A b s tra c t). A lle n , J . R. , Lambrecht, L. K. and B a r s o t t i, D. A .: Some general e f f e c t s of polybrominated biphenyls in nonhuman p rim ates. J . Am. V et. Med. Assoc. 173 11 :1485-1489, 1978. Lambrecht, L . K. , B a r s o t t i, D. A. and A lle n , J . R. : Responses of nonhuman prim ates to a polybrominated m ixtu re . E n v iro n . H ealth Persp ec. 23:139147, 1978. A lle n , J . R . , B a r s o t t i, D. A . , Van M ille r , J . P . , Abrahamson, L. J . and L a lic h , J . J . : Morphological changes in monkeys consuming a d ie t co n tain ­ ing low le v e ls of 2 ,3 ,7 ,8 - te tra c h lo ro d ib e n z o - £ - d io x in . Fd. Cosmet. , T o x ic o l. 15:401 -410, 1977. 5 A lle n , J . R. and B a r s o t t i, D. A .: Responses o f in fa n t primates to in te ru te rin e and neonatal exposure o f p o lych lo rin ate d b ip h e n yls. American Chemical So­ c ie t y , Proceedings o f 11th Great Lakes Regional Meeting, Jun e, 1977 (Ab­ s tra c t). A lle n , J . R . , B a r s o t t i, D. A. and Van M ille r , J . P . : Reproductive dysfunc­ tio n in nonhuman prim ates exposed to d io x in s . T o x ic o l. Appl. Pharmacol. 4 1 :1 7 9 , 1977 (A b s tra c t). Norback, D. H. and B a r s o t t i, D. A .: E ffe c t s o f p o lych lo rin ated biphenyls in nonhuman prim ates. Fed. Proc. 365 :3 9 6, 1977 (A b s tra c t). B a r s o t t i, D. A ., M arla r, R. J . and A lle n , J . R . : Reproductive d ysfu nctio ns in rhesus monkeys exposed to low le v e ls o f p o lych lo rin ate d biphenyls (A ro clo r 1248). Fd. Cosmet. T o x ic o l. 14:99 -1 03 , 1976. B a r s o t t i, D. A. and A lle n , J . R . : The a sso c ia tio n o f tra n sp la ce n ta l and mammary movement o f PCBs w ith in fa n t m o rb id ity and m o rta lity . Amer. J . Path. 8 2 :2 1 a , 1976 (A b s tra c t). A lle n , J . R. and B a r s o t t i, D. A .: The e f f e c t s o f tra n sp la ce n ta l and mammary movement o f PCBs on in fa n t rhesus monkeys. Toxicology 6:331-340, 1976. A lle n , J . R . , B a r s o t t i, D. A. and C a rs te n s , L . A .: Residual e ffe c t s of sh o rt term , low le v e l exposure o f nonhuman prim ates to p o lych lo rin ate d b ip h e n yls. T o x ic o l. Appl. Pharmacol. 3 0:440-451, 1974. - 6 1 0 Dr. Ronald Corderio, M.D., is an internist practicing in Philadelphia, Pennsylvania. His curriculum vitae will be supplied. Dr. Corderio will testify that he is currently engaged in the private practice of medicine as an internist. He will testify that he personally: has examined and/or treated over five hundred Vietnam veterans for complaints related to Agent Orange. He will testify as to the type of interview he has conducted with each veteran, the type of tests that each veteran should have performed, and the clinical significance of positive or negative findings on each of those tests. He will also discuss how toxins, and specifically Agent Orange, can cause changes in each of the tests and what such changes portend for the individual. Dr. Corderio will next discuss some of the available medical literature in both animals and humans to further validate his own work. Dr. Corderio will then outline in detail the results obtained from his own extensive investigation into Agent Orange toxicity based upon his examination of more than five hundred veterans, and will present those conclusions which he feels are reasonably appropriate based upon an analysis of his investigative work. With this material as background, Dr. Corderio will then proceed to present the test results which have been obtained for each court-approved representative veteran plaintiff. He will interpret each of the test results in terms of those individual plaintiffs. Finally, he will testify on generic causation and specific proximate causation in relation to each representative veteran plaintiff. He will also testify as to prognosis for each representative veteran plaintiff. 13167 ARTHUR W. GALSTON, Ph.D. Dr. Galston is Eaton Professor of Botany, Department of Biology, at Yale University. His Curriculum Vitae will be supplied. Dr. Galston is a plant physiologist and has personally observed the effect of the spraying of Agent Orange on the Vietnam ecosystem, i.e. the devastation of the Vietnamese countryside. Dr. Galston has been in Vietnam on four occasions between 1971 and 1982, and will describe those observations while in Vietnam, with such pictorial evidence as is available. Dr. Galston will testify to the potential and actual effects of phenoxy herbicides and their contaminants, both in Vietnam and elsewhere, including the United States and Sweden, and other places. The testimony will include the chemistry and the mechanisms of action of such chemicals on plant life. In addition, Dr. Galston will testify to the fate of Agent Orange and other phenoxy herbicides and their contaminants, especially TCDD, in the environment generally and in Vietnam in particular. Dr. Galston will testify to the persistence of such chemicals on plants, in water, and in soil, such that exposure to the phenoxy herbicides and their contaminants, especially TCDD, by the veterans in sprayed areas in Vietnam is presumed. The bases or grounds for Dr. Galston's testimony as to any facts and opinions expressed are a review of the scientific literature and his personal research and experience. Dr. John Garofalo is a immunologist practicing in Philadelphia, Pennsylvania. His curriculum vitae will be supplied. Dr. Garofalo will testify to the performance of certain tests on the veteran plaintiffs and their wives and children and to the interpretation of those test results. Specifically, he will be conducting phenotyping assay tests for, among others, B-lymphocytes, K cells, T-lymphocytes, T-helper cells, T-cytotoxic cells, and T-suppressor cells. The purpose of these tests is to determine antigen levels, antibody levels, and the presence of a viral defenses and immune surveillance systems, and to identify various types of cells that may be indicators of and/or precursors of malignancy Not only will the tests determine the presence of such factors, but they will also include functional assays of each. LENNART HARDELL, M.D. Dr. Hardell is employed by the University Hospital in its Department of Oncology in Umea, Sweden, where he specializes in internal medicine and oncology. His work includes diagnosis, treatment, and evaluation of possible causes of cancer, and education of medical students. Dr. Hardell will testify to several epidemiological studies which he and colleagues have conducted in Sweden. This research includes investigations concerning the relationship between the risk for different types of cancer and exposure to phenoxy herbicides and chlorophenols. The research has been published in the medical and scientific literature. These studies utilized the case-control study as the vehicle for investigation. Certain methodological aspects, such as selection of cases, selection of controls, assessment of exposure, and statistical methods, were considered; and then utilization was based upon thoroughly considered aspects of bias, all of which were well controlled. Specifically, these studies, four in number, involved soft tissue sarcomas, malignant lymphomas, and colon cancer. Highly statistically significant risks of soft tissue sarcomas and malignant lymphoma were found, whereas no association was found for colon cancer. In point of fact, the negative finding for colon cancer strongly supports the statistical significance of the increased risk demonstrated for soft tissue sarcomas and malignant lymphomas, i.e. a presumed causal relationship between exposure to phenoxy herbicides and human cancer particularly of soft tissue sarcoma and malignant lymphoma. 1 ? *-- 7 0 Dr. Hardell has also seen in his clinical practice basal cell carcinoma of persons previously exposed to phenoxy herbicides, with no other known confounding variables. With respect to those cases with soft tissue sarcoma, malignant lymphoma, and basal cell carcinomas, Dr. Hardell will testify that the presumed exposure to Agent Orange caused, in significant part, such neoplastic processes. The bases for Dr. Hardell’s testimony as to various facts and opinion include: educational background; professional training and experience; review of the applicable medical and scientific literature; personal research; and a review of the pertinent medical data of the relevant representative plaintiffs. «' RONALD H. KERMAN, Ph.D. Dr. Kerman is Associate Professor, and Chief, Cellular Immunology, Clinical Immunology Laboratories, the University of Texas Medical School at Houston. His Curriculum Vitae is attached. Dr. Kerman will testify that 2,3,7,8-TCDD in particular causes, among others, immuno-suppressive effects, as reported in the literature regarding the various animal species studies. Specifically, TCDD has been demonstrated to suppress T-cell mediated immunity in such species. This effect likewise has been demonstrated in humans by Bekesi, specifically an alteration of mature T-cells. Dr. Kerman will testify that the special scientific discipline involved is immuno-toxicology which has been defined as "the undesirable effects of an inappropriate response of the immune system". The bases for the facts and opinions to which Dr. Kerman will testify include a review of the applicable medical and scientific literature, his educational and professional background, and his work in connection with the Texas Agent Orange Study. Dr. Kerman will discuss the following in his testimony: the immune system, with its organic, cellular, and humoral components - most especially with regard to the latter, T-helper cells, B-cells, plasma cells and immunoglobulin production; immune response, both beneficial and harmful; the various experimental studies, particularly those demonstrating atrophy of the thymus, weight loss, depletion of lymphoid organs, lymphopenia, cutaneous type delayed hypersensitivity (skin thickness) and altered bacterial immuni ty. 1 o •? 7 s Dr . Kerman will testify that on the basis of the above a person exposed to TCDD might have increased predisposition to increased infection and neoplasm (cancer). 131^3 - 2 - CURRICULUM VITAE Ronald H. Kerman, Ph.D. DATE OF BIRTHr June 10, 1943 PLACE OF BIRTH: Chicago, Illinois NATIONALITY: U.S. Citizen SEX: Male EDUCATION: 1965 1967 1969 University of Illinois, B.S. (with Honors) University of Illinois, M.S. University of Illinois, Ph.D. in Immunology HONORS: 1965 1967-1969 1967 1969-1971 1970 Bachelor of Science with General Honors in the College Recipient of Public Health Service Predoctoral Traineeship Phi Sigma National Biological Honorary Recipient of Public Health Service Postdoctoral Traineeship Society of Sigma Xi RESEARCH AND PROFESSIONAL EXPERIENCE: 1983- 1981- 1977- 1977-1980 1974-1977 1973-1977 1972-1973 1969-1971 Associate Professor Department of Pathology, and Chief, Cellular Im­ munology, Clinical Immunology Laboratories, The Uni­ versity of Texas Medical School at Houston Associate Professor Department o f Surgery, and Head, Histocompatibility and Immune Evaluation Laboratories, Division o f Organ Transplantation, The University of Texas Medical School at Houston Member, Program in Immunology, Graduate School o f Bio­ medical Sciences, The University o f Texas Health Science Center at Houston Assistant Professor Department of Surgery, and Head, Histocompatibility and Immune Evaluation Laboratories, Division o f Organ Transplantation, The University of Texas Medical School at Houston Assistant Professor Department o f Surgery, Loyola University Stritch School o f Medicine, Maywood, Illinois Research Immunologist Chief, Immunobiology Research Laboratory, Research Service, V. A. Hospital, Hines, Illinois Assistant Professor Department of Microbiology, Jefferson Medical College Postdoctoral Fellow, (Immunology) Children's Hospital o f Philadelphia and The University o f Pennsylvania School o f Medicine Curriculum Vitae Ronald H. Kerman, Ph.D. 2 PROFESSIONAL SOCIETIES: The Transplantation Society (Editorial Board, Trans­ plantation and Member, Symposium Committee) American Association of Immunologists American Association for Cancer Research New York Academy of Sciences American Society of Transplant Physicians (Member, and Vice Chairman, Scientific Studies Committee) Society for Experimental Biology and Medicine International Society for Heart Transplantation American Association for the Advancement of Science American Society for Histocompatibility and Immunogenetics (Chairman, Finance and Audit Com m ittee, and Member, Laboratory Accreditation Committee) RESEARCH INTERESTS: Immunologic response to allotransplantation and malignancy Evaluation of immunocompetency RESEARCH SUPPORT: 1974-1978 1976-1979 1976- 1980 1977- 1978 197719771983-1984 OTHER ACTIVITIES: Co-principal Investigator: Bronchogenic Carcinoma: Immu­ nologic Profile, Radio and Immunotherapy - V.A. Medical Research Grant No. MRIS-8121-08. $213,000 Co-principal Investigator: Immunotherapy Adjuvant to Radiotherapy of Head and Neck Cancer - V.A. Medical Research Grant No. MRIS-8121-06. $73,814 Co-principal Investigator: Factors Influencing Immuno­ com pétence in Human Transplantation - V.A. Medical Research Grant No. MRIS-3068. $68,770 Principal Investigator: Functional and Surface Receptor D ifferences of Human T-lymphocyte Subpopulations General Research Support Funds, The University of Texas Medical School at Houston. $5,000 Principal Investigator: The Role of HLA Typing in Renal Transplantation, ESRD Program, No. 450068. $377,400 (last year) Principal Investigator: Immune Monitoring for the Diagnosis of Renal Allograft Rejection, ESRD Program, No. 450068. $544,800 (last year) Principal Investigator: Immune Evaluation of Veterans Exposed to Agent Orange. Texas Veterans Agent Orange Assistance Program, IAC(83-84)1266. $93,352 Special Consultant in Immunology to the Epidemiology and Disease Control Study Section, NIH Consultant in Immunology and Histocompatibility Testing to the Department of Laboratory Medicine, M.D. Anderson Hospital and Tumor Institute Editorial Board, Transplantation Review of manuscripts for the journal Human Immunology Review of manuscripts for the journal Transplantation Review of manuscripts for the journal Heart Transplantation Book reviewer for Journal of American Medical Association Literature Reviewer for The American Association of Clinical Histocompatibility Testing — AACHTion News Curriculum Vitae Ronald H. Kerman, Ph.D. 3 Grant Reviewer for the Kidney Foundation of Canada Grant Reviewer in Transplantation Immunology for The March of Dimes - Birth D efects Foundation Outside Reviewer of Research Proposals in Immunology for the Research and Development Committee, The Vet­ erans Administration Research Service Invited Participant (as a testing laboratory) in The Third American HLA Workshop Invited Participant (as a testing laboratory) in The Eighth International Histocompatibility Workshop "Relevance of DR typing to renal allograft survival" Invited Participant (as a testing laboratory) in The Inter­ national Transfusion and Transplantation Workshop Invited Participant (as a testing laboratory) for the Ninth International Histocompatibility Workshop Invited Presenter at an NIH Workshop, "The Biological Relevance of Immune Suppression as Induced by Genetic, Therapeutic and Environmental Factors" Invited Participant (as a testing laboratory) in the Inter­ national Collaborative Transplant Study Laboratory Inspector for Clinical Laboratory Accreditation in Histocompatibility for The American Society for His­ tocompatibility and Immunogenetics and The C ollege of American Pathologists Chairman, Finance and Audit Committee for The American Society for Histocompatibility and Immunogenetics Member, Symposium and Affiliations Committee, The Transplantation Society Member and Vice-Chairman, Scientific Studies Com m ittee, American Society of Transplant Physicians Member, Acquired Immune Deficiency Syndrome (AIDS) Working Group for the Houston Area Chairman, Organizing Com m ittee and Host for The Fourth International Immune Monitoring Symposium: Im­ munological Evaluation and Monitoring of the Transplant Recipient (1983) Member, Organizing Com m ittee for the International Sym­ posium on Relevant Immunological Factors in Clinical Kidney Transplantation, Heidelberg, West Germany, 1985 Member, UTMSH Admissions Interview Committee Member, UTMSH Admissions Committee Member, Medical Review Board, Organ Transplantation Center, UTMSH Member, Committee on Subject Selection for The University of Texas System Agent Orange Study Member, Steering Com m ittee, Program in Immunology, UT-GS3S Chairman, By-Laws Com m ittee, Program in Immunology, UT-GSBS Course Director, "Methods in Cellular Immunology," a Pro­ gram in Immunology Course, UT-GSBS Ü .JL*-•' 82 BIBLIOGRAPHY Ronald H. Kerman, Ph.D Publications 1. Kerman, R., Segre, D. and Myers, W.L.: Altered response to pneumococcal polysaccharide in offspring of immunologically paralyzed mice. Science 156:1514, 1967 2. Kerman, R., Segre, D. and Myers, W.L.: The role of immune and natural specific antibodies in immunologic paralysis and immunity of mice to pneumococcal polysac­ charide Type RI. J. Immunol. 104:655, 1970. 3. Kerman, R. and Segre, D.: Anti-pneumococcal polysaccharide Type III hemolytic plaques in mice: Cellular response in immunity and immunologic paralysis. J. Immunol. 104:1262, 1970. 4. Kerman, R. and Harris, T.N.: Resistance to dénaturation by periodate of a dialyzable histocompatibility antigen. Proc. Soc. Exp. Biol. Med. 141:179-183, 1972. 5. Kerman, R.H., Harris, T.N. and Harris, S.: Preparation of a dialyzable histocompati­ bility antigen from balb/c mice. Proc. Natl. Acad. Sci. 69:223-227, 1972. 6. Smith, R.A., Kerman, R., Ezdinli, E. and Stéfani, S.: A modified assay for the detection of human adult active rosette forming cells. J. Immunol. Meth. 8:175-184, 1975 7. Kerman, R. and Stefani, S.: Immunological evaluation of patients with solid tumors before and after radiotherapy. In Crispen, R.G. (ed.): Neoplasm Immunity: Mecha­ nisms, pp. 109-120. University of Illinois Press, 1976. 8. Stefani, S., Kerman, R. and Abbate, J.: Immune evaluation of lung cancer patients undergoing radiation therapy. Cancer 37:2792-2796, 1976. 9. Stefani, S., Kerman, R. and Abbate, J.: Serial studies of immunocompetence of patients undergoing radiotherapy for malignancies of the head and neck. Am. J. Roentgenol. 126:880-886, 1976. 10. Kerman, R.H. and Geis, W.P.: Total and active T -cell kinetics in renal allograft recipients. Surgery 79:398-407, 1976. U. Kerman, R., Smith, R., Stefani, S. and Ezdinli, E.: A ctive T-rosette forming cells in the peripheral blood of cancer patients. Cancer Res. 36:3274-3278, 1976. 12. Kerman, R., Smith, R., Ezdinli, E. and Stefani, S.: Unification and technical aspects of total T, active T and B lymphocyte rosette assays. Immunol. Comm. 5(7-3):685694, 1976. 13. Dodson, M.G., Kerman, R.H., Lange, C.F., Stefani, S. and O'Leary, J.A.: cells in pregnancy. Obstet. Gynecol. 49:299-302, 1977. T and B Bibliography Ronald H. Kerman, Ph.D. 2 14. Kerman, R.H. and Stefani, S.: PHA stimulation of lymphocytes from patients with lung cancer. Oncology 34:10-12, 1977. 15. Kerman, R.H. and Stefani, S.: Radio and immunotherapy of lung cancer: A preliminary report. In Crispen, R.G. (ed.): Neoplasm Immunity-Solid Tumor Therapy, pp. 29-35. Franklin Institute Press, 1977. 16. Stefani, S. and Kerman, R.H.: Lymphocyte response to PHA before and after radiation therapy in patients with carcinomas of the head and neck. J. Laryngol. Otol. 91:605-609, 1977. 17. Kerman, R.H., Ing, T.S., Hano, J.E. and Geis, W.P.: Prognostic significance of the active T-RFC in renal allograft survival. Surgery £2:607-612, 1977. 18. Marshack, M., Toto, P. and Kerman, R.H.: Delayed hypersensitivity in the hamster cheek pouch. J. Immunol. Meth. 15:325-330, 1977. 19. Marshack, M., Toto, P. and Kerman, R.H.: Immunotherapy of chemically-induced tumors in the hamster cheek pouch with dinitrochlorobenezene. J. Dental Res. 57:625-630, 1978. 20. Stefani, S. and Kerman, R.: Prognostic significance of pre-therapy delayed hypersen­ sitivity and T -cell levels in patients with lung cancer. In Nieburgs, H.E. (ed.): Proceedings of the Third International Symposium on the Detection and Prevention of Cancer, Vol. 1, Part II, pp. 785-797. Marcel Dekker, Inc., 1978. 21. Geis, W.P., Iwatsuki, S., Molnar, Z., Giaechino, J.L., Kerman, R.H., Ing, T.S. and Hano, J.E.: Immunoblastic pseudo-lymphoma in renal allograft recipients. Arch. Surg. 113:461-466, 1978. 22. Dodson, M., Klegerman, M., Kerman, R.H., Lange, C., Tessler, J. and O'Leary, J.: Bechet syndrome: With immunologic evaluation. Obstet. Gynecol. 5_l:621-625, 1978. 23. Dodson, M.G., Klegerman, M.E., Menon, M., Kerman, R.H., Lange, C.F. and O'Leary, J.A.: Establishment and characterization of a squamous cell carcinoma of the vulva in tissue culture and immunological evaluation of the host. Am. J. Obstet. Gynecol. 131:606-619, 1978. 24. Kerman, R.H. and Geis, W.P.: T-RFC monitoring of CMI events in renal allograft recipients. Transpl. Proc. 10(3):633-635, 1978. 25. Kerman, R.H., Ing, T.S., Hano, J.E. and Geis, W.P.: Predictive value of active T-RFC in renal allograft survival. Transpl. Proc. 10(3):637-638, 1978. 26. Kerman, R.H. and Stefani, S.S.: E ffect of BCG immunotherapy on the active T and total T-RFC in patients with lung cancer.. Cancer Immunol. Immunother. 4:41-47, 1978. 27. Kahan, B.D., Kerman, R.H. and McConnell, R.: Combination of immunological and radionuclide techniques to diagnose allograft rejection. Surgical Forum. 29:364-366, 1978. tsiDiiography Ronald H. Kerman, Ph.D. 3 28. Stéfani, S. and Kerman, R.H.: Prognostic value of the immunologic profile in inoperable lung cancer patients treated by radiation. In Muggia, F. and Rozencweig, M. (eds.): Lung Cancer (Progess in Cancer Research and Therapy), Vol. 11, pp. 465470. Raven Press, Inc., New York, 1979. 29. Kerman, R.H.: Identification of human T and B lymphocytes. In Natelson, S., Pesce, A.J. and D ietz, A.A.: Clinical Immunochemistry: Chemical and Cellular Bases and Applications in D isease, pp. 12-20. American Association for Clinical Chemistry, 1979. 30. Kahan, B.D., Floyd, M., Oka, T., Van Buren, C.T. and Kerman, R.H.: Immunological techniques in clinical renal transplantation. I. Cross-Match Methods, Jap. J. Trans­ plant. 14:1-13, 1979. 31. Kahan, B.D., Floyd, M., Oka, T., Van Buren, C.T. and Kerman, R.H.: Immunological techniques in clinical renal transplantation. II. Immunological Monitoring Post­ allografting. Jap. J. Transplant. 14:14-25, 1979. 32. Kerman, R.H., Floyd, M., Conner, W., McConnell, R., McConnell, B.J., Van Buren, C.T. and Kahan, B.D.: Combined immunological and radionuclide techniques to monitor renal allograft rejection. Transpi. Proc. Jll:1229-1231, 1979. 33. Geis, W.P., Giacchino, J.L., Buckingham, J.M., Bansal, V.K., Iwatsuki, S., Kerman, R.H., Ing, T.S. and Hano, J.E.: Does suppression of T-RFC determine in vivo immunosuppressive e ffe ct of ATG? Transpl. Proc. JL1:1433-1434, 1979. 34. Kerman, R.H., Floyd, M., Van Buren, C.T. and Kahan, B.D.: Improved allograft survival of strong immune responder-high risk recipients with adjuvant ATG therapy. Transplantation 30:450-454, 1980. 35. Kerman, R. and Kahan, B.D.: Clinical histocompatibility testing in renal transplanta­ tion: Potential keys to alloimmune specificity and reactivity. In Reisfeld, R. and Ferrone, S. (eds.): Current Trends in Histocompatibility, Vol. 2, pp. 201-226. Plenum Press, 1981. 36. Kerman, R.H. and Kahan, B.D.: Assessment of immune parameters of transplant recipients on immunosuppressive therapy. In Dean, J. and Padarathsingh, M. (eds.): Biological Relevance of Immune Suppression as Induced by Genetic Therapeutic and Environmental Factors, pp. 82-97. Van Nostrand R.einhold Co., New York, 1981. 37. Kerman, R.H., Floyd, M., Van Buren, C.T. and Kahan, B.D.: Prolonged allograft survival of strong pretransplant immune responders treated with ATG. Transpl. J?roc. 13:332-335, 1981. 38. Kerman, R.H., Floyd, M., Van Buren, C.T. and Kahan, B.D.: Correlation of non­ specific immune monitoring with rejection or impaired function of renal allografts. Transplantation 32:16-23, 1981. 39. Kerman, R.H., Floyd, M., Van Buren, C.T., and Kahan, B.D.: Prediction of cadaveric allograft survival based on pretransplant nonspecific immunocompétence. Transpl. Proc. 13:1533-1535, 1981. i 3 ■8 5 Bibliography Ronald H. Kerman, Ph.D. 4 40. Kerman, R.H., Floyd, M., Van Buren, C.T. and Kahan, B.D.: Serial measurement of nonspecific immune parameters of chronically hemodialyzed renal failure patients. J. Clin. Immunol. 1:163-168, 1981. 41. Kerman, R.H.: New developments in transplantation immunology. Bulletin 33(6):281-286, 1981. 42. Kerman, R.H.: E ffect of blood transfusion on renal allograft survival: Immunological considerations. Am. J. Kidney Diseases 2:125-127, 1981. 43. Kerman, R.H. and Kahan, B.D.: Immunological evaluation of transplant rejection: Pre and postoperative indices detecting immune responsiveness. In Hayry, P. (ed.): Present and Future Trends in Clinical Transplantation. Ann. Clin. Res. 13:244-263, 1981. 44. Kerman, R.H., Van Buren, C., Payne, W., Flechner, S., Agostino, G., Conley, S., Brewer, E. and Kahan, B.D.: Influence of blood transfusions on immune responsive­ ness. Transpi. Proc. 14:335—337, 1982. 45. Kahan, B.D., Van Buren, C.T., Lin, S.N., Ono, Y., Agostino, G., LeGrue, S., Boileau, M., Payne, W. and Kerman, R.H.: Immunopharmacologic monitoring of Cyclo­ sporin A-treated recipients of cadaveric kidney allografts. Transplantation 34:36-45, 1982. 46. Ono, Y., Kerman, R.H. and Kahan, B.D.: Natural cell-m ediated cytotoxicity and suppressor activity for natural cell-m ediated cytotoxicity in long-term renal trans­ plant patients. Transplantation 34:103-107, 1982. 47. Van Buren, C.T., Kerman, R.H., Agostino, G., Payne, W., Flechner, S. and Kahan, B.D.: The cellular target of Cyclosporin A action in man. Surgery 92:167-174, 1982. 48. Kahan, B.D., Kerman, R.H., Agostino, G., Friedman, A. and LeGrue, S.J.: The action of Cyclosporin A on human lymphocytes. In White, D.J.G. (ed.): Cyclosporin A, pp. 281-293. Elsevier - Biomedical Press, Amsterdam, 1982. 49. Agostino, G.J., Kahan, B.D. and Kerman, R.H.: Suppression of mixed leucocyte culture using leucocytes from normal individuals, uremic individuals and allograft recipients. Transplantation 34:367-371, 1982. 50. Kerman, R.H., Conklin, R., Cahall, D., Van Buren, C.T. and Kahan, B.D.: CMV and renal allograft survival. In Eisenstein, T. and Friedman, H. (eds.): Host D efenses to Intracellular Pathogens, pp. 517-519. Plenum Press, Inc., New York, 1983. 51. Ettenger, R.B., Kerman, R., Jordan, S.C., Warshaw, B.L., Harris, R. and Fine, R.: Sensitization following donor-specific transfusions for living related renal transplan­ tation. Transpl. Proc. 15:943-945, 1983. 52. Van Buren, C.T., Kerman, R.H., Agostino, G., Flechner, S., Payne, W., and Kahan, B.D.: E ffect of cyclosporine on immunoregulatory cells of renal allograft recipients. Transpl. Proc. 15:527-530, 1983. The Cancer 83 Bibliography Ronald H. Kerman, Ph.D. 5 53. Kerman, R.H., Van Buren, C.T., Payne, W., Flechner, S. and Kahan, B.D.: Monitoring T cell subsets and immune events in renal allograft recipients. Transpl. Proc. 15:1170-1172, 1983. 54. Flechner, S., Kerman, R., Van Buren, C.T., Payne, W., and Kahan, B.D.: The use of cyclosporine and prednisone for high MLC haploidentical living related renal trans­ plants. Transpl. Proc. 15:442-445, 1983. 55. Agostino, G., Kahan, B.D. and Kerman, R.: D etection of nonspecific suppressor cells from normal individuals, uremic patients and allograft recipients. Transpl. Proc. 15:724-728, 1983. 56. Kerman, R.H., Agostino, G., Van Buren, C.T., Payne, W., Flechner, S., Conley, S., Brewer, S. and Kahan, B.D.: E ffect of blood transfusions on graft survival and immune responsiveness. Transpl. Proc. 15:1022-1025, 1983. 57. Kerman, R.H., Van Buren, C., Payne, W., Flechner, S., Agostino, G., Conley, S., Brewer, 3. and Kahan, B.D.: The influence of pretransplant blood transfusions from random donors on immune parameters affecting cadaveric allograft survival. Trans­ plantation 36:50-54, 1983. 58. Kerman, R.H., Flechner, S., Van Buren, C.T., Payne, W., and Kahan, B.D.: Cyclo­ sporine improves allograft survival in immunologically high-risk renal allograft recipients. Transpl. Proc. 15:1909-1911, 1983. 59. Kerman, R.H., Van Buren, C.T., Payne, W., Flechner, S., and Kahan, B.D.: Immune monitoring of renal allograft recipients treated with cyclosporine or azathioprine using donor-specific and nonspecific assays as well as monoclonal T cell reagents. Transpl. Proc. 15:1971-1973, 1983. 60. Kerman, R.H., Payne, W., Van Buren, C.T., Flechner, S., and Kahan, B.D.: Detection of host presensitization to donor alloantigens utilizing a comprehensive immune crossmatch. Transpl. Proc. 15:1815-1816, 1983. 61. Flechner, S.M., Payne, W.D., Van Buren, C., Kerman, R., and Kahan, B.D.: The e ffe c t of cyclosporine on early graft function. Transplantation 36:268-272, 1983. 62. Verani, R.R., Bergman, D., and Kerman, R.H.: Glomerulopathy in acute and chronic rejection: Ultrastructural characteristics and relationship to graft survival. Am. J. Nephrol. 3:253-256, 1983. 63. Kerman, R.H.: Editorial: Influence of HLA A, B and DR antigen matching in transfused cadaver renal transplant patients. Cleveland Clinic Quarterly 50:216-217, 1983. 64. Kerman, R.H., Flechner, S., Van Buren, C.T., Payne, W. and Kahan, B.D.: Immuno­ logical monitoring of renal allograft recipients treated with cyclosporine. Transpl. Proc. 16:2302-2305, 1983. Bibliography Ronald H. Kerman, Ph.D. 6 65. Van Buren, C., Kerman, R., Agostino, G., Flechner, S., Payne, W.D., and Kahan, B.: E ffect of cyclosporine on immunoregulatory cells of renal allograft recipients. Transpi. Proc. 16:2293-2297, 1983. 66. Kahan, B.D., Van Buren, C., Flechner, S., Payne, W.D., and Kerman, R.: Cyclosporine immunosuppression m itigates immunologic risk factors in renal allotransplantation. Transpl. Proc. 16:2469-2478, 1983. 67. Flechner, S.M., Van Buren, C., Kerman, R.H., and Kahan, B.D.: The nephrotoxicity of cyclosporine in renal transplantation. Transpl. Proc. 16:2689-2694, 1983. 68. Flechner, S.M., Van Buren, C.T., Kerman, R., and Kahan, B.D.: The e ffe c t of conversion from cyclosporine to azathioprine immunosuppression for intractable nephrotoxicity. Transpl. Proc., 1983 (In press). 69. Flechner, S.M., Kerman, R.H., Van Buren, C., and Kahan, B.D.: Successful trans­ plantation of cyclosporine treated haploidentical living related renal recipients without blood transfusions. Transplantation, 1984 (In press). 70. Kerman,_ R.H., Van Buren, C.T., Flechner, S.M., and Kahan, B.D.: Correlation of visual, Slop-release, and flow cytometry crossmatch results to graft survival. Transpl. Proc., 1984 (In press). 71. Rogers, A.J., Kerman, R.H., and Kahan, B.D.: The pharmacokinetic and immunobiological activity of cyclosporine in man. Transpl. Proc., 1984 (In press). 72. Van Buren, C.T., Flechner, S.M., Kerman, R.H., Vaughn, W., and Kahan, B.D.: Cyclosporine improves outcome in high risk cadaveric renal allograft recipients. Transpi. Proc. 1984 (In press). 73. Kerman, R.H., Manner, C., Ford, K., and Hoots, K.: Comprehensive immune evaluation of 78 hemophiliacs. Ann. N. Y. Acad. Sc. 1984 (In press). Bibliography Ronald H. Kerman, Ph.D. 7 Abstracts and Presentations 1. Kerman, R., Clark, J. and Wheelock, E.F.: Mononuclear infiltrate into an air pouch: A new in vitro cell mediated immune assay. Fed. Proc. 32:973, Atlantic City, New Jersey, April 1973. 2. Wheelock, E.F., Kerman, R.H., Clark, J. and Toy, S.: Cell mediated immunity in dormant friend virus infections. Proc. Am. Assoc. Cancer Res. 14:68, Atlantic City, New Jersey, April 1973. 3. Stefani, S., Kerman, R. and Abbate, J.: Serial studies of immunocompetence in head and neck cancer patients undergoing radiotherapy. Abstract, American Radium Society Meeting, San Juan, Puerto Rico, May 1975. 4. Kerman, R., Stefani, S. and Geis, W.P.: Total and active T -cell dynamics in renal allograft recipients. Abstracts of the American Society Transplant Surgeons, Chicago, Illinois, May 1976. 5. Kerman, R., Stefani, S., Smith, R., Ezdinli, E. and. Geis, W.P.: Immunological evaluation of patients with solid tumors and hematological malignancies. Presented at the 1975 Cancer Symposium, Neoplasm Immunity: Mechanism, Chicago, Illinois, September 1975. 6. Stefani, S., Kerman, R. and Abbate, J.: Immunological evaluation of patients with bronchogenic carcinoma. Presented at the American Society of Therapeutic Radi­ ology, San Francisco, California, October 1975. 7. Stefani, S. and Kerman, R.: Determination and prognostic value of immunocompe­ tence in patients with lung cancer treated by radiotherapy. Abstracts of the Third International Symposium on Detection and Prevention of Cancer, New York, April 1976. 8. Geis, W.P., Vaz, A.L. and Kerman, R.H.: Steroid sparing e ffect of ATG in high risk renal allograft survival. Presented at the American Society of Transplant Surgeons Meeting, Chicago, Illinois, May 1976. 9. Kerman, R.H., and Geis, W.P.: Prognostic significance of the active T -cell in renal allograft survival. Presented at the American Society Transplant Surgeons Meeting, Chicago, Illinois, May 1976. 10. Stefani, S. and Kerman, R.: BCG and radiotherapy in bronchogenic carcinoma: Preliminary report. Presented at the American Society of Therapeutic Radiology, • .Atlanta, Georgia, October 1976. 11. Kerman, R. and Geis, W.P.: T-RFC monitoring of CMI events in renal allograft recipients. Presented at the Sixth International Congress of the Transplantation Society Special Session Immunological Monitoring of Transplant Recipient, New York, August 1976. 12. Kerman, R. and Stefani, S.: Radio and immunotherapy of lung cancer: A preliminary report. Presented at the 1977 Chicago Symposium: Immunotherapy of Solid Tumors, Chicago Illinois, February 24-25, 1977. Bibliography Ronald H. Kerman, Ph.D. 8 13. Stefani, S. and Kerman, R.H.: Relevance of immunologic analysis for patients with inoperable lung cancer treated by radiotherapy. Presented at an NCI sponsored Symposium "The Second Conference on Lung Cancer Treatment," at Airlie House, Virginia, May 22-24, 1977. 14. Kerman, R.H., Ing, T.S., Hano, J.E. and Geis, W.P.: Prognostic significance of active T-RFC in renal allograft survival. Abstracts of First International Symposium on Immunological Monitoring of the Transplant Recipient. London, Ontario, June 8-10, 1977. 15. Kerman, R.H. and Geis, W.P.: T-RFC monitoring of CMI events in renal allograft recipients. Abstracts of First International Symposium on Immunological Monitoring of the Transplant Recipient. London, Ontario, June 8-10, 1977. 16. Ezdinli, E., Simonson, K., Icli, F. and Kerman, R.: E ffects of single vs. multiple agent therapy on cell-m ediated immunity. Proc. Amer. Assoc. Clin. Oncol. 18:355, Denver, Colorado, May 1977. 17. Geis, W.P., Iwatsuki, S., Molnar, Z., Giacchino, J.L., Kerman, R.H., Ing, T.S. and Hano, J.E.: Immunoblastic pseudo-lymphoma in renal allograft recipients. Presented at the Western Surgical Association, Las Vegas, Nevada, November 15, 1977. 18. Kerman, R.H., Roesler, H. and Kahan, B.D.: Specific stimulation of active T -R osette forming cells by 3M KC1 solubilized antigen. Fed. Proc., 1973. Presented at the FASEB-AAI Meeting, Atlanta, Georgia, June 1978. 19. Kerman, R.H., Floyd, M., Conner, W., McConnell, B.J., McConnell, R. and Kahan, B . D.: Correlation of active T-RFC and spontaneous blastogenesis with decreased renal allograft function. Abstracts of the American Association for Clinical Histocompatibility Testing, Boston, Massachusetts, June 1978. 20. Kerman, R.H., Roesler, H. and Kahan, B.D.: Increased active T-RFC with in vitro stimulation by soluble donor antigen. Abstracts of the Amer. Assoc, of Clin. Histocomp.. Testing, Boston, Massachusetts, June 1978. 21. Kerman, R.H., Floyd, M., Conner, W., McConnell, R., McConnell, B .J., Van Buren, C. T. and Kahan, B.D.: Combined immunological and radionuclide techniques to monitor renal allograft rejection. Presented at the VII International Congress of The Transplantation Society, Rome, Italy, September 1978. 22. Kerman, R.H.: Invited speaker to a special workshop "Immunological Monitoring of the Transplant Patients", VII International Congress of The Transplantation Society, Rome, Italy, September 1978. 23. Kahan, B.D., Kerman, R. and McConnell, R.: Combination of immunological and radionuclide techniques diagnoses allograft rejection. Presented at the American College of Surgeons, San Francisco, California, October 1978. 24. Michelson, J., McConell, Kerman, R. and Kahan, B.: Association of acute rejection episodes in renal transplant patients with scored results of computer analyzed data. Presented at the Southwest Society of Nuclear Medicine Meeting, March 16, 1979, San Antonio, Texas. 190 Bibliography Ronald H. Kerman, Ph.D. 9 25. Kerman, R.H., Macek, C. and Kahan, B.D.: Increase in 3 different E-rosette markers on human T cells following PHA activation. Fed. Proc. 38 (No. 3, Part n):1282. Presented at the Annual Meeting of The American Association of Immunologists, Dallas, Texas, April 1979. 26. Kerman, R.H.: Immunological considerations in renal transplantation. Clinical Oncology Grand Rounds, M.D. Anderson Hospital and Tumor Institute, September 1979. 27. Kerman, R.H. and Kahan, B.D.: Assessment of immune parameters of transplant recipients on immunosuppressive therapy. Presented at an NIH Workshop on "The Biological Relevance of Immune Suppression as Induced by Genetic Therapy and Environmental Factors," Williamsburg, Virginia, November 1979. 28. Invited participant in a working cadre for the NIH to develop a "Consensus On Immunotoxicology" for the National Toxicology Program, November 1979, Research Triangle Park, N.C., NIEHS, NIH. 29. Kerman, R.H.: Histocompatibility testing in transplantation. Rounds, St. Luke's Hospital, January 1980. 30. Van Buren, C.T., Kerman, R.H. Van Buren, D. and Kahan, B.D.: Correlation of immune responsiveness with nutritional indices in chronic renal failure patients. Presented at the American Society for Parenteral and Enteral Nutrition, Annual Meeting, Chicago, Illinois, January - February 1980. 31. Kerman, R.H.: Immune monitoring of renal allograft recipients. Rounds, University of Miami School of Medicine, March 1980. 32. Kerman, R.H.: Pre- and postoperative immune monitoring of allograft recipients. Medical Grand Rounds, Division of Dialysis and Transplantation, Children's Hospital of Los Angeles, April 1980. 33. Kerman, R.H. and Semchuk, R.: Delineation of a radioresistant T cell subpopulation. Fed. Proc. 39(3):945. Presented at the Annual Meeting of The American Association of Immunologists, Anaheim, California, April 1980. 34. Kerman, R.H.: E ffect of heat on the ability of human T cells to express the active T and total T receptors. Fed. Proc. 39(3): 1137. Presented at the Annual M eeting of The American Association of Immunologists, April 1980, Anaheim, California. 3-5. Kerman, R., Peddada, L. and Kahan, B.D.: Correlation of hyperacute rejection with " .LDA and CD A vs. 51cr-labeled donor T and B cell targets. Presented at The American Association for Clinical Histocompatibility Testing, St. Louis, Missouri, April 1980. 36. Kerman, R., Floyd, M., Van Buren, C.T. and Kahan, B.D.: Improved allograft survival of strong responder-high risk cadaver recipients with adjuvant immunosuppressive therapy. Presented at the Annual Meeting of The American Association for Clinical Histocompatibility Testing, April 1980. Pathology Grand Surgical Grand 12191 Bibliography Ronald H. Kerman, Ph.D. 10 37. Kerman, R., Conklin, R., Cahall, D. and Kahan, B.D.: Association of cytomegalovirus and renal allograft survival. Presented at the meeting of the American Association for Clinical Histocompatibility Testing, St. Louis, Missouri, April 1980. 38. Kerman, R., Floyd, M., VanBuren, C.T. and Kahan, B.D.: Delineation of donor specific and nonspecific pretransplant immunocompétence as a predictor for LRD allograft survival. Presented at the Meeting of The American Association of Clinical Histocompatibility Testing, St. Louis, ?/lissouri, April 1980. 39. Kerman, R.H., Floyd, M., VanBuren, C.T. and Kahan, B.D.: Improved allograft survival of strong immune responder-high risk recipients with adjuvant immuno­ suppressive therapy. Presented at the annual meeting of The American Society of Transplant Surgeons, Chicago, Illinois, May 1980. 40. Kerman, R.H., Floyd, M., VanBuren, C.T. and Kahan, B.D.: Correlation of nonspecific immune monitoring of renal allograft recipients with rejection and impaired renal function. Presented at the Annual Meeting of The American Society of Transplant Surgeons, Chicago, Illinois, May 1980. 41. Kerman, R., Floyd, M., VanBuren, C.T. and Kahan, B.D.: Prolonged allograft survival of strong pretransplant immune responders treated with ATG. Presented at the VUIth International Congress of The Transplantation Society, Boston, Massachu­ setts, June 1980. 42. Kerman, R., Floyd, M., Van Buren, C.T. and Kahan, B.D.: Prediction of renal allograft survival based on pretransplant non-specific immunocompétence. Presented at The Second International Symposium on Immunological Monitoring of the Trans­ plant Recipient, Leiden, The Netherlands, September 1980. 43. Kerman, R.H., Floyd, M., Van Buren, C.T., McConnell, B.J., McConnell, R. and Kahan, B.D.: Delineation of renal allograft rejection and impaired renal function by serial measurement of non-specific immune parameters. Presented at The Second International Symposium on Immunological Monitoring of the Transplant Recipient, Leiden, The Netherlands, September 1980. 44. Kerman, R.H. and Kahan, B.D.: Increased expression of the active T-RFC receptor as a measure of allosensitization following in vitro stimulation of recipient lympho­ cytes by soluble donor HLA antigens. Presented at The Second International Symposium on Immunological Monitoring of the Transplant Recipient, Leiden, The Netherlands, September 1980. 45. Kerman, R.H., Floyd, M., Van Buren, C.T. and Kahan, 3.D .: Correlation of HLA A,B ■. and DR typing to cadaveric and living related renal allograft survival. Presented at The Second International Symposium on Immunological Monitoring of the Transplant Recipient, Leiden, The Netherlands, September 1980. 46. Floyd, M., Kerman, R., Woo, J., Van Buren, C.T. and Kahan, B.D.: Relationships of beta-2-microglobulin metabolism, immune reactivity and renal allograft rejection. Presented at The Second International Symposium on Immunological Monitoring of the Transplant Recipient, Leiden, The Netherlands, September 1980. 92 Bibliography Ronald H. Kerman, Ph.D. 11 47. Kerman, R.H.: Immune monitoring of renal allograft recipients. Rounds, University of Chicago, June 1981. Surgical Grand 48. Kerman, R.H., Van Buren, C.T., LeGrue, S.J. and Kahan, B.D.: Immunopharmacological monitoring of cadaveric renal allograft recipients receiving Cyclosporin A. Presented at the Annual Meeting of the American Society of Transplant Surgeons, Chicago, Illinois, June 1981. 49. Kerman, R.H., Conklin, R., Cahall, D., Van Buren, C.T. and Kahan, B.D.: CMV and renal allograft rejection. Presented at a Symposium on Host Defenses to Intra­ cellular Pathogens, Franklin Plaza Hotel, Philadelphia, Pennsylvania, June 1981. 50. Schoenberg, L.P., Kahan, B.D. and Kerman, R.H.: The use of Cyclosporin A as immunosuppressive medication in renal transplantation. Presented at The National Kidney Foundation, Inc., Washington, D.C., November 1981. Amer. J. Kidney Diseases, Program for Clinical Dialysis and Transplantation Forum, p. 29. 51. Ettenger, R., Kerman, R., Arnett, J., Jordan, S., Warshaw, B., Harris, R., Wassner, S. and Fine, R.: Sensitization following donor-specific transfusions for live-related renal transplantation. American Society of Nephrology, Washington, D.C., November 1981. 52. Flechner, S., Boileau, M., Payne, W., Van Buren, C., Kerman, R. and Kahan, B.: The use of Cyclosporin A in strong immune responder, high risk renal transplant reci­ pients. American Urological Association, Kansas City, Kansas, 1982. 53. Kerman, R., Van Buren, C., Payne, W., Flechner, S., Agostino, G., Conley, S., Brewer, E. and Kahan, B.: Influence of blood transfusions on immune responsiveness. Presented at The Transfusion and Transplantation Conference, Los Angeles, Cali­ fornia, January - February 1982. 54. Agostino, G., Kahan, B.D. and Kerman, R.H.: Suppression of mixed leucocyte culture using mononuclear leukocytes from normals, urémies and allograft recipients. Pre­ sented at the Annual Meeting of The American Association of Immunologists, FASEB, New Orleans, Louisiana, April 1982. 55. Agostino, G.J., Kahan, B.D. and Kerman, R.H.: Measurement of suppressor cell status in potential allograft recipients. Presented at the Annual Meeting of The American Association of Clinical Histocompatibility Testing, San Francisco, Cali­ fornia, April 1982. 56. Kerman, R.H.: Invited presenter at two workshops on 1) Immune monitoring of allograft recipients and 2) The e ffect of transfused blood and blood products on uremic hosts. Presented at the Annual Meeting of The North American Transplant Coordinators Organization, San Antonio, Texas, May 1982. 57. Kerman, R.H., Van Buren, C., Flechner, S., Agostino, G., Conley, S., Brewer, E. and Kahan, B.D.: The influence of pretransplant blood transfusions from random donors on immune parameters affectin g cadaveric allograft survival. Presented at The Annual Meeting of The American Society of Transplant Surgeons, Chicago, Illinois, June 1982. 1 JLC 93 Bibliography Ronald H. Kerman, Ph.D. 12 58. Agostino, G., Kahan, B.D. and Kerman, R.H.: Suppression of mixed leucocyte culture using leucocytes from normal individuals, uremic individuals, and allograft recipients. Presented at The Annual Meeting of The American Society of Transplant Surgeons, Chicago, Illinois, June 1982. 59. Kerman, R.H.: Invited presenter at a workshop on "Human T lymphocyte subpopula­ tions: Their role in rejection and immunosuppression." Presented at the International Congress of The Transplantation Society, Brighton, England, August 1982. 60. Kerman, R.H.: Invited presenter at a workshop on "Mechanisms responsible for blood transfusion effects." Presented at The International Congress of The Transplantation Society, Brighton, England, August 1982. 61. Ettenger, R.B., Kerman, R., Jordan, S.C., Warshaw, B.L., Harris, R. and Fine, R.: Sensitization after donor-specific transfusions for live-related renal transplantation. Presented at The International Congress of The Transplantation Society, Brighton, England, August 1982. 62. Van Buren, C.T., Kerman, R.H., Agostino, G., Flechner, S. Payne, W. and Kahan, B.D.: E ffect of cyclosporine on immunoregulatory cells of renal allograft recipients. Presented at The International Congress of The Transplantation Society, Brighton, England, August 1982. 63. Kerman, R.H., Van Buren, C.T., Payne, W., Flechner,.S. and Kahan, B.D.: Monitoring T cell subsets and immune events in renal allograft recipients. Presented at The International Congress of The Transplantation Society, Brighton, England, August 1982. 64. Flechner, S., Kerman, R., Van Buren, C.T., Payne, W. and Kahan, B.D.: The use of cyclosporine and prednisone for high MLC haploidentical living related renal trans­ plants. Presented at The International Congress of The Transplantation Society, Brighton, England, August 1982. 65. Agostino, G., Kahan, B.D. and Kerman, R.: D etection of nonspecific suppressor cells from normal individuals, uremic patients and allograft recipients. Presented at The International Congress of The Transplantation Society, Brighton, England, August 1982. 66. Kerman, R.H., Agostino, G., Van Buren, C.T., Payne, W., Flechner, S., Conley, S., Brewer, E. and Kahan, B.D.: E ffect of blood transfusions on graft survival and immune responsiveness. Presented at The International Congress of The Transplantation Society, Brighton, England, August 1982. 67. Kahan, B.D., Kerman, R., Payne, W.D., Flechner, S. and Van Buren, C.T.: Immunopharmacologic studies of cyclosporine-treated renal allograft recipients. Fifth Tripartite Meeting, Society of University Surgeons, Salzburg, Austria, September 1982. Bibliography Ronald H. Kerman, Ph.D. 13 68. Kerman, R.H., Flechner, S., Van Buren, C.T., Payne, W., and Kahan, B.D.: Cyclo­ sporine improves allograft survival in immunologically high-risk renal allograft recipients. Presented at the Third International Immunological Monitoring Sym­ posium, Key Biscayne, Florida, November 1982. 69. Kerman, R.H., Van Buren, C.T., Payne, W., Flechner, S., and Kahan, B.D.: D etection of host presensitization to donor alloantigens utilizing a comprehensive immune crossmatch. Presented at the Third International Immunological Monitoring Sym­ posium, Key Biscayne, Florida, November 1982. 70. Kerman, R.H., Payne, W., Van Buren, C.T., Flechner, S., and Kahan, B.D.: Immune monitoring of renal allograft recipients treated with cyclosporine or azathioprine using donor-specific and nonspecific assays as well as monoclonal T cell reagents. Presented at the Third International Immunological Monitoring Symposium, Key Biscayne, Florida, November 1982. 71. Kerman, R.H.: Invited plenary speaker at the First Annual Meeting of The American Society of Transplant Physicians, "Optimizing immunosuppression: Mode of action of cyclosporine." Chicago, December 1982. 72. Kerman, R.H., Van Buren, C.T., Payne, W., Flechner, S., and Kahan, B.D.: Cyclo­ sporine improves allograft survival in immunologically high-risk renal allograft recipients. Presented at The Annual Meeting, National Kidney Foundation, Clinical Dialysis and Transplant Forum, Chicago, December 1982. 73. Kerman, R.H.: Role of immune evaluation in clinical medicine. Clinical Immunology Grand Rounds, The Children's Memorial Hospital, Chicago, Illinois, December 1982. 74. Kerman, R.H.: Immunologic effects of toxic materials. Presented at Toxicology Clinical Update, University of Texas Medical Branch, Galveston, Texas, January 1983. 75. Kerman, R.H.: Cyclosporine improves allograft survival in immunologically high risk renal allograft recipients. Presented at Pathology Grand Rounds, University of Pittsburgh School of Medicine, February 1983. 76. Kerman, R.H.: Immune evaluation of renal failure patients and allograft recipients. Presented at Surgical Grand Rounds, St. Louis University Medical Center, St. Louis, Missouri, March 1983. 77. Kerman, R.H.: Immunological evaluation of hemophiliacs. Presented at a Symposium on Current Problems in the Management of Hemophiliac Complications, Houston, • Texas, April 1983. 78. Flechner, S., Kerman, R.H., Van Buren, C.T., Payne, W., and Kahan, B.D.: Successful transplantation of high mixed lymphocyte culture haplo-identical living related donors using cyclosporine and prednisone. Presented at the Annual American Urological Association, Las Vegas, Nevada, April 1983. 79. Kerman, R.H., Flechner, S., Van Buren, C.T., Payne, W., and Kahan, B.D.: Immunolo­ gical monitoring of renal allograft recipients treated with cyclosporine. Presented at The First International Congress on Cyclosporine, Houston, Texas, May 1983. c ■*q JL \ 25. Levin, A.S., Transfer Factor Therapy: Current Status. So. Med. Journal (invited editorial) _6^3, 1465-1466, 1975 26. Fudenberg, H.H., Byers, V.S., Levin, A.S., and Hackett, A.J.: Additional evidence for viral etiology of certain human tumors in A.A. Gottlieb, M.D., Fundamental Aspects of Neoplasia. New York: SpringerVerlag, 1974 27. Fudenberg, H.H., Byers, V.S., and Levin, A.S., : Immunologic Evidence for a Viral Etiology of Certain Malignant Tumors, in Perspectives in Virology (Gustav Stern Symposium), New York, February 4-5, 1974. 28. Levin, A.S., Byers, V.S., Fudenberg, H.H., and Wybran, J.: Immunologic Parameters for monitoring immunotherapy with tumor-specific transfer factor. Trans. Assoc. Amer, Phys.,_87, 153-158, 1974 29. -Fudenberg, H.H., Byers, V.S., Levin, A.S., and Hackett, A.J.: Immunologic Evidence for a Viral Etiology of Certain Human Malignant Tumors. Ann. N.Y. Acad. Sci. (In Press, 1975) 30. Wybran, J., Levin, A.S., Fudenberg, H.H., and Goldstein, A.L.: Thymosin: Effects on Normal Human Blood T Cells. Ann. N.Y. Acad. Sci. 249:301-307, 1975 31. Carter, J.B., Ponce, B., Byers, V.S., Barr, G.D., Fudenberg, H.H. and Levin, A.S.: Standardization of tissue culture conditions for spontan­ eous thynidine-2l4c incorporation by unstimulated lymphocytes: Circadian rhythm in Human Lymphocytes. J. of Allergy and Clinical Immunology 56, 191-196, 1975. 32. Byers, V.S., Levin, A.S., Hackett, A.J., and Fudenberg, H.H.: Tumor specific cell mediated immunity in household contacts of cancer patients. J. of Clin. Invest. 55-500-517, 1975. 33. Levin, A.S., Byers, V.S., Fudenberg, H.H., Hacketc.^ A.J., Johnston, J.O., and J.E. Wybran: Osteogenic sarcoma: Immunologic parameters before and during therapy with tumor specific transfer factor. J. Clin. Invest _55: 487-499, 1975. 34. Levin, A.S., Spitler, L.E., and Fudenberg, H.H.,:' Transfer Factor 1. -Methods of Therapy, (end Int. Conf. on Immunodeficiency in Man. St. Petersburg, Fla. 1973), in BIRTH DEFECTS: Original Article Series (Editors: D. Bergsma and R.A. Good), Sinauer, Assoc., Inc., N.Y., 1975. 35. Spitler, L.E., Levin, A.S., and Fudenberg, H.H.: Transfer Factor II. Results of Therapy. (2nd Int. Conf. on Immunodeficiency Disease in Man, St. Petersburg, Fla., 1973), in BIRTH DEFECTS:. Original Article Series (Editors: D. Bergsma and R.A. Good), Sinauer Assoc., Inc., N.Y., 1975. 4 «“ > ’ 03 I 36. Fisher, J., Byers, V.S., Shafrin, M., and Levin, A.S.: Relationship of Cu and Zn levels to metastatic events in human bone sarcomas. Cancer, 37, 356-364, 1976. 37. Spitler, L.E., Levin, A.S., and Fudenberg, H.K.: The Wiskott-Aldrich Syndrome: Immunological Studies in Patients and Family Members Cellular Immunology, 19, 201-218, 1975. 38. Byers, V.S., Levin, A.S., Hackett, A.J., and Johnston, J.W.: Quantitativ Iramunofluorescent Studies on the Tumor Antigen Bearing Cell in Giant Cell Tumor of Bone and Osteogenic Sarcoma, Cancer Research, 35:2520 2531, 1975. 39. Jones, L.W., Levin, A.S., and Fudenberg, H.K.: Glomerular Antigen Comple Associated with Transitional Cell Carcinoma. Surgery, Gynecology and Obstetrics 140:896-898, 1975 40. Kaplan, M.A., Byers, V.S., Levin, A.S., German, D., Fudenberg, H.H., and LeCam, L.: Circadian Rhythm in Human Lymphocyte Function. J. Allergy and Clinical Immunology: 58 I, 180-189, 1976. 41. Spitler, L.E., Levin, A.S., and Wybran, J.: Adjuvant Immunotherapy for Malignant Melanoma with BCG and Transfer Factor. Cellular Immunology 21, 1 - 19, 1976. 42. Levin, A.S., Byers, V.S., Hackett, A.J., Johnston, J.O., and LeCam, L.M. Tumor Specific Transfer Factor Therapy in Osteogenic Sarcoma, Immunotherapy in Cancer, Proceedings of ITR-C’ nicago, 1975. 43. Byers, V.S., Levin, A.S., Hackett, A.J., Johnston, J.O., and LeCam, L.M. Tumor Specific Transfer Factor Therapy in Osteogenic Sarcoma, A Two-Year Followup Study, Annals of New York Academy of Science, 277, 621-627, 1976. 44. Byers, V.S. and Levin, A.S., Tumor Immunology, in Basic and Clinical Immunology: Eds. Caldwell, J. , Fudenberg, H.H., .-^tites, D.P. and Wang, A.S., Lange Books, 1976. 45. 'Levin, A.S., Byers, V.S., LeCam, L.M., and Johnston, J.O., An Unusual Metastasis in an Osteogenic Sarcoma Patient on Tumor Specific Transfer Factor Therapy, Transfer Factor, 537-542, Academic Press, 1976. 46. Byers, V.S., LeCam, L.M., Hackett, A.J., Johnston, J.0. and Levin, A.S.: Familial Incidence of Breast Carcinoma Immunity - A Statistical Survey. Cancer Immunology and Immunotherapy. 2, 163-172, 1977 47. Byers, .S., and Levin, A.S.: Tumor Antigen Density on Osteogenic Sarcoma Cells in Vitro. Cancer Research. 37, 3173-3183, 1977. «#»^ ^'3;\***? 1-•V J 5 L i Chun. Shi —i-.i, :rco:L, C.R., Giblett, E .R ., Levin, A.S.: Adenosine Deaminase Dei iciency: Another Family with a "Silent" Ada Allele and Normal Ada Activity in Two Ketcrozygotes. American Journal of Human Genetics. Vol. 29, 642-644, 1977. 49. Mamor, M.D., Nelson, J.W., Levin, A.S.,: Copper Metabolism in American Retinitis Pigmentosa Patients: British Journal of Opthalmologv. Vol. 6_2. 163-171, 1978. 50. Byers, V.S.,. LeCam, L., Levin, A.S., Johnston, J.O., and Hackett, A.J.: Osteogenic Sarcoma: Immunotherapy of Clinically Disease Free Patients with Transfer Factor: Long-Term Follow-up. Cancer Immunology and Immunotherapy - 6_. 243-251, 1979. 51. Byers, V.S., Levin, A.S.: Poison Oak III: Genetic Restriction in T Cell Mediated reactivity-Journal of Clinical Investigation.-Submit ted. 52. Newman, B.R., Byers, V.S., German, D., and Levin, A.S.: Variability of Lymphocyte Function by Serum Factors. Journal of Clinical Laboratory Immunology 2, 151-154, 1979. 53. McGovern, J.J.,Jr., Lazaror.i, J.L., Saifer, Phyllis, Levin, A.S., Rapp, D.J., Gardner, R.W.: Clinical Evaluation of the Major Plasma and Cellular Measures of Immunity. Journal of Orthomolecular Psychiatry. Vol. 12, No. 1. , 1933. 54 . Lev in, A. s., Emb le ton, M .J ., and Price, M.R .r Use in the Diagnosis and Treatment of :1s ar.d Ca nee'r, PP- 15 - 3d . L. LeCam and nd, 1932 . ao. Binder, R.L., Callaway, E. Relationship Lev in, A. s., S ti tes, D P ise and I-mu n 32. Silbergeld. E.K., Miller. L.P., Kennedy. S., and Eng. N . : Lead. GABA and seizures: effects of subencephalopathic lead exposure on seizure sensitivity and GABAergic function. Environ. Res. 19.: 371-382. 1979. 33. Silbergeld, E.K. and Hruska. R.E.: Effects of ergot drugs on serotonergic function: behavior and neurochemistry. Eur. J. Pharmacol. 58.:1-10. 1979. 34. Silbergeld, E.K. and Hruska. R.E.: Effects of kainic acid on behavioral and biochemical aspects of cholinergic function. In: Chase. T.N.. Wexler, N.S.. and Barbeau, A., eds.. Advances in Neurology, Vol. 23 (Huntington's Disease). Raven. N.Y.. pp. 633-644, 1979. 35. Silbergeld. E.K. and Hruska. R.E.: Lisuride and LSD: Dopaminergic and serotonergic interactions in the "serotonin syndrome". Psychopharmacology 65.:233-237, 1979. 36. Silbergeld. E.K. and Hruska. R.E.: Tremor: Role of striatal cholinergic neurons and the effect of intrastriatal kainic acid. Neurosci. Letters 15:235-242. 1979. 37. Silbergeld, E.K. and Goldberg. A.M.: Problems in experimental studies of lead poisoning. In. Singhal, R.D. and Thomas, J.A. (eds.): Lead Toxicity. Baltimore: Urban and Schwartzenberg. pp. 19-42. 1980. 38. Hruska, R.E. and Silbergeld, E.K.: Estrogen treatment enhances dopamine receptor sensitivity in the rat striatum. Eur. J. Pharmacol. 62_:397-400, 1980. 39. Silbergeld, E.K.. Goldstein. G.W., and Wolinsky, J.: Electron probe microanalysis of isolated brain capillaries poisoned with lead. Brain Res. 189 :369-376. 1980. 40. Silbergeld. E.K., Hruska, R.E.. Miller, L.P., and Eng, N.: Effects of lead in vivo and iji vitro on GABAergic neurochemistry. J. Neurochem. 14:1712-1718. 1980. 41. Hruska, R.E. and Silbergeld. E.K.: Increased dopamine recepton sensitivity after estrogen treatment using the rat rotation model. Science 208:1466-1468, 1980. 42. Hruska, R.E. and Silbergeld. E.K.: Cortical neurochemical changes after intrastriatal injection of kainic acid. Brain Res. 191:572-576. 1980. S' ( 7 v T9 2 3 9 43. Hruska, R.E. and Silbergeld, E.K.: Effect of ergot derivatives on post-decapitation convulsions. Commun. Psychopharm. 4.:57-62, 1980. 44. Hruska. R.E.. Ludmer. L.M., and Silbergeld, E.K.: Hypophysectomy prevents the striatal dopamine receptor supersensitivity produced by chronic haloperidol treatment. Eur. J. Pharmacol. 65.:455-456 (1980). 45. Silbergeld. E.K. and Hruska. R.E.: Neurochemical investigations of low level lead exposure. In: Needleman. H.L.. ed.. Low Level Lead Exposure: The Clinical Implications of Current Research. Raven, N.Y.. pp. 135-157,1980. 46. Hruska. R.E. and Silbergeld. E.K.: Inhibition of [ H]sp? roperidol binding by in, vitro addition of ethanol. J. Neurochem. 3j>.:750-752. 1980. 47. Silbergeld. E.K., and Lamon. J.M.: Role of altered heme synthesis in lead neurotoxicity. J. Occup. Med. 22^: 680-684, 1980. 48. Hruska. R. E. , Ludmer, L.M.. and Silbergeld. E. K.: Characterization of the striatal dopamine receptor supersensitivity produced by estrogen treatment of male rats. Neuropharmacol. 19.: 923-926. 1980. 49. Silbergeld. E. K.: Detection of neurotoxicity using neurochemical methods In: R.M. Gryder and V. H. Frankos, (eds.). The Effects of Foods and Drugs on the Development and Function of the Nervous System: Methods for Predicting Toxicity. FDA (No. 80-1076). Washington. D.C., pp. 99-105. 1980. 50. Silbergeld. E. K.: Erythrosin B is a specific inhibitor of high affinity 3H-ouabain binding and ion transport in rat brain. Neuropharmacol. 20: 87-90. 1981. 51. Silbergeld, E. K., and Caine. D. B.: parkinsonism. Pharmacol. Ther. 12.: 52. Goudsmit. J.. Rohwer, R. G.. Silbergeld. E. K., and Gadjusek. D. C.: Hypersensitivity of central serotonin receptor activation in scrapie-infected hamsters and the effects of serotonergic drugs on scrapie symptoms. Brain Res. 220: 372-377. 1981. Animal models of 159-166, 1981. 8 13240 53. Hruska, R. E., and Silbergeld, E. K.: Inhibition of neurotransmitter binding by ergot derivatives. J. Neurosci. Res. 6.:1-11. 1981. 54. Silbergeld, E. K., Lamon, J. M.. Bradley, D., Hruska. R.E., Pitman, K.. Hess. R. A., and Frykholm. B. C.: Heavy metal neurotoxicity; porphyrinopathic mechanisms. Procs. Internat. Symp. on Heavy Metals, WHO-EEC-EPA. Amsterdam, pp. 561-564, 1981. 55. Chisolm. J. J.. and Silbergeld. E.K.: Increased excretion of homovanillic acid in children with increased lead absorption. Procs. Internat. Symp. on Heavy Metals. WHO-EEC-EPA. Amsterdam, pp. 565-568. 1981. 56. Weir, R. L.. Hruska, R. E.. and Silbergeld. E. K.: Binding of antiparkinsonian ergot derivatives to the dopamine receptor. Psychopharmacol. 75.: 119-123, 1981. 57. Silbergeld. E.K.: Neurochemical and ionic mechanisms of lead neurotoxicity. In: (Vernadakis. A., and Prasad. K. N., (eds.). Mechanisms of Action of neurotoxic Substances. Raven. New York. pp. 1-24. 1982. 58. Hruska, R. E.. Pitman. K. T.. Silbergeld. E. K.. and Ludmer, L. M. : Prolactin increases the density of striatal •dopamine receptors in normal and hypophysectomized male rats. Life Sci. 30.: 547-553, 1982. 59. Hruska, R. E., Ludmer. L. M.. Pitman, K. T., DeRyck. M . . and Silbergeld. E. K. : Effects of estrogen on striatal dopamine receptor function in male and female rats. Pharmacol. Biochem. Behav. 16.: 285-291, 1982. 60. Silbergeld. E. K., and Anderson, S. M . : Artificial food colors and childhood behavioral disorders. Bull. N.Y. Acad. Med. 5£: 375-295, 1982. 61. Morris. S. J.. Silbergeld. E. K.. Brown. R. R., and Haynes. D. N.: Erythrosin B (USFD&C Red 3) inhibits calcium transport and ATPase activity of muscle sarcoplasmic reticulum. Biochem. Biophys. Res. Commun. 104: 1306-1311, 1982. 62. Silbergeld, E.K.: Current status of neurotoxicology, basic and applied. Trends in Neurosci. 8.-.291-294, 1982. 9 1 0 9 1 63. Silbergeld, E.K.. Anderson. S.M., and Morris, S.J.: Interactions of erythrosin B (U.S. F. D & C Red 3) with rat cortical membranes. Life Sci. 3.1:957-969. 1982. 64. Silbergeld. E. K.. Hruska, R. E., Bradley. D.. Lamon. J. M . , and Frykholm. B. C.: Neurotoxic aspects of porphyrinopathies: lead and succinylacetone. Environ. Res., 29:459-471. 1982. 65. Silbergeld. E. K.: Experimental and environmental neurotoxins: correlation of behavioral and biochemical effects. In Levy. M. and Spiegelstein. A. (eds.) Behavioral Models and the Analysis of Drug Action Elsevier-North Holland. Amsterdam, pp 297-315, 1982. 66. DeRyck. M . . Hruska. R.E., and Silbergeld, E.K.: Estrogen and haloperidol-induced versus handling-related catalepsy in male rats. Pharmacol. Biochem. Behav. 17:1027-1035. 1982. 67. Silbergeld. E. K.. Lafferman, J.. and Finkel. T.: In vitro testing for neurotoxicity. In: Kolber, A.. Wong. T.K., Grant, L.D.. Dewoskin, R.S.. and Hughes. T.J. (eds). In Vitro Toxicity Testing of Environmental Agents. New York. Plenum, pp 473-486, 1982. 68. Silbergeld, E.K.. and Lamon. J.M.: Effects of altered porphyrin synthesis on brain neurochemistry. Neurobehav. Toxicol. Teratol. 4/.635-642. 1982. 69. Hruska, R. E.. Weir. R. L.. Pitman. K. T.. and Silbergeld, E. K.: Ergot derivatives are potent drugs at CNS aminergic receptors: correlations to behavior and aging. In: Agnoli. A.. Trabucchi. M.. and Spano. P. F. (eds). Aging Brain and Ergot Alkaloids. New York, Raven, pp 215-226. 1983 . 70. Silbergeld, E.K.: Experimental studies of lead neurotoxicity: Implications for mechanisms, dose-response, and reversibility. In Rutter, M.. and Russell-Jones. R. (eds) Lead Versus Health. London. John Wiley, pp 191-216. 1983 . 71. Silbergeld. E.K.: Effects of lead on reproduction: a review of experimental studies. In Rutter. M.. and Russell-Jones. R. (eds) Lead Versus Health. London. John Wiley, pp 217-227. 1983. 10 13242 72. Silbergeld. E.K.: Indirectly acting neurotoxins. Psychiat. Scand. 67. Suppl. 303, 16-25, 1983. Acta 73. Mattison. D.R., Takizawa, K.. Silbergeld. E.K., Nightingale. M.S.. Jerina. D.. and Yagi. H.: Genetics of ovarian benzo(a)pyrene, metabolism, oocyte destruction, and impaired fertility. In Rydstrom, J.. Monteluis. J.. and Bengtsson, M. (eds) Extrahepatic Drug Metabolism and Chemical Carcinogenesis. Amsterdam. Elsevier, pp 337-350. 74. Silbergeld. E.K.: Localization of lead: implications for mechanisms of neurotoxicity. Neurotoxicol. 4/.193-200, 1983. 11 - 13243 IN PRESS: Silbergeld. E.K.: Behavioral teratology of lead. In Yanai. J. (ed) Behavioral Teratology. Elsevier/North Holland. Silbergeld, E.K.: Neurotoxicity of lead. Blum, J. (eds) Neurotoxicology. Dekker. In Manzo, L. and Fowler, B.F., and Silbergeld, E.K.: Mechanisms of metal toxicity. In Nriagu, J.. and Hornig. D.F. (eds) Changing Geochemical Cycles of Metals and Implications for Human Health. Berlin, Springer Verlag. Mattison, D.R.. and Silbergeld. E.K.: Occupational risks to reproduction. In Osofsky, H. (ed) Advances in Gynecology and Obstetrics. Baltimore. Williams & Wilkins. Silbergeld. E.K.: Mitochondrial mechanisms of lead neurotoxicity. In Narahashi, T. (ed) Cellular and Molecular Mechanisms of Environmental Neurotoxins. Raven Press, NY. in press. Silbergeld, E.K.: Review of occupational health studies on PCBs. In Kuiper. H. (ed) PCBs. Marcel Dekker. in press. Silbergeld. E.K.: Effects of PCBs in Occupational Populations. In Visser. R. (ed) PCBs. Amsterdam. Elsevier. Mattison, D.R., and Silbergeld, E.K.: Reproductive toxicity of TCDD. In Lowrance, W. (ed) Dioxins. Rockefeller University Press. IN PREPARATION: Silbergeld, E.K., and Mattison, D.R.: Effects of three polycyclic aromatic hydrocarbons on fertility in female mice: A lifetime study of the effects of single-dose treatment. Silbergeld. E.K.: A Textbook in Neurotoxicology. 12 13244 B. ABSTRACTS 1. Silbergeld, E. K.: Effects of lead on neuromuscular funetions: In vitro evidence for site of action at the presynaptic level. Fed. Proc. 32.:275, 1973. 2. Silbergeld, E. K. and Goldberg. A. M . : Lead poisoning: an animal model of hyperactivity. Pharmacologist ¿5:143. 1973. 3. Silbergeld. E. K. and Goldberg, A. M. : cholinergic-aminergic interactions in lead induced hyperactivity. Pharmacologist ¿6:335, 1974. 4. Goldberg. A. M. and Silbergeld, E. K.: Neurochemical aspects of lead induced hyperactivity. Trans. Amer. Soc. Neurochem. p.185. 1974. 5. Silbergeld. E. K., Carroll, P. T. and Goldberg, A. M . : Monoamines in lead-induced hyperactivity. Pharmacologist ¿3:203. 1975. 6. Goldberg. A. M.. Carroll. P. T. and Silbergeld. E. K.: Cholinergic aspects of hyperactivity. Fifth Internatl. Meeting for Soc. Neurochem., 1975. 7. Pfeiffer. R. . and Silbergeld. E. K.: Differential behavioral and neurochemical effects of. three dopaminergic agonists. Neurosci. Abst. ¿1:720, 1976. 8. Silbergeld, E. K. and Miller. L. P.: Lead intoxication: changes in seizure threshold and gamma-aminobutyric acid function. Neurology ¿(27):405, 1977. 9. Adler. H. S. and Silbergeld, E. K.: Intrasynaptosomal interactions of lead and calcium in dopaminergic neurotransmission. Pharmacologist ¿¿(2):40, 1977. 10. Silbergeld. E. K. and Walters, J. R.: Dopamine uptake and release in substantia nigra: Effects of gamma-aminobutyric acid and substance P. Pharmacologist ¿9.(2) :544, 1977. 11. Silbergeld. E. K.. Miller, L. P., Kennedy, S. and.Eng. N.: Lead and seizures: Role of gamma-aminobutyric acid. Neurosci. Abst. Ill:1039. 1977. 12. Adler. H. S. Costa, J. L. and Silbergeld. E. K.: X-ray microanalysis in neurochemistry: Localization of an 13 C O 'Z r Kjf elemental neurotoxin and manipulations of mitochondrial Ca++. Neurosci. Abst. Ill:1235. 1977. 13. Baring. M. D., Walters. J. R.. Silbergeld. E. K.. Eng. N.. and Lakoski. J. M.: Effect of systemic apomorphine on firing rates of dopamine cells in rats with striatal kainic acid lesions. Neurosci. Abst. 4.. 267. 1978. 14. Hruska. R. E. and Silbergeld. E. .: Ergot drugs inhibit spiroperidol and serotonin receptor binding. Soc. Neurosci. Abst. 4.: 425, 1978. 15. Silbergeld. E. K., Hruska, R. E.. Walters. J. R.. Kennedy. S.. Eng, N., and deSantis. S.: Effects of intrastriatal kainic acid on motor behavior in rats. Soc. Neurosci. Abst. 4: 49. 1978. 16. Kennedy, S., Hruska, R. E.. and Silbergeld. E. K.: Serotonergic-dopaminergic effects of ergot drugs. Soc. Neurosci. Abst. 4.: 426, 1978. 17. Silbergeld. E. . Hruska. R. E., Lamon. J. M . . Frykholm. B. F., and Hess, R. A.: Neurotoxic mechanisms in porphyria and lead intoxication: Possible role of a-aminolevulinic acid. Clin. Res. 27.:307A, 1979. 18. Lamon. J. M. , Silbergeld. E. K.. Frykholm. B. F., and Hruska. R. E.: Extra-erythropoietic heme metabolism in lead intoxication. Clin. Res. 27_: 299A, 1979. 19. Silbergeld. E. K.. Hruska. R. E.. Lamon. J. M . . Frykholm. B. F., and Hess. R.A.: The effects of lead (Pb) on hepatic heme synthesis and drug metabolism. Pharmacologist 21: 209. 1979. 20. Silbergeld. E. K., Hruska. R. E., and Lafferman. J. A.: Actions of lead (Pb) on GABAergic neurotransmission: Discrepancies between in vivo and in vitro effects. Soc. Neurosci. Abst. 5.: 416, 1979. 21. Lafferman. J. and Silbergeld. E. K.: Erythrosin B (Food. Drug and Cosmetic Red No. 3) inhibits dopamine uptake in rat caudate synaptosomes: a kinetic study. Soc. Neurosci. Abst. 5. 562. 1979. 22. Hruska, R. E. and Silbergeld, E. K.: Increased dopamine receptor sensitivity after estrogen treatment. Soc. Neurosci. Abst. 5.: 73 (1979). No. 236. 14 :a 23. Silbergeld. E. K., Hruska. R. E.. Schwarcz. R.: GABA in the basal ganglia: effects of selective lesions. Brain Res. Bull., 4: 696, 1979. 24. Weir, R. L., Hruska. R. E. and Silbergeld, E. K.: of dopamine agonists on 3H-spiroperidol receptor binding. Soc. Neurosci. Abst. 5: 81, 1979. 25. Hruska, R. E.. Ludmer. L. M . , and Silbergeld, E. K.: Prolactin increases the number of striatal dopamine receptors. Pharmacologist 22.:220 (1980). No. 338 . 26. Silbergeld. E. K.: Erythrosin B: ouabain-like actions of an artificial food dye in rat brain tissue. Pharmacol. 21:198. 1980. 27. Hruska, R. E., Ludmer. L. M . . and Silbergeld. E. K.: The striatal dopamine receptor supersensitivity produced by estrogen may be mediated through prolactin. Soc. Neurosci. Abst. 6.: 441, 1980. 28. Chisolm, J. J., and Silbergeld. E. K.: Increased excretion of homovanillic acid (HVA) in urine by young children with increased lead absorption. Neurosci. Abst. vol. 6_:508. 1980. 29. Silbergeld. E. K., and Anderson, S. M . : Erythrosin B: specific inhibitor of high affinity [3H]-ouabain binding and ion transport in rat brain. Neurosci. Abst. vol. 1:56, 1980. 30. Silbergeld, E. K., Anderson. S. M.. DeRyck. M . . Chronwall, B.. and Morris, S. J.: Neurotoxicity of an artificial food color (erythrosin B): methods for rapid testing. Abstr. 8th Meeting Internat. Soc. Neurochem.. p. 238. 1981. 31. Ptiman, K. T.. Hruska, R. E.. Ludmer. L. M.. and silbergeld. E. K.: Prolactin increases the density of striatal dopamine receptors in normal and hypophyse.ctomized male rats. Soc. Neurosci. Abstr. 7: 217. 1981. 32. DeRyck. M.. Hruska. R. E.. and Silbergeld, E. K.: Estrogen potentiates haloperidol-induced catalepsy/akinesia in male rats. Soc. Neurosci. Abstr. 7: 217, 1981. 33. Silbergeld, E.K.: The biochemical basis of lead neurotoxicity. Abstr. Ann. Mtg. AAAS. Toronto. 1981. Effects 15 13247 34. Hruska. R. E.. Pitman. K. T., Ludmer. L. M . , DeRyck. M . . and Silbergeld. E. K.: Comparison of the biochemical and behavioral effects of estrogen in male and female rats. So-Cr Neurosci. Abstr. 7: 218, 1981. 35. Silbergeld, E. K., Morris, S. J., and Anderson, S. M . : Erythrosin B and Na,K-ATPase: receptor-like interactions with brain synaptic membranes. Soc. Neurosci. Abstr. 7: 105. 1981. 36. Silbergeld, E. K.: Basic and applied neurochemistry of hazards. Abstr. Annual Meet. AAAS. Washington, D.C.. p. 63. 1982. 37. Silbergeld. E. K.: Neurotoxic implications of altered heme synthesis in lead poisoning. Neurotoxicol. 3_:119-120, 1983. 38. Silbergeld, E. K., Nightingale. M. S., and Mattison, D. R.: Effect of oocyte destruction by polycyclic aromatic hydrocarbons (PAH) on fertility of DBA/2N (D2). C57BL/6N (B6). and (D2 x B6) FI mice. Soc. Gynecol. Invest. Abstr., p. 51. 1983. 39. Silbergeld, E.K., Nightingale, M.S., Godlove. K.. Malley, J. , and Mattison, D.R.: Reproductive toxicity of polycyclic aromatic hydrocarbons (PAHs) in female mice. Pharmacol., 25_*.655 , 1983 . 40. Mattison, D.R., Takizawa, K.. Silbergeld, E.K.. Nightingale. M.S., Jerina. D.. and Yagi. H.: Genetics of ovarian benzo(a)pyrene metabolism, oocyte destruction, and impaired fertility in inbred DBA/2N and C57BL/6N mice and D2xB6 FI heterozygote mice. Abstr. Internat. Conf. Extrahepatic Metabolism of PAHs and Carcinogenesis, 1983. 41. Mattison, D.R., and Silbergeld. E.K.: Occupational exposures and pregnancy, Abstr. 15th Ann. Cong. Col. Soc. Obstet. Gynecol., Bucarananja, Columbia, 1983. 42. Mattison, D.R., Nightingale, M.S.. Shiromizu, K.. Takizarva K. . Silbergeld. E.K.. Kay, H.H.. and Swartz. W.J.: Ovarian toxicity, Abstr. 15th Ann. Cong. Col. Soc.. Obstet. Gynecol. Bucaramanga, Colombia. 1983. 43. Swartz, W.. Silbergeld. E.K., Malley. K.. and Mattison. D.R.: The effects of benzo(a)pyrene on urine ovarian function and fertility. Abstr. Amer. Assoc. Anat.. in press, 1984. 16 1C OTHER PUBLICATIONS REVIEWS Silbergeld. E.K.: "Lead in Man and the Environment" for Trends in Pharmacological Sciences. 1981 Silbergeld. E.K.: "Hazardous Waste in American" for Quarterly Review of Biology, in press Silbergeld. E.K.: "Nutrition and Brain Function" for Trends in Neurosciences, in press OTHER Silbergeld, E.K.: "US Lead Program Vital" (editorial) Clin. Chem. News. February. 1983, page 4 Silbergeld, E.K.: "Where do we go from here?", in Legator, M.S. (ed) Community Health STudies: A Guide for Citizens. Johns Hopkins Press. Baltimore. MD. in press Silbergeld. E.K.: "Health Effects" in Environmetal Defense Fund. Dumpsite Cleanups: A Guide to the Superfund Program. Washington. DC. 1983 Silbergeld. E.K.. and Highland, J.: "Ghost Dumps" (letter) Science. 216:462. 1982 Silbergeld, E.K.: "Cancer Policy: Has the Dust Settled?" Environmental Forum. 2.:25-29, 1983 Hall. K.L.. and Silbergeld, E.K.: "Reappraising Epidemiology" Harvard Environmental Law Review. 7:441-44.8, 1983 17 1 3249 Dr. Raymond Singer, Ph.D., is a neurotoxicologist and neuropsychologist practicing at Occupational Health Consulting, Inc., of New York, New York. Dr. Singer's curriculum vitae is attached. Dr. Singer will prepare reports concerning each of the veteran plaintiffs. These reports will be based upon personal interviews and review of appropriate himself and/or by others. a thorough test findings performed by The personal interview will consist of account of the veteran's background and current and historic symptoms. It will also detail the educational and occupa­ tional background of each veteran. Various neuropsychologic tests will be given and discussed with particular reference to whether:: any deficits or changes noted are due to the results of any toxic chemical exposures. Neurophysiologic tests will also be given or reviewed and interpreted, with particular emphasis placed upon nerve conduction velocity findings, and the results will be set out and discussed, with particular reference to whether the findings are related to toxic chemical exposures. To the extent warranted, Dr. Singer will relate any findings to Agent Orange exposure. Dr. Singer will also testify to the effects of toxic chemical exposures as they have been studied in a number of research efforts in both animals and humans. He will discuss the findings reported in various populations exposed to toxic chemicals 13250 and particularly to TCDD through the mechanism of industrial ac­ cidents. He will also discuss the findings concerning demyelination of the fatty sheaths surrounding the nerves and the "dying-hack" neuropathy which has been associated with toxic chemical exposures. Dr. Singer will also discuss the results of his own work in relation to occupational exposures to TCDD, and will, explain how his results are consistent with those obtained from tests per­ formed on the veterans here, and how those results are consistent with causation by phenoxy herbicides and their contaminants. 13251 RESUME Name: Raymond M. Singer Born: August 20, 1950; Philadelphia, Pennsylvania Address: 415 East 85th Street, #10H New York, NY 10028 (212) 744-1728 EDUCATION AND DEGREES Ph.D. M.S. B.A. Washington State University Washington State University University of Rochester 1978 1975 1972 Psychology Psychology Psychology PROFESSIONAL ORGANIZATIONS Certified Psychologist, New York State Board of Psychology Member, American Psychological Association Member, National Academy of Neuropsychologists Member, Society for Occupational and Enviromental Health Member, American Public Health Association Associate Member, College of Toxicology PROFESSIONAL EXPERIENCE 1983 1983 1982 1982 1982 1981 1982 1979 1981 1978 1979 1978 1979 Adjunct Instructor, Mount Sinai School of Medicine Department of Community Medicine, New York City Consultant, New York State Department of Social Services, Office of Disability Determinations President, Occupational Health Consulting, Inc. Clinical Psychologist, Private Practice, New York City Reviewer, The American Journal of Industrial Medicine Fellow, Mount Sinai School of Medicine, Department Community Medicine, Enviromental Sciences Laboratories, New York City NIH Post-Doctoral Fellow in Environmental Epidemiology, Mount Sinai Medical School of Medicine, New York City NIH Post-Doctoral Fellow in Biological Psychiatry, Millhauser Laboratories, New York University Medical Center, New York City Clinical Psychology Intern, Park East Psychological Associates, New York City 1 ^ 0 52 Dr. Raymond Singer 1972 - 1978 December 5, 1983 Teaching and Research Assistant/ Department of Psychology, Washington State University, Pullman, Washington PUBLICATION AND PAPERS. Singer, Raymond. Peripheral nervous system assessment in the evaluation of toxic chemical exposure. Paper to be presented at the 12th Annual Meeting of the International Neuropsychological Society, Houston, February, 1984. Singer, Raymond. Neural indicators of phenoxy herbicide exposure. Paper presented at the 1983 Annual Meeting of The Society for Occupational and Environmental Health, Washington (D.C.), December, 1983. Singer, R., Valciukas, J., and Lilis, R. Lead exposure and nerve conduction velocity: The differential time course of sensory and motor nerve effects. Neurotoxicology, 4, 2, 193-202, 1983. Presented at the' XI Triennial World Congress of Pathology, Jerusalem (Israel), September, 1981. Singer, R., Moses, M., Valciukas, J., Lilis, R., and Selikoff, I.J. Nerve conduction velocity studies of workers employed in the manufacture of phenoxy herbicides. Environmental Research, 29, 297-311, 1982. Presented at the XX International Congress of Occupational Health, Cairo (Egypt), September, 1981. Valciukas, J. and Singer, R. The embedded figures test in epidemiological studies of environmental neurotoxic agents. Environmental Research, 28:183-198, 1982. Lilis, R., Valciukas, J., Singer, R., et al. Assessment of Lead Health Hazards in an Autobody Shop at an Automobile Assembly Plant. Report to the National Institute of Environmental Health Sciences, June, 1981. Valciukas, J., Lilis, R., Singer, R., et al. Lead exposure and behavioral changes: Comparisons of three occupational groups with different levels of lead absorption. American Journal of Industrial Medicine, 1:421-462, 1980. Singer, R. The Neuropsychological Evaluation of Patients Affected by Occupational Neurotoxic Agents. Invited address, New York State Psychological Association Convention, New York City, May, 1980. Dr. Raymond Singer December 5, 1983 Valciukas, J., Lilis, R., Singer, R., et al. Neurobehavioral studies of painters. Presented at the International Symposium on Occupational Health Hazards Encountered in Surface Coating, Handling of Paints in the Construction Industry, Stockholm (Sweden), October, 1979. Manuscript submitted, Archives of Environmental Health. Singer, R. The role of the psychologist in the prevention of myopia. Paper presented at the annual meeting of the American Psychological Association, New York, New York, September, 1979. Singer, R. The Camphill approach to the education of the retarded person. Symposium presented at the annual meeting of the American Psychological Association, New York, New York, September, 1979. Singer, R. The behavioral etiology of myopia. Paper presented at the annual meeting of the Eastern Psychological Association, Philadelphia, Pennsylvania, May, 1979. Singer, R. The relationship between visual refractive error and interests, values, personality, academic performance, and reading. Doctoral dissertation, Washington State University, 1978. Singer, R . , Young, F., and Rokeach, M. Values as predictors of visual refractive error (in Barrow Eskimos). Paper presented at the Western Psychological Association Convention, Seattle, Washington, April, 1977. Singer, R. Can myopia be prevented? Invited address - Presented to the Washington State University Chapter of Sigma XI, February, 1976. Singer, R. The association of personality and myopia. Papers presented at the Western Psychological Association Convention, Sacramento, California, April, 1975. Young, F., Singer, R., and Foster, D. The psychological differentiation of male myopes and non-myopes. American Journal of Optometry, October, 52, 10, 679-686, 1975. 1 r'/ r~i-)' *-i T H E O D O R D . S T E R L I N G , P h . D . Dr. Sterling is Professor in the Facility of Interdisciplinary Studies and Department of Computing Science, Simon Fraser University, Vancouver, British Columbia, Canada. His Curriculum Vitae is attached. Dr. Sterling is a mathematician, statistician, and epidemiologist; as well, Dr. Sterling is intimately familiar with existing data and analyses concerning the effects of phenoxy herbicides and impurities, e.g. 2,3,7,8-TCDD, contained therein. Dr. Sterling has devoted much of his teaching and research to the collection and analysis of data and their use for scientific inference. Dr. Sterling will testify that there exists a considerable body of medical and scientific evidence which demonstrates that the preparations of 2,4,5-T and 2,4-D are toxic, teratogenic, and carcinogenic. Further, there is no credible scientific evidence of a no effect level; said another way, as a carcinogen, there is no safe level and therefore a single exposure years ago may be responsible for human cancer which develops today. In addition, Dr. Sterling will testify that there is ample evidence that exposure to 2,4,5-T is teratogenic in humans when the mother is exposed, and convincing evidence is now extant that the outcome of pregnancy is influenced by exposure to the father alone. Most especially, Dr. Sterling will testify of the incidence of subjective symptoms and/or medical records documenting such symptoms. These symptoms are those which have been compiled by the National Center for Health Statistics, and will be compared, to the extent available, to those symptoms of the Vietnam veterans, particularly those of the representative plaintiffs. 9* 1 O - DO The purpose will be to ascertain the incidence of such symptoms in the general population so as to analyze statistically the symptoms of the plaintiffs. The product of such overall incidence will be calculated to examine the possibility or likelihood of such a constellation of Agent Orange/dioxin related symptom complex to occur in a random fashion. The bases or grounds for the facts and opinions of Dr. Sterling's testimony are: educational and professional background; publications regarding the subject phenoxy herbicides; review of the applicable medical and scientific literature; attendance and participation in various symposia dealing with the scientific issues in question; training as a mathematician, statistician, and epidemiologist; and training and experience in the computer sciences. VJ ■i -2- C U R R I C U L U M V I T A E Theodor D.Sterling EDUCATION B. A. (CUM LAUDE) , 1949, M.A., 1952, University of Chicago; Ph.D., 1955, Tulane University. PROFESSIONAL AFFILIATIONS Present: Professor, The Faculty of Interdisciplinary Studies and Department of Computing Science, Simcn Fraser University. Previous: Visiting Professor, Department of Statistics, Princeton University, (78). Chairman, Department of Computing Science, Simon Fraser University, (72-77). Professor in the Department of Applied Mathematics and Computer Science, Washington University, St. Louis, Missouri (66-72). Also Joint appointment as Professor in the Department of Sociology (66-68) , and Visiting Professor in Computers and Humanities, Hebrew Union College, Cincinnati, Ohio (68-70). Professor of Biostatistics and Director of the Computing Center, College of Medicine, University of Cincinnati, Ohio (58-66). Previously instructed in the Department of Statistics, Michigan State University and Department of Mathematics, University of Alabama. PROFESSIONAL ACTIVITIES ACM Committee on Scientific Freedom and Human Rights; President of the Computer Science Association cf Canada (75-80) ; Chairman, Ombudsman Committee, Canadian Information Processing Society (73-80); Chairman, President of Biological Information Processing Organization (64-65); Chairman, CIPS Special Interest Groups, Humanization of Information Systems (73-80) ; Chairman, SIGCAS Committee of Information and Public Policy (72- ) ; President of Missouri Chapter, American Association of Workers for the Blind (70-72) ; Member of the Panel for Biology, Management, and Social Sciences of the Mathematics Association of America (62-67) ; Chairman, Committee on Professional Activities of the Blind of the Association for Computing Machinery (63-71); Chairman, Ad Hoc Committee on Accreditation, Association for Computing Machinery (66-67); Committee on Radiation Dosimetry, American Association of Physicists in ' Medicine (66-69); National Lecturer for Association for Computing Machinery (72-3, 75-6). EDITORIAL ACTIVITIES: Associate Editor - Canadian Journal of Statistics (73-78); Editorial Board - International Journal of Biomedical Computing (69- ); Computers and Applied Mathematics (73- ), Humanist in Canada (73- ). < rr GOVERNMENT AND OTHER SERVICES: (Consultant/adviser, now and previous): (In Canada) Canadian Standards Board; Environment Canada, The Royal Commission (B.C.); Consumers Association of Canada; Society for Professional and Environmental Control. (In U.S.) NIH; PHS; EPA; FTC; SR A; U.S. National Academy of Science, National Research Council; American Lung Association; Natural Resource Board (Wisconsin); Environmental Defense Fund, MECCA (Minnesota); Citizens. Against Toxic Sprays (Oregon) . (In Kuwait) - Ministry of Health. PROFESSIONAL SOCIETIES: Can. Inf. Pxoc. See. ; Can. Comp. Sci. Assoc. ; Assoc. Comp. Machinery; Amer. Math. Assoc.; Math. Soc. ; Inst. Math. Stat.; Amer. Stat. Assoc.; Biometric Soc-; N.Y. Acad. Sci.; Amer. Assoc. Phys. Med.; Assoc. Res. Opthamology. HONORS AND AWARDS: Fellow, Amer. Assoc. for Advancement of Science; Fellow, Amer. College of Epidemiology; Fellow, Amer- Stat. Assoc.; Fellow, Car. Com. of Scientists and Scholars; Sigma Xi; Pi Nu Epsilon, Morrison Cressy Award in National Science; University Research Professor (1980-1981). 5I3LIOGRÀPHY Theodor D. Sterling So ok s A Guide to PL/1 and Structured r rog ramm in g . doit, ¡iinenart and Winston, February, 1969. Second edition - 1976. Third Eaition 1900. Essentials cf PL/1. Molt, Rinenart and Winston, January, 1S73. Visual Prosthesis - The Interdisciplinary Academic Press, March, 1971. Dialogue. (Editor), Computing and Computer Science with 1 970 . Macmillan, January, Computing ana Computer January,1970. Introduction June, I9 6 0 . to Science Statistical PL/1. with Data Fortran Processing. IV. Macmillan, Prentice-Hall, Advances in Biomedical Computing Applications (Editor), of The New York Academy of Science, Vol 1 2 3 , 1966. Annals Computers and the Life Sciences. Columbia Press, December, 1965. In preparation: People are Trouble: The Human Side of a Computerized Society. Concepts of Machine Computation. s 2259 Articles 1984 The Economics and Politics of building Illness: The NAS/NRC Report on Indoor Pollutants. International Journal of Health Services 14(1): 43-53. Second Thoughts: On Filtering Information About Occupation, Smoking and Disease. Journal of Chronic Diseases. (In press) Computers and Society. Encyclopedia. (In press) In Adriana Davies, (ed.) The Canadian Investigations on the Effect of Regulating Smoking on Levels of Indoor Pollution and on the Perceotion of Health ana Comfort of Office Workers. Proceedings of workshop on Effects and Exposure Levels, Geneva, Switzerland, ¡larch 15-1 7 , 1983. (In press) The Emerging Key Role of White-Collar Computer Workers Vis A Vis Organized Labor. Technology and People. (In press) What is the Host Advanced Technology on Earth Today and for What is it Used? In Gallup, G. and Ncrtack, C.T. (oas.). America Wants to Know: Ihe Experts' Answer H , New York. A 6 w Publishers, Inc. (In ¡.ress) o o k 198 3 The Health Effects of Low-Dose Radiation on Atomic workers: A Case Study of Employer-Directec Research. In Navarro, V., and Berman, d . (eas.), Health and Work Jnder Capitalism: An International Perspective. Eaywood Publishers, New York, NY. pp. 55-bd. Concatenation. In A. Ralston and E. Reilly, Jr., (ed.) Encyclopedia of Computer Science and Engineering (second edition). Van Nostranci Reinhold Company, New York. pp. 395-396. Programming. In A. Ralston and E. Reilly, Jr., (ed.) encyclopedic: of Computer Science and Engineer i r.q (second edition). Van Nostrand Rainhold Company, New York. pp. 119U-1217. Statements. In A. Ralston and E. Reilly, Jr., (ed.) Encyclopedia ot Computer Science and Engineering (seccna edition). Van Kostrana. keinhold Company, New York, pp. 1d04-iu07. Trap. In A. Ralston ana £. Reilly, Jr., (ad.) Encyclopedia of Computer science ana Engineering (second edition) . Van Nostrand Reinnolc Company, e w York, pp . 1 5 3a-1 b35 . Corporate Planning and Technological Transmitter, Special Issue V ( b ): S. Change. Buildinu Illness jn the White-Collar Workplace. Journal cf health Servises 13:277-287. The TV U I;iter nat iona i Possible Erfects on Occupational Lung Cancer from Smoking Relatec Changes in the Mucus Content of the Lung. Journal ot Chronic Diseases. Jo (10 ) :6 fc?-b76 . The Impact or Different Ventilation Levels and fluorescent Lighting Types on Building Illness: An Experimental Study. Canadian Journal ot Public Health. (E. Sterlinq, senior author) Sep tern ter/October. Unemployment Follows from the Changes in Telecommunications. Telecommunications workers Union Transmitter 17(3): 9. Air Quality in Puolic Buildings with Health Related Complaints. ASHRAE Transactions 89(2). Perceived vs Actual 7-»r* iû,it)0 The lise- of an Information System to "iluinanizo" Procedures in a rehabilitation Hospital. International Journal or -io-tfedical Computing. Voi 5 : 51-57. Information for Public Policy. Computers m i 2. (Invited editorial). Society. Vcl 1(1 ): The Simon Fraset One-Track Universal Curriculum for Computing Science.. 5 1G S C L Bulletin, ACM. February, Vo 1 6(1): 28-12. 1171 The Statistician vis-a-vis Issues of Public Health. The American Statistician. December, Vcl 27(5): ¿12-217. Extending the General Fiell Equation to lit the Dose Distributions of a Variety of Therapy Units. British Journal cf Radiology. Vol 46: 535-990. (J . e in x a m , senior author.) Air Pollution and 5 m o k i ng . Environ ment. Vol 15(b): J-b, 25-26. U s in Dynamic b l s ; 1 a y o i n a c i ct he ra .jy Plans Films. Radiology. June, voi 107: o ?9 - b 9 1 . Human!s t s a rid tne Ccni.u ter Ccvru:■.i t y . humanist 2b: f- . C o ir.pu t *-r - P ro a u c e a L a n2 j d * in Computing and the nu ma ni sa ti or. of ?. ed lei no . Journal ot riomedical Ccnputin ;. Editorial, July, voi I nterr.ationai Voi 4(1): 159. 19 7s Difficulties ci Measuring tne effects of Air Pollution v s the-. Effects of Smoking. Presented at the 135th Meeting of the American Association tor tne Advancement or Science, EacemLer 1 972 . A Versatile System for Three-Dimensional Radiation Dose Computation and Display , HTP. Computer Programs in biomedicine. Vol 2: 178-192. (J. weinkam, senior author.) Fitting the General Field E g u 1 i on to tne Siemens 5a»matron Te chnical Report on Research Ag reement do. 1051/CF for In ternaticnal Atomic Energy A .money , Vienna, Austria. The In cidence of Lung Cancer in the U.S. Since 1955 tc the Etiology or the Disease. Am erican Journal Health. February: 152-158. J. the in Relation or Public 1y71 A Critical Assessment of the Evidence on the Cigarette Snoxinq Lung Cancer Relationship. Presented at the 13i31h Meeting of the American Association for the Advancement of Science, Symposium on Smoking and Health Now. Philadelphia, December, 1971. Difficulty of tvaiuatinc t.i“ Toxicity and Teratogenicity of 2,h,5,-T from Existing Animal Experiments. Science. December, Vol 17U: 1358-1359. Some Thoughts on Treatment Strategy. Computers in Hadiotherapy (proceedings of the nth International Conference on Computers in Radiotherapy, Glasgow, September 1970). Edited by A. S. Glicksman, ;1. Cohen, and J. R. Cunningham. Published as Special Report No. 5 (1971) by the British Institute of Radiology, London. Three-Dimensional Treatment Plan Display Films. Computers in Radiology, op. 12 -1 d . on Computer-Produced A Review of the Claim that Excess Morbidity and Disability Can Be Ascribed to Smoking. Journal of the American statistical Association. Vol to (33d): 251-257. A Critical Reassessment of the Evidence Bearing on Smoking as the Cause or Lung Cancer. Special Report on the Washington university Project on the Review of Crucial Data Rearing on the Cmokint! and Health Issue, St. Louis. Robot Data Screening, An Intelligent (?) Data Search Technique. AOARD Conference Proceedings No. 9d on Artificial Intelligence, 2-1- ¿ - r , Technical e d i t inc and Reproduction Limited, Loncon. Comment on Smoking Dogs. Letter to the Environmental health, vol. 22: b31-632. Editor. Archives of 1970 Problems in Determmina if a Commonly-Used Herbicide (2,d,5-T) lias an Effect on Human Health. Proceedings or the Sixth Berkeley Symposium on Mathematical Statistics and Probability, Reid at the Statistical Laboratory, University cf California. University of California Press, pp. U79-H9U. Experience with a "Universal" Introductory Course in Computer Science. Proceedings of SIGCSE Technical Symposium on Academic Education in Computer Science, Noveuner 16, 1970. Houston, Texas. SIGCSE Bulletin, Vol 2(3), Association tor Computing Machinery, New York. 38 Robot Lata Screening, An Automatic Search Technique, i:io-flea ical Computing. Voi 1: 61-7a. (from the Proceedings of tha Conference on Statistical Computation, University of Wisconsin, April, 1y69 .) Report on Progress in the Development of visual Prosthesis. The New OutiooK for the blind. Feoruary, vol 54: ul-up. ivss Automatic Data Screening: A Practical Solution to the Multivariate Pro M e m in Clinical Data. Annals oi tn e hew York Academy or Sciences. Vol 151: bji-ouQ. A Comment on "Air Pollution -- The Industrial viewpoint". Journal of Occupational Medicine. July, Vol 11: jb Computer Interlace, Incut Metnocs, 1res en tat ion of Results. A o 1 e o i c o m p u 1 1 rs in } a nctherapy , In t r n a trinai .-.to a ic E n e rc y Agency, Vienna. Paper ho. 15, pp. lab-141. Opti mi ration as a Joint Result of Piar.ninu mu Implementation. Role or Computers i .-..idiotn o r a p y , international Atomic Energy Agency, Vienna, pp. 153-157. Display Devices ror Computer Translatai a raille. Proceedings Conference cn New Processes tor •:r a ii 1 a .Mnurac tu re , 196c, Center tor sensory hies Evaluation ana Development, ii= ssacn us t ts Institute ot Technology. February, pp. 14-20. 1M / Automation cf Radiation Treatment Pia n ni r.g, vi: A Generai Fie la liquation to Calcúlate Percent Deptr; Dose m thè Ir rao. latea Volume of a Cobalt 50 Beam. Britisn Journal or Kauiolocy. Voi 4 0 : 'i6 3-4 b b . ürcan hospital Korbiaity and Air Pollution: Second Archives or Envxrcr.rsental Health. Vol 1 b : 35 2 - 3 7u . Report. A New Direction in Re ha bi l it a t i on Through Advance d I nst ru men ta tio n and Computation. Journal of the American Medical As soc iation. Vol 200 (7): 625-629 . The Use of Comp ute rs in T h e ra p e u ti c Radiology, Summary Report of an Intern ati on al C o n f e r e n c e held in Camoridge, England, June 19tb (iaitor) . m t i s h Institute of Radiology, London. final Narrative Report, Training Co mpu te r Work. D epartment of SD-1 a*» b-S-67-C,. . of the Blina tor Health, Education, Professional and Welfare, 1 966 Robot Data Screening: A Solution to Mu lt ivariate Type Proclems in the biological and Social Sc iences. Co mm unicatons of the ACM. Vol 9(7): 529-522 . A B io lo g ic a l l y - O r i e n t e d York Academy of Sciences. senior eaitcr.) Computer Language. Vol 128(3): 755-765. Annals of the hew (S. V. Pollack, Cancer Therapy - Co mp utation ana Visualization Distribu ti ons in External seam Therapy. Journal Diseases. Voi 19: 523- 5 39 . of Dose or Chronic Use of t he Com pu t er to Teach Introductory Communications ot the ACM. vol 9: 274 - 27b . st a t is ti c s . Computers : No Longer a Eig H a rga in Comouters ¿IUi Automation. Vol 15: 1-4 . tor Uneducated (3 . V . Pollack, U s e r.s . senior author.) The Selection, Training, and Pl acement of Blind Computer Programmers, report or the Association tor Computing Machinery . Is Medical Diagnosis a General Co mputer ProDlem? Journal American Medical Association. Vol 196(3): 281-266. [efogging the Issue: control auto exhaust California has discov er ec that fumes. B a r r o n ’s, May 2, pp. b, Urban norcidity and Air Pollution: A first Invironmental Health. Vol 13: 150-170. The Blind as Co mputer 7(1): 7-10. Programmers. Report. Rehabili ta tio n Role of S ta ti sti cs in the World of Computers. Annals York Academy ot Science. Vol 128(3): 1108-1115. of laws 14-15. the can't Arc hives of Record. Vol of the New o f' The Role et tne 3lina in Data Annual Co nle re n ce on Computer Washington University, 1965. Automation. Voi It: 2b - 2 7 . Processing. Presented at Third Personnel Research Group, held at Reprinted in Computers and Pro cee di ngs on the i-raille Research ana Development Conference, Sensory Aids, Evaluation ana Development. Massach use tt s Institute c t T (■c n n o i c a y , November, 1 9 6 6 . 19 65 Automation of Radiation Treatment Planning, v : Calculation una Visualisation of the Total Treatment Volane, dr i t is n Journal or. Radiology . Voi 58 : 9 0b- 91 1 . Robot Data Processing Tecnniques tor ilu 1 1 i varia te Epidemiolceical Predictions. Anriols ot the New York ncacemy ot Science. Vox 116(2): 77 9-79'«. The Role of the Blind in Data Processing. Procedures oi Third Annual Co a pu ter Pur son r,oi Research Conference, June 1 b 5 . (11. H . Gctterer, ? :. ; Computers in Personnel Research Group, Silver Spring, Do.; pp . u 1 - i 9. Computation or Radiation D.osa-jes. In Stacy, R. and 9asman, (Ed.), Computers in :,i o.-sed ica i Research. Academic Press, York, Vol 1 (Chapter Id). ( Proof ,n dea ici;, e. u t.u t F e aeration Careers tor the: Elina in Elec renie Data Processing. Data Processing. Occu pa tio na l Outlook „uarterly. Voi ai ec t ro n ìc , (1 ) : 1-è . Toward a Under:: redd «ato F.e se a r c n e r s in the iuJ'is o i Proceedings. Vci 2 d (1 ) : 5-9. a tn em aticr io lo a y m e B ., ..ew Employment Potential ter the Elina in Computer Hc-Iat<-a Fields. The International Journal for Education of tne Blind. October, pc. 1 —5 • The timo. in D P . ACM Co mm i t tee on Professional Activities ot Archives of En vironmental the Blind. 19(>u Ma th ematical Analysis of Health. 6: dd-51. Lead Burdens. Design ano Operation of a Medical Co mputing t he ew York 3 a e n gsr , senior Academy author) of Science. Voi Center 1 1 5 (2 ): Annals 91-599. ct ( E. 1co A i Planning F.aaiation Treatment or. the Computer. Annals or the hew York Academy of Science. Vol 115(2): 976-997. Professional Computer Work for the Blind. Communications of the ACM. Vcl 7 (4) : 226-211 . Computer vcr;; as a Profession Rehabilitation. Vol 1C: 20-21. for the Blind. Journal of Epidemiology of Disease Associated with Lead. Archives of Environmental health. Vol 8 : 133-148. '!at nom at ica 1 Analysis or Lead Burdens. Archives of Environmental Health. Vol 8 : 44-51. Automation of Radiation Treatment Planning, IV: Derivation of a Mathematical Expression for the Per Cent Depth Dose Surface of Cobalt 60 Beams and Visualisation of Multiple Field Dose Distributions. British Journal of Radiology. Vol 37(439) : 544-550. Locating Placenta Praevia. Procedures or the Rochester Conference on Data Acquisition ana Processing in biology ana Medicine, Hew York, 1963. Pergamon Press, New York, pp. 103-111. 19 6 3 Do Malignancies Result rron Diagnostic and radiation? Genetics ana the .ipiueiiioiogy of 2 U.S. Dept, of health, Education and Welfare, pp. Therapeutic MEDCOMP, Part 1, Statistical Systems. Medical Computing University of Cincinnati, Ohio. Center, Boron, Cadmium, Chromium, and riicxel in the Blood ana Urine. Arcnives of fcnvironrental health. Vol 6 : 236-295. (H. Imbus, senior author.) Potential Hazard of Exposure to Leaa. Archives of Environmental Health. Vol 6 : 255: 272 . (R. Kehoe, senior autnor.) Carcinogenic Effects of Till Compared with X - Irraoietion - k Review. Health Physics. Vol 9: 1371-1 j;4 . (2 . Saer.ger, senior author.) Automation of Radiation Treatment Planning, 111: A Simplified System of Digitizing Isodoses ana Direct Print-Gut of Dose Distribution. British Journal of Haaiclogy. vol 36: 522-527. Intravenous Methotrexate (Amethopterin) Thirapy in the Treatment of Acute Leukemia. Pediatrics. Vol 31: 834-339 . (J . Perrin, senior author.) Autonation cf Radiation Treatment Planning, II: Calculation or lion-Convergent Fiala Dose Distributions. British Journal ot Radiology. Voi 36(427): 63-67. Roto t Treatment Planning, i’roceduies ut t n a i-ioc tester Cor. ierence on Data Ac qui sition ana Processine in a i o l o cy and medicine, ie« Yorx, 1962. Peraason Press, New Yorh, pp. 294-319. Robot Lata Screening. Proceedings ot m e Hocnes tei Conference on Data Acquisition ana Processing in Biology and Medicine, New Yorh , 1462. Per can. on Press, New Yor't , p p . 31 -2^2 . 19 6 2 Occupational Exposure to Organic Leac Compounds. Archives oi Environmental health. Vol 6: 532 -336. (h . DeTriviiie, senior author.) New Developments in Chronic .'.'isease Epidemic log y : Competing Risks ana Eligibility. American industrial hygiene Association Journal. Vc i so: u 3 j -1 g 6 . !: .a a i a t io t: ruoic •:v . C a nc e Comparative Studies enviro n m e n t a l t-t-ai th . n 1 Certain Lead ï 5. Alxyls Archives ot (E . Hinqham. senior author.) 19 61 A Practical Procedure for Automating Radiation Treatment Planning, ciitish Journal ot iat, ioiogy. Vox i-i: 7 ¿6-7 33. Epidemiological Methods ana Community Air Pollution, .ircnives or Environmental health. Vol 3: 267-275. (J. ah air, senior author.) Competing Causes ct Deatn in Coal Tar «or/ters. .-lettering Report. 1 9 60 Cesium-137 Retention and Distribution in x-Irraaiateu Rats. U.S. Army Medical Research Laboratory, Fort Knox, Ken tucity. Report N o . 504. (G. Keri altes, senior author.) Seasonal Variations in the American Journal e i public Birth e a 11 n dentally 01 the V0 1 5 0 : À 33-^6 3 . Deficient? 1 The Leaa Content o Meeting of apca, author.) the Atmosphere. Presented at the 63rd Annual Ch olaK , senior Hay 1960, Cincinnati. (J . V.hat is so E e c u liar About Accepting Psycnolccica1 htports. Vol 7: 363-36u. the hull hypothesis? Neoplasia following Therapeutic Irradiation tor Benign Conditions m C h i i a hood. Radiology. Vol 7 4 : o39 -90 4 . (L. Ssender, senior author.) 19 59 Inferences Drawn Public Decisions ana Their PossiDle Effects of the from Tests of Sigr.it icanee J o ur nc - or Vic e - ve rsa. A m e n c e n S tatisticai Association. Vol 54 : 3Ü-J*. Pulmonary function l n Children, I and LI . Journal or Voi 3ü ( z ) : f 1u - b a J . (I. L. -trnste. in , seni or au t h ci .) Aile ru y Tables of Pulmonary function Values in Children Ages o to 19. K reaer Printing Co., Cincinnati, Ohio. (I. L. Eernsttin, senior author.) Doxtro-iop n at a i r.e Sulfate upon The A nor x i 4 er. ic Action of Comparative Feeding ne s ^o ns«- s or .:-itiering o 11ena tn . Journal of ana Physiclogica i Psychology Vol 52 : 1 79- 1 8 2 . (P . S i e g e l , senior author.) Sources o 1 Contextual C o ns tralnt p c :i .-.oris in Sen tenets . Journal of Experimental Psychology, Voi 5 7 : 1 71 - n. c . (¡1. Adorn, senior author.) 19 L 7 Effect or Irrelevant Drive on Extinction F syc no loci cal Reports. Vol 1 : 61 5 - 1 n . or Bar-Pressing. A Central surveillance System dessurement Model, Pro I'-'Ct M ; o!. : pin Z 34 o , Z71'!, :ti ve rs 1 1 y or nicnig^n. A General Survey of Statistical Decision Michigan Z915, University of t i c m q a n . Part I, II. Theory. Project 132 Bio-Statistician/MathematicianThis witness will be identified in the near future. At that time a curriculum vitae will be supplied. This witness will describe the mathematical/statistical model which will be used in the presentation of the figures to which the witness will testify. The theory subserving the testi­ mony is that the m u l ti-faceted presentation of symptoms and signs and test results in the same v eteran makes a random compo­ sition of such an array extremely unlikely in view of the relative in-frequency of each facet of the array. As such, this testimony will be used in the generic and specific proximate causation areas. 1 3275' S c h l e g e l & T r ä f e l e t . Lt d . A t t o r n e y s a t L aw O n e N o r t h La S a l l e S t r e e t C h i c a g o , Il l i n o i s G 0 G 0 2 S tephen J . Schlegel D e a n M. T r a p e l k t S u it e oooo (3 1 2 ) 782-1001 I v a r R. A z r a i h S t e v e n P. P o l io k February 13, 1984 J am es A . Romanyak Honorable Shira Schneindlin Magistrate & Special Master United States District Court Eastern District of New York 225 Cadman Plaza East Brooklyn, New York 11201 Re: In re "Agent Orange" Product Liability Litigation - MDL No. 381 Dear Magistrate Scheindlin: In conformity with the representation made by the Plaintiffs to you at the hearing he d on February 9, 1984, we are tendering the following as our preliminary list of our priority witnesses. Plaintiffs wish to depose: Debdas Mukerjee, EPA - D.C. Philip J. Landrigan, CDC, NIOSH Janet Springer, EPA - D.C. Vemon N. Eouk, CDC - Atl. James Mason, CDC - Atl. Dr. Diane Courtney, EPA - D.C. Peter Infante, NIOSH, D.C. Umberto Saffiotti, NCI - D.C. Donald Bames, EPA - D.C. 1327? DIAMOND-SHAMROCK WITNESSES I. Diamond-Shamrock employees: David J. Porter S . B . Honour J. 0. King Melvin Hochberg Howard E. Edison Lex Creamer (Would like to depose, but unable to locate) II. Government witnesses: M. Isele, DCAS - Contracting officer J. K. Murphy, Chief - Contracts branch E. R. Sabala, DCAS - Contracihg officer I. Wolin, DCAS - Cleveland, Ohio DCASR - Commander Contracting officer 1367 E. 6th Cleveland, Ohio -2- 13278 DOW CHEMICAL COMPANY Employees: George E. Lynn Julius Johnson H. R. Hoyle Ross Mulholland Larry G. Siiverstein Ray Holmes R. D. Wilcox V. K. Rowe G. Goer gen Paul Orrefice Sam Birkman John Barber Joseph G. Temple, Jr. Etcyl H. Blair David L. Rooke 13279 HERCULES' WITNESSES I. First priority list : C . L . Dunn T. Eagon A. E. Sidwell A. L. Triesback H. E. Wilder II. Second priority list : J. G. Copeland Rafael H. Huston Charles E. Minarick, U.S. Army - Biochemical Custodian of Records of NACA - National Agriculture Chemicals Association, Washington, D.C. Custodian of Records of Bionetics Research Laboratories, Bethesda, Maryland III. Third priority list : Otis Fancher, Industrial Biotests Laboratories Custodian of Records of Industrial Biotests Laboratories, Illinois R. T. Yates Custodian of Records of Hazleton Laboratories, Falls Church, Virginia 13280 HERCULES' WITNESSES - cont. IV. Defense Personnel Supple Center - Contracting officers: Government witnesses Donald Elmore Thomas P. Dalby Jacob L. Bolton Ellis Cash 1328 4i -5- MONSANTO WITNESSES Charles Luecke John Mullendore Carl Bohl Phillip Balderson Homer Payton Frederick L. Rupel Ronald R. Smith R. L. Payne Tom K. Smith Richard Wallace, M.D. Nel Putzel Louis Schwartz Robert R. Rumer (Recall) U . L . Sims R. L. Null Toby White Howard Minkler E. Weger Nick Machacrola Paul Ekberg Jim Starrett Bruce Ely MONSANTO WITNESSES II. cont. Contracting; officers - Richmond, Virginia : John Blish George Collins Jesse Gershberg III. Monsanto inspectors - St. Louis region : Ten Eyck R. D. Fisher M. McCalley Roy Meyers N. Wirz R. Wright 1328 -7- THOMPSON CHEMICAL COMPANY WITNESSES I. Employees : John Mayer Leo Crivello D. Halleck Cecil McGill James Reagan F. Vargas II. Government witnesses : DCSR, Director Commander - St. Louis, Missouri III. Miscellaneous witnesses: Dr. Earnest Velasco Kosciusko Medical Clinic St. Louis, Missouri American Mutual Liability Insurance Company St. Louis, Missouri 13284 -8- UNIROYAL, INC. WITNESSES Defense Contract Administration Service Office : F. H. Placet (Process inspector) A. Matasauage - Industrial Specialist M. Dojny - Quality Assurance Rep. (Chemical inspector) A. W. Glenn - Preservation Packing Specialist Harold A. Lloy - Administration Contracting officer Wayne Vandervendor - Specialist for Technical Orange Herbicides T-H AGRICULTURE & NUTRITION CO. WITNESSES I. T-H Agriculture & Nutrition Co. employees: L. S. DeAtley Bill Sulzen Art Wilson Dr. Charles Lewis Bob Mayer Jack Hallen II. Government witnesses: Edward E. Adams - St. Louis, Missouri A. A. Block - Kansis City, Missouri James E. Bowers - St. Louis, Missouri Charles Dilley - Kansas City, Missouri Frank W. Kleman - St. Louis, Missouri Joseph W. Fowler - Kansis City, Missouri Respectfully submitted, Management Committee 132-86 -10- AGENT ORANGE SERVICE LIST Judge Jack B. Weinstein ** United States District Court Eastern District of New York 225 Cadman Plaza East Brooklyn, New York 11201 Neil Peterson, Esq. ** Gene Lo'cks, Esq. Greitzer & Locks 1500 Walnut St., 21st FI. Philadelphia, Pa. 19102 Honorable Shira Schneidlin ** Magistrate - Special Master United States District Court 225 Cadman Plaza East, Rm. 285 Brooklyn, New York 11201 Phillip E. Brown, Esq. Hoberg, Finger, Brown, Cox & Molligan, P.C. Central Tower 703 Market Street San Francisco, Calif. 9410 Honorable Sol Schreiber Milberg, Weiss, Bershad & Specthrie One Penn Plaza New York, New York 10019 John O'Quinn, Esq. O'Quinn, Hagans & Wettman 3200 Texas Commerce Tower Houston, Texas 77002 Stephen J. Schlegel, Esq. Schlegel & Trafelet, Ltd. One N. LaSalle St., Ste. 3900 Chicago, Illinois 60602 Plaintiffs' Management Commi c/o Jan Levien, Esq. ** 26 Court St., Suite 905 Brooklyn, New York 11242 Thomas W. Henderson, Esq. ** Henderson & Goldberg Frick Building, Rm- 1601 Pittsburgh, Pa. 15219 Irving Like, Esq. ** Reilly, Like & Schneider 200 West Main Street Babylon, New York 11702 David J. Dean, Esq. ** Dean, Falanga & Rose 1 Old Country Road Carle Place, New York 11514 Clerk of the Panel ** Judicial Panel on Multi­ district Litigation 1120 Vermont Avenue, N.W. Suite 1002 Washington, D.C. 20005 Benton Musslewhite, Esq. ** 609 Fannin - Suite 517 Houston, Texas 77002 Newton B. Schwartz, P.C. Houston Bar Center Bldg. 723 Main, Suite 325 Houston, Texas 77002 Stanley M. Chesley, Esq. Waite, Schneider, Bayless & Chesley Co., L.P.A. 1318 Central Trust Tower Fourth & Vine Streets Cincinnati, Ohio 45202 Arvin Maskin, Esq. ** United States Attorney United States Dept, of Justic Safeway Bldg. - Room 904D Washington, D.C. 20530 Leonard Rivkin, Esq. ** Rivkin, Leff, Sherman & Radle 100 Garden City Plaza Garden City, New York 11530 John C. Sabetta, Esq. ** Townley & Updike 405 Lexington Avenue New York, New York 10017 Wendall B. Alcorn, Jr., Esq. ** Cadwalader, Wickersham & Taft One Wall Street New York, New York 10005 Thomas Beck, Esq. ** Arthur. Dry & Kalish, P.C. 1230 Avenue of the Americas New York, New York 10020 Howard Lester, Esq. ** Lester, Schwab, Katz & Dwyer 120 Broadway New York, New York 10271 Michael V. Corrigan, Esq. ** Simpson, Thatcher & Bartlett One Battery Park Plaza New York, New York 10004 Judith L. Spanier, Esq. ** Shea & Gould 330 Madison Avenue New York, New York 10017 Morton B. Silberman, Esq. ** Clark, Gagliardi & Miller 99 Court Street White Plains, New York 10601 Mr. Robert Heinemann ** Clerk of the United States District Court 225 Cadman Plaza East Brooklyn, New York 11201 William A. Krohley, Esq. ** Kelley, Drye & Warren 101 Park Avenue New York, New York 10178 David R. Gross, Esq. ** Budd, Lamer, Kent, Gross, Picillo & Rosenthal 33 Washington Street Newark, New Jersey 17102 Herbert L. Fenster, Esq. McKenna, Conner & Cunes 1575 Eye Street, N.W. Washington, D.C. 20005 *** _ Hand Delivered ** - Delivery by Federal Express Delivered regular mail to everyone else. ** John M. Fitzpatrick, Esq. ** Stillworth, Paxson, Kalish & Levy 2600 Fidelity Building Philadelphia, Pa. 19109 Paul V. Esposito, Esq. Lewis, Overbeck & Furman 135 S. LaSalle Street Suite 1060 Chicago, Illinois 60603 *** 132B& -2- UNITED STATES DISTRICT COURT EASTERN DISTRICT OF NEW YORK ■X In re: "AGENT ORANGE" MDL #381 Product Liability Litigation •X PRESENT LIST OF PLAINTIFFS' CAUSATION WITNESSES WITH ATTACHED EXPANDED SUMMARIES IN ACCORDANCE WITH FRCP 26(b)(4)(A)(i) AND GENERAL STATEMENT OF SCIENTIFIC' PRINCIPLES AND ASSUMED FACTS PLAINTIFFS’ MANAGEMENT COMMITTEE ---- Thomas W. Henderson, Esquire / I d GENERAL STATEMENT OF SCIENTIFIC PRINCIPLES AND ASSUMED FACTS A. BACKGROUND The Plaintiffs' experts represent a cross-section of the scientific and medical community who have individualized areas of specialization, but, who, because of their training and expertise, have a common nucleus of scientific principles and assumed facts, which would be virtually unknown to the lay person and the jury without some explanation. This will serve to inform the Court and the Defendants of those areas which any one or more of the Plaintiffs' individual experts may testify to and which represent a "common consensus" of scientific principles and assumed scientific facts which the credible medical and scientific community, including all plaintiffs' experts, share. The complexity of the instant litigation from the perspective of a layman necessitates a rather comprehensive overview of the basis scientific and medical disciplines. See Plaintiffs' Supplemental Answer to Interrogatory No. 2(d) which lists the basic scientific medical disciplines involved. Plaintiffs have attempted to select causation experts who have unique areas of specialization which will in large part form the bases of u 13230 their testimony, but, more importantly, these particular experts, because of*their broad based experiences and qualifications, will hopefully be able to synthesize for the jury the broad scope of issues which are at the crux of : / this lawsuit including: (1 ) The chemistry, biochemistry of the defendants' products, including Agent Orange and its dioxins; (2 ) The manufacturing and industrial processes used by the defendants to formulate Agent Orange and as a by-product the formation of dioxins; (3) The extreme toxicity of one particular dioxin, 2,3,7,8 -TCDD, which is the most toxic chemical ever synthesized by man. Specifically, the toxic effects of Agent Orange and 2,3,7,8-TCDD and its other dioxins, on our entire ecosystem and the balance of life that nature tries to maintain, including TCDD's threat to plant life, animal life, and human life, and more specifically, to the Veteran class of plaintiffs who were exposed to this most toxic of all poisons while serving their country in Vietnam. Plaintiffs have exerted their best efforts to avoid repetition and unnecessary overlap of testimony. While the plaintiffs' experts testimony may in some instances overlap, each individual expert will be able to enlighten the Court and jury within their own specialty areas. ■ *> 1 3 2 ^ -2- B. DEFINITIONS AND SHORT EXPLANATIONS OF EACH DISCIPLINE (Tabors' Cyclopedic Medical Dictionary, lLth Ed., F.A. Davis CoTT (1915 Arch St., Phil) 1970) I. Chemistry/Botany 1. Botany/Plant Physiology Science of cells, tissue and organs of plants 2. Biochemistry The chemistry of living things; the science of the chemical changes accompanying the vital function of plants and animals 3. Bio-Assay Greek bios - life French essayer - to try Estimation of strength of a drug by noting its effect in test animals and comparing such with effect of a standard preparation 4. Chemistry The science that treats the molecular and atomic structure of matter and composition of substances, their formation, decomposition, and various transformations which they may undergo. 5. Biological Chemistry The chemistry of living things involving all chemical processes which take place within an organism, such as, digestion of food, anabolism and catabolism. 6. Inorganic Chemistry The chemistry of compounds not containing carbon. 7. Organic Chemistry The chemistry of carbon compounds. 8. 13293 Pathological Chemistry The study of chemical change by disease processes; changes in -3- Chemistry or organs and tissues, blood, secretions, excretions, etc. 9. Physiological Chemistry Study of chemical nature of living matter and the changes occurring in the metabolic activities of plants and animals . Animal Toxicology 10. Animal Toxicology The study or science of poisons, their nature, effects and antidotes in animals 11. Toxic Greek: poison/poisonous To, resembling or caused by poison 12. Toxicity The extent, quantity and degree of being poisonous 13. Toxicide A chemical antidote for poisons 14. Toxicology The study or science of poisons, their nature, effects and antidotes. 15. Toxigenic/Toxigenicity Producing toxins or poisons; the virulence of a toxin - producing pathogenic organism. 16. Toxins A poisonous substance of animal or plant origin 17. Bacterial Toxin A.. Exotoxins (extracellular) Toxin produced by bacteria, which diffuse from bacterial cells into surrounding medium B. Endotoxins (intracellular) Toxin produced by bacteria, which are liberated only when bacterial cell is destroyed III. Neuro-Behavorial 18. Neurotoxicity Study of the behavior of poisons on the neurological system (nervous tissues) of animals and humans, particularly TCDD 19. Neurology The branch of medicine that deals with the nervous system and its diseases 20. Neurolysin A substance which destroys nerve cells 21. Neuron A nerve cell, the structural and functional unit of nervous system consisting of a cell body (perikaryon) and its processes (on axon and one or more dendrites) initiators and/or conductors of messages from the terminal branches of cell to the cell body or receptor 22. Peripheral Nervous System Whose processes (messages) constitute the nerves conducting messages from the brain and the spinal cord throughout the body of animals and humans into the body’s extremities 23. Central Nervous System The brain and spinal column nervous of an animal and human which send messages to all other parts of body via peripheral nerves. 24. Porphyrin Levels One group of cells forming basis of animal and plant respiratory pigments, obtained from hemoglobin (blood - human/animals) and chlorophyll (plants) -5- 25. P o r p h y r i a ( P C T ) Porphyrin in the blood; a rare metabolic disease characterized by excessive excretion of porphyrins, acute abdominal pain and neurologic disturbances, sensitivity to light is characteristic 26. Myelin Sheath A fat-like substance or protective covering for nerve fibers; Greek word: myelos = marrow) A complex lipoid (fatty) substance present in the brain in small quantities, but predominantly a protective shield for the nerves conducting messages throughout the bodies of animals and humans IV. Immunology 27. Immunology Study of how body responds to foreign (antigenic) stimulation and tries to protect itself 28. T - Lymphocytes; B - Lymphocytes Immunoregulatory cells of immune system - regulates a number of responses which destroy host cells bearing foreign substances; and regulates cell - mediated resistance to infectious agents 29. Immune Bodies Substances in those afflicted with an infectious disease or toxic foreign substance formed by the tissue and possessing power to destroy or injure the disease producing or poison producing agent or to neutralize the toxins. These substances are formed in serium of coagulated blood, in blood plasma and in lymph glands - called antibodies; each is result of specific antigen (foreign substance) or disease producing factor which acts only upon the same antigen. They are determined by the effect they cause. If the antigen is poisonous it is called toxin and its antibody, is called an Antitoxin. 29a. Immuno-Toxicology The undesirable effects of an inappropriate response of the immune system. -6- V. Oncology 30. Oncology The diagnosis, treatment and care of cancer victims with emphasis upon the cause of the cancer so that preventive medicine may prevent the occurrence of cancer in others. 31. Carcinogen Any substance that has been shown to cause tumors in animals or man. As a matter of principle all chemical carcinogens which are shown to be active in men are also active in animals. Scientifically, there is no way to determine a "safe" level for substances (chemical) known to produce cancer in animals or man. A malignant tumor or neoplasm; a sarcoma or carcinoma. VI. Reproductive Toxicology 32. Reproductive Toxicology Study of poisons which affect the process by which plants, animals and humans give rise to offspring or create a similar structures or living bein^ (the act of duplicating oneself). VII. Other Definitions 33. Internal Medicine The study of the human body as a whole with emphasis on the internal body structure and organs, their functions and interrelationships of the various body systems. 34. Psychology The study of medicine dealing with mental processes, both normal and abnormal and their effects upon behavior, including four primary methods: (1) experimental; (2) comparative; (3) genetic; and (4) pathological. 35. Physiologic; Psychology The study of the structure and function of nervous system and other bodily organs and their relationship to behavior. 7- 36. F e t o t o x i c i t y / T e r a t o t e n i c i t y Fetotoxicity is a general term used to describe all abnormalities (both transient and permanent) originating in an embryo or fetus regardless of the timing of any such action. A special fetotoxic effect is called teratotenicity which is an abnormality from impairment of an event which occurs at a specific time in an embryo's or fetus' development in the mother. 37. Mutagenicity/Cytotoxicity Sudden, permanent variation with offspring differing from the parents in a marked characteristic as differntiated from gradual variation through many generations; a dramatic change in genes and/or chromosomes potentially capable of being transmitted to offspring. 38. Epidemiological and Biostatistics The methods by which cause and effect relationships are determined in the medical and scientific community. The study of medicine concerned with explaining the interrelationships of the host, agent and environment in causing or contributing to cause a disease or physical condition. 39. Gonadotoxicitv The study of substances which poison the gonads; "Gonad" refers to • both the female sex glands or ovaries, and the male sex gland or testes. The embryonic sex gland before differentiation into testes or ovary. 40. Genetics The science that accounts for natural differences and resemblances among organisms related by descent; the study of heredity and its variation 41. Dermatology The study of the skin and the diseases of the skin. 132S7 c. CHEMISTRY/BIOCHEMISTRY I. Chemical Formulation of 2,4-D, 2,4,5-T and 2,3,7,8-TCDD Plaintiffs as a class represent the veterans who served in Vietnam between 1961 and 1972 and were exposed to the spraying of a herbicide known as Agent Orange which was composed of 2,4-D (Dichlorophenoxyacetic acid) and 2,4,5-T (trichlorophenoxyacetic acid), which chemical compounds are known to be neuro­ toxins by the credible scientific and medical community. It has further been established that a family of chemical compounds, commonly known as dioxins (dibenzo-p-dioxins), are produced in the manufacturing processes utilized by the Defendants in the instant lawsuit since the date production of these herbi­ cides began in approximately 1925 through the last days of spraying operations in Vietnam in approximately 1972. The Defendants comprise almost 99% of the relevant herbicide production market between 1961-1972 which was sold to the U. S. Government for spraying operations in Vietnam. The World Health Organiza­ tion in 1971 found "no acceptable daily intake for man" for 2,4,5-T. Because of the extreme toxicity of all dioxins, and particularly of 2,3,7,8-TCDD, a known contaminant of 2,4,5-T and hence of Agent Orange, it is important to understand the chemical formation of dioxin 2,3,7,8-TCDD, the "most toxic chemical synthe­ sized by man." II. Chemistry of Dioxin Formation The basic chemical composition of the family of compounds known as "dioxin" consists of two double-bonded benzene rings interconnected with a pair of oxygen atoms which close a third center ring. The nucleus of a "dioxin" is clearly shown in the diagram below, and represents a triple ring structure. Each of the numbered positions as shown in the diagram can hold a chlorine or 13288 , -9- other halogenated or organic radical. Or, if there are no other substituents in the formula in the manufacturing or process formula, a hydrogen will be attached at one or more of the numbered positions. 9 | 1 rS i y j 1 0 ^2 ^ 3 4 The only difference in the "dioxin" family is the nature and positions of the substituents which are attached to the benzene rings at the numbered positions above. Most of the environmental interest in the dioxin group is centered in chlorinated dioxins where chlorine atoms are attached to one or more of the eight positions on the two benzene rings. There are theoretically seventy-five (75) positions available for chlorine atoms to attach in various formations. These represent differences in the number of chlorine atoms which attach to the eight positions available and to the relative positioning of chlorine atoms in the "dioxin" nuclues itself. See list of all seventy-five theoretical Chlorinated Dioxins on the Table which follows. For example, there are two possible isomers of monochlorodibenzo-pdioxin (MCDD). Therefore, there are two places on the two benzene rings which allow only one chlorine atom to attach and those are at positions no. 1 or no. 4. Also important is that the particular type of dioxin, tetrachlorodibenzo- p-dioxin (TCDD's) which has been classified as most toxic, has twenty-two (22) isomeric possibilities. On page 4 of the EPA Chart which follows is the diagram of the 2,3,7,8-TCDD nuclues, the most toxic contaminant of Agent 132S9 Orange and of all dioxins. -10- Table I lists the 75 possible chlorinated dioxins, an d also notes the 40 that have been prepared and tdenim ed and whose analvttcal characteristics have been punlished tlluser, Bosshardt. and Rappe I97X; Huser ISJ” 5: Pohlanu and Yana 1972: Bolton I97X|. Five others, as noted in the table, have been identified as distinct co m p o u n d s but have not been clearlv differentiated from each other I Baser. Bosshardt. and Rappe I97X: Buser 1975: R ap p e 1978). TABLE 1. CHLORINATED DIOXINS 1 cnloro 2-cnloro 1,2-dicnloro 1 3-dichloro 1,4-dicnioro ) ,6-dicnloro 1.7 aicnloro 1 8-dichloro 1,9-dicnloro a 3 a a a a 2 .3 - d ic n la r o a a a a a 2.7 -dicnloro 2.8-dicnloro 1,2,3-tricnloro 1,2.4-trichloro 1 2.6-tricnloro 1.2.7-tricnloro 1,2.8-trtcnioro 1,2.9-tricnloro 1,3.5-tncnioro 1,3.7-tncntoro 1,3.8-tncnloro 1,3 .9 - tn c n lo ro 1.4 6-tricnioro 1.4.7-tricnioro 2.3.6-tricnloro 2.3.7-tricnloro a 1,2.3.4-tetrachloro 1,2.3.6-tetracnloro 1,2.3.7-tetrachloro 1,2.3.8-tetracnloro 1,2.3.9-tetracnloro 1.2.4.6-terrachloro 1,2.4.7-tetrachloro 1 2.4.8-tetrachloro 1 2.4.9-tetracnloro 1.2.S.7->9tracnioro 1,2.6.8-tetracnloro 1 2.6.9-tetracnloro 1.2.7.3-tetracnloro 1.2.7.9-tetracnioro 1,2.3.9-tetracnloro 1 3.6.8-tetracnloro 1.3.6 9-tetracnioro 1.3. 7.3-tetracnloro 1 3.7.9-tetracnloro 1,4.6.9-tetracnloro f 4 .7.3-tetracnloro 2.3.7.8-retracnloro a a.d a a a a a a a a a a a 1.2.3.4.6-oentacn loro 1.2.3.4.7-oentacnloro 1,2.3.6.7-pentachloro 1,2.3.6.8-oentacnioro 1.2.3.6.9-pentacnloro 1 2.3.7.8-oentacnloro 1,2.3.7.9-pentacnloro 1.2.3.8.9-pentacnloro ' .2.4.6.7-pentacnloro 1.2.4.6.8-pemacnloro 1,2.4.6.9-oentachloro 1.2.4,7 8-pentacnioro 1,2.4.7.9-pentachloro 1.2.4 8.9-pentachloro 1.2.3.4 6.7-hexacnioro 1.2.3.4 6 .8 -hexaemoro 1.2.3.4.6.9-hexacnioro 1.2.3.4.7.8-hexacnloro 1.2.3.6.7.8-hexacnioro 1,2.3.6.7.9-hexacnloro 1,2.3.6.8.9-hexachloro 1,2.3.7.8.9-hexacbloro 1,2.4.6.7,9-hexachloro 1,2.46.8.9-hexacnioro 1,2.3.4.6.7.3-heptachloro 1 2.3 .4.6.7.9-heptacnioro Octacnloro a a c a c a c a a a a a a b a a b a a 3 a—identified comoounas. b—One or tne otner of these comoounas has been oreoared. c—A mixture of these three comoounas has oeen oreoareo. 0—The Oow Chemical Comoanv has recently reoortea the synthesis of ail 22 TCDO isomers The interest oi health and environmental researchers in dioxins arose principally because of the toxicity and distribution of one of th e s e c o tn p o u n d s. 2..C7.X-1 CD D. whose structural fo rm ula is as tollows: 13300 - l i - The nucleus of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is unusual in its symmetry on the horizontal and vertical axes and represents a chemically stable and non-reactive molecule. liquids. It is not soluble, in water and most organic It is extremely lipophilic molecule and colorless crystaline solid at room temperature. The only other formation of dioxin which is similar to the TCDD's is the OCDD's which has the same two-fold symmetry. III. Precursors/Predioxins Dioxins apparently are not constituents of a normal growing environ­ ment. They are not formed biosynthetically by living organisms. In order to cosntitute a dioxin precursor, a chemical compound used in industry has to meet two conditions: (1 ) the precursor compound must be an ortho-substituted benzene ring in which one of the substituents includes an oxygen atom directly attached to the right. It should be noted that a singe oxygen atom is very unstable and does not occur by itself; therefore, usually a phenol group (OH) is used in order to detach the oxygen atom from the hydrogen in a process known as hydrolosis. (2 ) it must be possible for the two substituents excluding the oxygen atom to react with each other to form an independent compound. The most common manufacturing for this two step reaction is the hydroxal group of phenols, which supplies the ring attached oxygen and the hydrogen of the hydroxal atom is capable of reacting with chlorine. The most common predioxins are trichlorophenol potasium salt and trichlorophenol sodium salt. The condensation of 2,4,5-trichlorophenol (TCP), the first step in the 13301 process, results in the formation of a dibenzo-p-furran (two benzene rings with -12- four symmetrical chlorine atoms (2 ,3,7,8 ) and one oxygen atom connected at the top of the two benzene rings, and also produces industrial salt NACL or KCL, sodium chloride or potassium chloride. The second step then substitutes the second oxygen which closes the benzene ring or which has the potential for closing the benzene ring with the second oxygen connecting it and allows the sodium or potassium to react with chlorine to make industrial salt used primarily in fertilizers. All of these reactions occur under heat and pressure and over and in the presence of metal catalysts. The importance of the manufacturing process itself is emphasized because process engineers choose various chemical compounds to create an end product, not based on its safety, but simply based on the ability of the manufacturer to produce the maximum amount of the product at the lowest possible cost; hence, various manufacturing processes themselves yield differing amounts of the 2,3,7,8-TCDD contaminant based on factors such as (1) heat, (2) pressure, (3) photostimulation, (4) precursor chemical compounds used and (5) the catalysts, reagents and solvents which are used to encourage the reaction from the clorinated precursors to the predioxins and into dioxins themselves. The importance of chemical structure of the compounds of 2,4-D, 2,4,5-T emphasize their close similarity with polychlorinated biphenols and other chlorinated napthalenes which have similar chemical structures although somewhat less complex than the triple bonded ring structure of dioxin and have a long history of toxic effects and hazards to humans. The following quotations from the EPA Dioxin Report, 1978 are relevant: I Q o n. o Od> U / "On a molecular basis, 2,3,7,8-TCDD is perhaps the most poisonous, synthetic chemical . . . only bacterial exotoxins are more potent poisons." "It is reasonable to presume, therefore, that the slightest trace of 2,3,7,8-TCDD in the environment may have adverse effects on the health of both human and animal populations." Toxicity of 2,3,7,8-TCDD "Because of the remarkable stability of this substance (2,3,7,8-TCDD) in biological systems and its extreme toxicity, cumulative effects of extremely small doses are a major concern." EPA Dioxin Report, 1978, p.l - 1 4 - D . E X P O S U R E I. Modes T O D I O X I N S Because of the extreme toxicity of all dioxins, but particularly of 2,3,7,8 -TCDD, it is important to carefully scrutinize the probable avenues of contamination of the environment. It is known that 2,3,7,8-TCDD can be produced in the manufacture of 2,4,5-Trichlorophenol and other chlorophenols. The amounts of dioxin may vary in each commercial product with temperature and pressure. Since dioxin contaminants are present in the manufacturing process, the amounts of dioxins varying with different process controls by each individual manufacturer, they are present in chemical waste and sludges remaining from these processes. If these waste products are indiscriminately discharged into the environment or not properly disposed of, contamination of water, air, or food stuff results in widespread exposure of the population to TCDD's and other dioxins. Humans can absorb these chemicals by absorption through the skin; by inhalation while breathing; by ingestion through food and water; and exposure from the use, of proximity to and/or spraying of herbicides. exposure has occurred in the following situations; Occupational (1 ) in manufacturing plants when TCDD was formed in excessive amounts because the reaction temperature and pressure were high enough to favor dioxin formation, but not high enough to produce an explosion; (2 ) in explosions at manufacturing plants where the re­ action temperature and pressure levels reached exothermic proportions; and (3) from contaminated waste products of these same manufacturers which were released into the environment and/or handled by scientists testing these products. See attached charts on documented human exposures (VA Review of Literature, Exhibit A1-A3). Military exposure to TCDD resulted from the spraying of enormous quanti­ ties of 2,4,5-T in South Vietnam which was contaminated with TCDD. - 1 5 - 13304 I N D U S T R I A L E X P L O S I O N S References on Industrial Explosions That Involved TCDD REFERENCES LOCATION Monsanto Nitro, WV Suskind (1973); VA (1980). Zack and Suskind (1980) BASF Ludwigshafen, W. Germany Goldmann (1972); Goldraann (1973) Thiess and Frentzel-Beyme (1977) Rhone Poulenc Grenoble, France Dugois et al. (1958) Italy Joint NIESH/IARC Working Group (1978) Young et al. (1978) Philips-Duphar Amsterdam, Netherlands Dalderup (1974); Berlin et al. (1976) Rawls and Sullivan (1976); Hay (1977) Rhone Poulenc Grenoble, France Dugois et al. (1963) Rawls and Sullivan (1976) Coalite & Chemicals Products Boisover, Derbyshire, U.K. Jensen and Walker (1972) Jensen et al. (1972; May (1973) ICMESA Seveso, Italy Commoner and Scott (1976; Hay (1976) Rawls and Sullivan (1976); Fara (1977) Gianotti (1977); Walsh (1977) Bonaccorsi, et al. (1978); Greim (1978) Laporte (1973); Reggiani (1978) Hornberger, et al. (1979) Malizia, et al. (1979) Pocchiari, et al. (1979) Reggiani (1979); Strik (1979) Reggiani (1980); VA (1980); VA (1981) References Which Review Industrial Exposures to TCDD Forth (1977) IARC (1977) IARC (Joint NIESH/IARC-1978) Hay (1979) Moses and Moore (1979) Esposito et al. (1980) Hay (1977) Firestone (1978) Young et al. (1978) Malizia et al. (1979) Crow (1980) Suskind (1980) 13305 - 1 6 - I N D U S T R I A L E X P O S U R E S References on Industrial Exposures to TCDD YEAR LOCATION REFERENCES 1949 Nordheim, WestfalLen, We sc Germany Baader & Bauer (1951) 1951-52 2 factories in Middle Rhein, W. Germany Bauer et al. (1961) 1954 Boehringer, Ingelheim Hamburg, West Germany Kimmig & Schulz (1957) Kimmig & Schulz (1957) Schulz (1957); Bauer ec al. (1961) 1956 Diamond Alkali Newark, N.J. Bleiberg et al. (1964) Poland et al. (1971) 1964 U.S.S.R. LARC (1977) 1964 Dow Chemical (2,4,5-crichloropheno 1 production) Midland, Michigan Firescone (1978) Cook et al. (1980) Rowe (1980) 1965-9 Spoiana Czechoslovakia Jirasek et al. (1973) Jirasek et al. (1974) Pazderova et al. (1974) Jirasek et al. (1976) Pazderova-Vejlupkova et al. (1980) 1970 Japan Miura ec al. (1974) 1972 U.S.S.R. Zelikov and.Danilov (1974) 1950-1975 Dow Chemical (2,4,5-T production) Midland, Michigan Kramer (1974)* Ott et al. (1980) Townsend ec al. (1980)* 1955 - 1977 Monsanto Nitro, West Virginia VA (1980) *unpublished reports 13306 - 1 7 - . R E F E R E N C E S O N O T H E R H U M A N E X P O S U R E S T O T C D D YEAR LOCATION POPULATION DESCRIBED 1971 Missouri Farm residents Carter et al. (1975) Case (1976) Beale et al. (1977) Kimbrough et al. (1977) Crow (1980) 1970 England 3 laboratory workers 01 iver (197 5) 1967-1970 Vietnam Vietnamese residents NRC (1974) Vietnamese refugees Tung et al. (1971) Rose and Rose (1972) Tung et al. (1980) Vietnam veterans Bogen (1979) Halprin (1980) Stellraan & Stellman (1980) VA (1980) Vietnam military Harmon (1971) Allen .(1980) REFERENCES 133G -18Exhibit A3 I I . T h e F a t e o f 2 , 4 , 5 - T a n d I t s D i o x i n I m p u r i t i e s Conclusions about the environmental fate of 2,4,5-T vary somewhat with the exosystem being considered. There is general agreement, however, that it is (a) rapidly degrated microbiologically in soil (Norris 1966) ; (b) not readily leached from soil into the water table (Wiese and Davis 1964) ; (c) immobilized by soil organic matter (Helling, et al. 1973); and (3) photodecomposed on the soil surface by ultraviolet light (Crosby and Wong 1973). In animals, 2,4,5-T is known to be hydroxylated, degraded to the halogenated phenol, detoxified by coupling to glycine and taurine, and rapidly excreted in the urine (Grunow and Bohme 1974; Shafik, et al. 1971). Where massive doses are given, some residues are detectable in the milk (Leng 1972) and bodily organs (Clark, et al. 1975). In microbes and plants, 2,4,5-T is degraded to the phenol (Fitzgerald, et al. 1967; Sharpee 1973) and subsequently to carbon dioxide in water. TCDD, by contrast is relatively immobile in soil and not photodecomposed'*' when attached to soil (Helling, et al. 1973; Kearney, et al. 1972). TCDD is not readily removed from soil to plant, and in the plant does not accumulate in the edible seeds or fruits of soybean or oats (Isensee and Jones 1971). However, in aquatic systems, soil containing 0.1 parts per billion (ppb) TCDD (a concentration that could occur under normal field use of 2,4,5-T) caused appreciable TCDD accumulation in algea, crustaceans, snails,, and fish (Isensee and Jones 1975). In order to decompose this molecule, Crummet of Dow Chemical Co. has done studies that indicate that dioxin survives burning up to 1150° C. Recently, evidence has been presented that TCDD breaks down in ultraviolet light (Wong and Crosby 1978) . 13308 -19- Further, although certain higher chlorinated dioxins may lose chlorine atoms on exposure to sunlight or to some types of gammaradiation, the basic dioxin structure is largely unaffected and TCDD is highly stable (Crosby, et al. 1971; Buser, Bosshardt, and Rappe 1978). "In comparison to any other organic compound, the biological degradation rate of chlorinated dioxins is slow, although measured rates differ widely." It has been further established that . . . 2,3,7,8-TCDD can enter the human body from a 2,4,5-T - treated food chain and can accumulate in the fatty tissues and secretions including milk (Galston 1979). "Because of the remarkable stability of this substance (2,3,7,8-TCDD) in biological systems and its extreme toxicity, cumulative effects of extremely small doses are a major concern." (EPA at p. 1) 1. Metabolism A large portion of guinea pigs administered 2,3,7,8-TCDD show that this chemical persists in unmetabolized form in the liver and is responsible for its toxic effects in animals and men. There is some indication that persons with high dietary iron intake are more susceptible to 2,3,7,8-TCDD liver toxicity than persons with marginal iron intake. (a) Pharmacokinetics & Tissue Distribution Pharmacokinetics is the study of the rate of elimination and retention of any chemical in animals or humans. Tests performed on tissue distribution of ingested 2,3,7,8-TCDD on rats, guinea pigs, monkeys and chick embryos, as well as the tests performed on humans show accumulation of this toxin in animals as well as humans. (b) Enzyme Effects Several investigations show that 2,3,7,8-TCDD has a dramatic influence upon various enzyme systems in many species including man. Several J3309 -20- studies show that 2,3,7,8-TCDD induces many enzyme systems and suppresses others. The mechanism of AHH induction of 2,3,7,8-TCDD and possible the mechanism by which the substance produces other toxic effects had been advanced; 2,3,7,8-TCDD moves into a cell and binds to a specific receptor. The receptor-dioxin complex then moves into a cell's nucleus where it "turns on" the synthesis of a specific messenger RNAs which direct the synthesis of cytochrome Pl/450 and related enzymes. This enzyme induction increases the metabolism of TCDD itself as well as other compounds; as a consequence, reactive and cytotoxic and carcinogenic compounds are formed. (c) Effect on Lipids 2.3.7.8- TCDD has dramatically altered the lipid profiles in laboratory animals and man. Studies of workers occupationally exposed to 2,3,7,8-TCDD have shown lipid abnormalities, elevated serum cholesterol levels, abnormalities in lipid metabolism and liver function. Further, these lipid abnormalities resulting from 2,3,7,8-TCDD exposure may be a significant risk factor to ischemic vascular disease. (d) Gross and Histopathologies The macroscopic-gross pathology and histopathology-microscopic of tissues of dioxin-exposed chickens, rats and monkeys have been examined extensively. At post-mortem examination, the most striking findings in dioxin-exposed animals are usually: (1 ) substantial loss of body fat; (2 ) involution lesions of thymus; (3) testicular alterations, including atrophy, necrosis, and abnormal spermatocyte development; and (4) liver cell pathology. (e) Acute Toxicity 2.3.7.8- TCDD is a highly toxic material, several orders of magnit more potent than many pesticides or herbicides. Some consider it to be the most toxic small molecule made by man (Poland & Kende, 1976). -21- 13310 E . A D V E R S E H E A L T H E F F E C T S Plaintiffs will testify to their individual exposures to Agent Orange in Vietnam and all experts will base their testimony upon the presumed fact of exposure. Experts will testify that there is no "safe" level of any carcinogen to humans. and/or carcinogen. Agent Orange is a chemical caricnogen There is no "safe" level for any human exposure to 2,3,7,8-TCDD and other dioxins. Human exposure to 2,3,7,8-TCDD has induced chloracne, and often disfiguring and persistent dermatologic disorders, polyneuropathy (multiple lesions of peripheral nerves), mystagmus (involuntary rapid movement of the eye ball), and liver dysfunction as manifested by hepatomegaly (increase in liver size), and enzyme elevations. In animals and man, this compound has been shown to be teratogenic, mutagenetic, immunotoxic, embryotoxic, carcinogenic, and co-carcinogenic, and caused untoward pregnancy outcomes and birth defects in the wives and children of the veteran plaintiffs. For further explanation of all adverse effects of Agent Orange in the Plaintiffs and the human population, see Plaintiffs' Answers and Supplemental Answers to Defendants' Interrogatories Nos. 1, 2(d), 3(a), 4(a), and 4(c). 13311 -22- E R N E S T M . B A R A N , M . D . I. Qualifications (See Curriculum Vitae) II. Subject Matter Dr. Baran will testify as to the performance and interpretation of various tests in the veterans. These will include an electroencephalogram on both sleep and waking states with nasopharyngeal leads. He will also perform electromyograms, nerve conduction velocity tests, and somato sensory evoked potentials of the upper and lower extremities. Dr. Baran will then testify as to the mechanisms by which toxins produce the changes noted in the tests and what the various tests are capable of determining as to the medical status of the patient. Then he will relate the results obtained in the testing of each plaintiff examined, give opinions as to the causation of those results where possible from the evidence revealed by the .tests, and state the prognosis for the individual plaintiff for further deterioration in test results and/or for the individual's condition as a whole. III. General Scientific Principles Various substances cause sensory conduction deficits. are neurotoxins. Among them Agent Orange is a neurocoxin capable of causing a sensory conduction deficit. The mechanisms by which such deficits are caused are either by a demyelinating process in which the sheath of the nerve itself is gradually erroded or by an axonal degeneration in which the nerve itself is broken. ' The result of the demyelinating process is that nerve impulses are slowed and, on a functional basis, cause lack of sensation in coordination. 13312 The result of axonal degeneration is that the impulse stops where the break has occurred. If enough of the nerve fibers themselves are caught, there is no response whatsoever. there is a smaller response. If a lesser number of fibers are caught, Functionally, a severence of the nerve chain results in impairments dealing with feeling, touch, and discriminative sensation (i.e. telling rough from smooth surfaces, etc.). Additional tests may help to specify the particular causative agent for the sensory conduction deficit. Tests would include those which show which fibers had degenerated, tissue assays and a study of antibody deposits on the nerves. IV. Substance of Opinion 1. V. Agent Orange could cause sensory conduction deficit. Grounds for Opinion Dr. Baran has been out of town and has not been able to prepare the grounds for his opinion as yet. He must do some library work in preparation for it, and he indicates that he will forward the grounds for his opinion as soon as he has done his library work. Dr. Baran will also rely, in addition to medical and scientific articles, on testing on which he has done on 10 to 15 Vietnam Veterans. Additionally, Dr. Baran served as an Army medical officer in Vietnam from August, 1969 to July, 1970. and general surgeon. During that time, he was an orthopedic For approximately six months, he operated in the fields in various Vietnamese villages. He has personally observed defoliation in Vietnam, especially on the perimeters of the compounds in which he was stationed as a surgeon. -2- DEBORAH A. BARSOTTI, Ph.D . I. QUALIFICATIONS Dr. Barsotti is an Assistant Professor of Tocicology in the Department of Pharmacology and Toxicology of the Philadelphia College of Pharmacy and Science in Philadelphia, Pennsylvania. Her curriculum vitae is attached. II. SUBJECT MATTER Dr. Barsotti is a toxicologist who has done substantial personal investigative work with halogenated aromatic hydrocarbons. This category of. chemicals includes various biphenyls and dioxins, and specifically includes tetrachlorodibenzo-p-dioxin (TCDD). She will testify as to the relative chemical stability and lipophilicity of these chemicals as well as their resistance to degradation, and will testify that these qualities are what account for the perceived and documented bioaccumulation of the chemicals in the human system. Dr. Barsotti will emphasize the difference in results between chronic and acute exposures to these chemicals, testifying as to the varying types of responses to acute and chronic exposures. Dr. Barsotti will discuss her own work as well as review the literature in these areas, noting differences in routes of 13314 D. That TCDD accumulates and persists in the lipid E. That TCDD, stores. in chronic doses, cularly toxic to reproductive system, is toxic, is teratogenic, is parti­ and is fetotoxic. F. There are ample scientific bases, ing animal experimental data to man, for extrapolat­ in the case of TCDD, for example, as demonstrated by Dr. Barsotti's work on rhesus monkeys. V. GROUNDS FOR EACH OPINION A. General Review of applicable medical and scientific litera­ ture; education and training; personal research. The work on the chronic toxicity of HAHs in rhesus monkeys has culminated in numerous publications as p resented in Dr. Barsotti's curriculum vitae. In addition, she has been invited to speak or present her work in various atmospheres including community meetings and scientific symposia. B. Specific 1. With respect to opinion IV A, see generally references attached. 2. With respect to Opinion IV B, note the following: 13315 Dr. Barsotti will contrast the acute toxicity that one observes in accidental or intentional ingestion of toxic or lethal doses of chemicals with the effects of chronic or lower levels of exposure to chemicals such as HAHs. 4. With respect to Opinion IV D, note the following: Dr. Barsotti will comment on the state of the literature on the fate of TCDD once in the body, (Vinopal and Cassida, 1973; i.e. TCDD metabolism Ramsey et a l . , 1979; Schlatter, 1979). Efforts to identify metabolites in tissues and excreta from various studies have been unsuccessful. Recent advances in detection methodology indicate elevated levels of TCDD in Vietnam veterans and other exposed persons. Generally, however, that if metabolism does occur the rate is slow the data indicate (Guenthner et a l ., 1979) The ramification of this finding is that the body would be incapable of or slow in ridding itself of TCDD and TCDD would accumulate and persist in the lipid stores. others', In Dr. Barsotti's work, as well as this appears to be the case with rhesus monkeys and man (Montagna et al^. , 1979; Van Miller, 5. 1981; McNulty et a l . , 1983) . With respect to opinion IV E, note the following: Not only did the rhesus monkey appear a good model for HAH toxicity but established, species, as had been in other animal that the reproductive system was extremely sensitive to PCBs at intake levels below that required for the manifestation of toxic signs in the adult (Barsotti et a_l. , 1976) . PCB induced reproductive toxicity, In addition to PCBs were found to be fetotoxic 13316 three months in animals receiving TCDD in the diets at levels of 500 parts per trillion (ppt) and in animals consuming diets contain­ ing 50 ppt TCDD these same symptoms occurred after consuming the diets for 30 months (Allen et a l ^ , 1977; Schantz £t al,, 1979). This indicates cumulative toxicity associated with ingestion of TCDD. Thus, there is evidence for bioaccumulation and associated chronic toxicity at lower doses than that required for acute toxi­ city in rhesus monkeys and presumably man Ideo et al., (Pazderova ^ t £l, 1981; 1982.) 6. With respect to Opinion IV F, see ge references attached and V A above. 13317 REFERENCES P.W. Albro, J.T. Corbett, M. Harris and L.D. Lawson, Chem-Bio. Interact., 25, 515, 1979 J.R. Allen, D.A. Barsotti and L.A. Carstens, Toxicol. Appl. Pharmacol., 50, 440, 1974* J.R. Allen, D.A. Barsotti and L.K. Lambrecht, New York Academy of Sciences, 521, 419,1979* J.R. Allen, D.A. Barsotti, J.P. Van Miller, L.J. Abrahamson and J.J. Lalich, Fd. Cosmet. Toxciol., 15, 401, 1977. J.R. Allen and D.A. Barsotti, Toxicol., 6, 551, 1976. D.A. Barsotti, R.J. Marlar and J.R. Allen, Fd. Cosmet. Toxicol., 14, 99 1976. D.A. Barsotti, Doctoral Thesis, University of Wisconsin, 1980. 13318 D. A. Barsotti, L.J. Abrahamson and J.R. Allen, Bull. Environ. Contain. Toxicol., 21, 463, 1979- R.E. Bowman, M.P. Heironimus and D.A. Barsotti, Neurotoxicol,m 2, 251, 1981. K.D. Courtney and J.A. Moore, Toxicol. Appl. Pharmacol., 20, 396, 1971 • T.M. Guenthner, J.M. Pysh and D.W. Nebert, Pharmacol., 19 12, 1979. G. Ideo, G. Bellati, Al Bellobuono, P. Mocarelli, A. Marochhi and P. Brambilla, Clinica Chimica Acta, 120,.273, 1982. A.R. Isensee and G.E. Jones, Environ. Sei. Technol., 9, 668, 1975 E. E. McConnell, J.A. Moore, J.K. Haseman and M.W. Harris, Toxicol Appl. Pharmacol., 44, 335, 1978 a. E.E. McConnell, J.A. Moore, and D.W. Dalgard, Toxicol. Appl. Pharmacol., 175, 1978 b. W.P. McNulty,K.A. Nielsen-Smith, J.O. Lay, D.L. Lippstreu, N.L. Kangas, P.A. Lyon and M.L. Gross, Pd. Chem. Toxic., 20, 371, 1982. I. Manara, P. Coccia and T. Croci, Drug Met. Rev., 13, 423, 1982. A.C. Marinucci and R. Bartha, Bull. Environm. Contam. Toxicol., 29, 326, 1982. J. Mes, D.J. Davies and D. Turton, Bull. Environm. Contam. Toxicol., 28 97, 1982. M. Meselson, P. O'Keefe and R. Baughman, In: Symposium on the use of herbicides in forestry, 91, February 21-22, 1978. M. Montagna, A. Fornari and S. Facchetti, In: Forensic Toxicology, 78, 1979- J.R. Olson, M.A. Holscher, and R.A. Neal, Toxicol., Appl. Pharmacol., 55, 67, 1980. J. Pazderova, M. Nemcova, J. Pickova, 1. Jirasek and E. Lucas, Arch. Environ. Health, 36, 5, 1981. A. Poland and E. Glover, Molec. Pharmacol., 17, 86, 1980. A. Poland and J.C. Knutson, Ann. Rev. Pharmacol. Toxicol.,22, 517, 1982. H. Poger, H. Buser, H. Weber, U. Zweifel and C. Schlatter, Experimentia, 4 484, 1982. 1332-0 R. C. Ramsey, J.G. Hefner, R.J. Karbowski, W.H. Braun and P.J. Gehring, Toxicol. Appl. Pharmacol., 47, A162, 1979 - S. L. Schantz, D.A. Barsotti and J.R. Allen, Toxicol. Appl. Pharmacol., 46, 180. 1979- S.L. Schantz and R.E. Bowman, The Toxicologist, Vol. 4, Abstract number 333, March, 1984- J.P. Van Miller, Doctoral Thesis, University of Wisconsin, 1981. J.H. Vinopal and J.E. Cassida, Arch. Environ. Contam. Toxicol. 1, 122, 1973- 13321 DR. RONALD CODARIO I. QUALIFICATIONS See the attached curriculum vitae. II. SUBJECT MATTER Dr. Codario will testify concerning acute and chronic toxicity of herbicides and TCDD in animals and humans. He will also testify concerning the metabolism of TCDD in body fat, and its mechanism of action, environment, and its persistance in the including both the surrounding environment and the body itself. He will also testify concerning exposures and the amounts of herbicides sprayed, the particular types, and the component elements of TCDD therein. III. GENERAL SCIENTIFIC PRINCIPLES Dr. Codario will testify that an organism can have varying types of exposures to toxins, including acute and chronic exposures. An acute exposure, according to the literature, is that which is used to define all the effects of a single exposure on an organism. A chronic exposure or more. toxin, is a continuous exposure for up to thirty days A chronic exposure can be an exposure to an exterior or an exposure to a toxin contained in some manner within the body itself after an exterior exposure. upon the following systems: a. Teratogenicity b. Mutagenicity c. Carcinogenicity d. Neurotoxic affects Toxins can have effects e. Gastro-intestinal disturbances, f. Immunologic and hematologic g. Renal h. Cardiovascular i. Endocrine and metabolic j. Pulmonary The metabolism of herbicides, TCDD is known for animals, including porphyrins. including Agent Orange, and but not directly known for humans. It is located in all body tissues in animals, but the herbicides are eliminated through the renal system because they are water soluble. The elimination period in humans appears to be between twelve and twenty-four hours. but is fat soluble. unless Therefore, However, TCDD is not water soluble it is not eliminated by the kidneys it is converted to a water soluble substance, which does not appear to occur in humans. In animals, TCDD is metabolized in the following manners: a. eliminated It is broken down to a water soluble substance and in the urine. b. It is eliminated in bile fluid. c. It is sequestered in fat. d. It is converted to a different toxic substance. The mechanism of action of herbicides and TCDD in particular is determined at the micromolecular level. changes At that level, TCDD the body chemistry and initiates enzyme induction. is persistent, and internally. especially in the human environment, In the external environment, TCDD both externally it was thought that the half-life of TCDD in the soil after being sprayed in Agent Orange was approximately three years (900 days). However, the measurements were done in the top soil and it appears that the under-soil has both five to seven times higher concentrations than the top-soil does and that its half-life is longer at the sub-soil level. At least one of the herbicides sprayed in Viet Nam has been determined to exist in soil, ten years after spraying, and recent reports indicate concentrations both longer and deeper than previously thought. The amount of exposure any individual had in Viet Nam may be determinable in part through use of H E R B S T A P E S ,which record the spraying missions flown by aircraft in Viet Nam. However, the HERBSTAPES do not cover nearly all of the spray missions flown there by various aircraft. The doctor will testify as to the totals of each type of herbicide sprayed per year and in total, how much TCDD was was in each type of herbicide, and the acreage sprayed each year for each herbicide. IV. SUBSTANCE OF OPINIONS Dr. Codario will testify to the following opinions: 1. Agent Orange, and in particular, TCDD is a chemical 2. Animal research experience 3. Agent Orange and its constituents and its contaminant toxin. TCDD effect all of the systems is relevant to humans. listed above in both man and animals. 13324 4. The doctor will furnish conclusions as to individual plaintiffs in his reports on those individual plaintiffs. 5. TCDD, the particularly harmful toxin, is stored in body fat and furnishes a constant source of exposure to all body systems. 6. The literature and his research documents that chronic exposure to TCDD exhibits many more deleterious effects than single or acute exposures. 7. TCDD binds to a cytosol receptor, which is a gene product of the Ah locus on the chromosomes. 8. TCDD drifts. 9. The Ah locus of the chromosome determines whether the organism will demonstrate toxic effects and whether the liver will go about breaking the substance down. individual This is what accounts for susceptability and the fact that different people exposed to the same toxin do not necessarily get any effects or the same effects. 10. TCDD persisted in the soil of Viet Nam for the duration of the war. 11. The individuals serving in Viet Nam were exposed to TCDD by spraying operations, wild animals, 12. by drinking contaminated water, by eating and by clearing underbrush and digging in the soil. Substantial amounts of TCDD were sprayed throughout Viet Nam to the point that the presence of any veteran in Viet Nam, in any location, means that he was exposed to TCDD through one mechanism or another, which exposure was sufficient to give him some form of disease depending upon the genetic predetermination of the Ah locus of his chromosomes. V. GROUNDS FOR OPINIONS The grounds for Dr. Codario's opinions include: 1. See the attached bibliography. 2. Young, Toxicity And Persistance Of Agent Orange And TCDD In The Environment. 3. Herbicides And Related Dioxins - A Review Of The Literature, J.R.B. 4. Associates. The doctor's own clinical and research work on approximately 500 veterans whom he has personally examined. This work is currently being translated into computer language, and will be computerized for analysis and comparison purposes. The computer data will be furnished as soon as it is completed. 13326 R O N A L D A. C O D A R IO. M. D. 1427 SO UTH BRO AD STREET P H IL A D E L P H IA . • OARO CIKTiriXO IN T K R N A L 10147 CURRICULUM VITAE M IO IC IN K ADDRESS: PA 2 I B . 467*3083 Home - 205 Porter Street Philadelphia, Pennsylvania 19148 215-46 5-9476 DATE OF BIRTH: 12-9-47 (Pennsylvania Hospital) PERSONAL: Married Celeste DiSabatino Children: Ronald Anthony (6-16-81) (Pennsylvania Hospital) Maria Celeste (6-14-83) (Pennsylvania Hospital) EDUCATION : LaSalle High School (1961-1965) LaSalle College (1965-1969 B.A. Biology) Hahnemann Medical College (1969-1973 M.D.) St. Agnes Hospital (1973-1974 Medical Internship) University of Pennsylvania.Division of Philadelphia Genera Hospital (Medical Residency 1974-1976) PROFESSIONAL SOCIETIES: American Medical Society Philadelphia County Medical Society Pennsylvania Medical Society AWARDS: WHO'S WHO OF MEDICAL SPECIALISTS 1977-1978 MARCONI RECOGNITION AWARD - June 1980 (Outstanding contributio in the efforts to build Marconi Plaza) DISTINGUISHED ACHIEVEMENT¿AWARD - St. Agnes Hospital, Dept, of Medicine - February, 1980 FREEDOM'S FOUNDATION AT VALLEY FORGE GOLD MEDAL - April, 1981 (Outstanding achievement and humanitarian efforts in treating Vietnam veterans and their families free of charge)■ E GUBERNATORIAL CITATION: -.April 1981 - (Special achievement in working with Vietnam veterans exnosed to herbicides) PENNSYLVANIA HOUSE OF REPRESENTAT!VES CITATION - December 7. 1 (special citation-sponsored by Rep. Paul Clymer and Rep. George Sauerman in recognition of work done to aid Vietnam veterans) AGENT ORANGE NATIONAL HOTLINE CERTIFICATE OF APPRECIATION December 10, 1981 (Volunteer work with Vietnam veter CHAFEL OF FOUR CHAPLAINS LEGION OF HONOR AWARD - February 28, UNITED STATES CONGRESSIONAL.CERTIFICATE OF MERIT - June 24, 19 SPECIAL CITATION -DISABLED. AMERICAN VETS - July, 1982 (Outstandingrseiad.ce to Vietnam veterans) CHAPEL OF FOUR CHAPLAINSCÉEGION OF HONOR - September 12, 1982 UNITED STATES CONGRESSifl^RTIFICATE OF MERIT - September 19, 19 (Outstanding '.setyice tfo Vietnam Vets) VIETNAM VETERANS OF AMEEqSf^WARD OF MERIT - November, 1982 (Outstandingv^p^tiS'teer service to Vietnam vets) HONARARY MEMBER OF THElOffijpEARY BOARD OF THE UNITED VIETNAM VETERANS 0RGANIZATI0N~-«fflaÿ£l982- (honorary position due to "your positionnas a leader of the community") SIGNUM FIDEI MEDAL - NoTêà|èy. 18, 1983 - (Awarded annually to trie individual^wno'has manifested the highest tradi tions of Christianity and humanitarianism)LaSalle 13327 ColleE R O N A L D A. C O D A f tlO , M. D. 1427 SOUTH BROAO STREET P H IL A D E L P H IA ■ O A f lO \ M K 0 IC IN S LECTURES/TEACHING: 'Tm a t P-VV. ’linL IS 14 7 213.407.3883 C C R T t F IIO IN T K ftN A U PA. Administrative Head - Division of Internal Medicine 1978 (St. Agnes Hospital) Director of Clinical Pathological Conferences 1977-1978 (St. Agnes Hospital) Lecture - Clinical Pathological Conference (January 1977 - Pseudomonas septicemia in a burn patient) Lecture - Medical Grand Rounds - St. Agnes Hospital December 1981 - "Human Manifestations of Herbicide Poisoning" Lecture - Medical Grand Rounds - Methodist Hospital, February, 1982 - "Medical .Effects of Agent Orange Exposure" Lecture - Medical Grand Rounds - Albert Einstein Hospital, August 1982 - "Medical Effects of Herbi­ cide Poisoning Lecture - Clinical Pathological Conference "Sudden Death in a Patient with Lung Carcinoma" January, 1984 Lectures - 1983 - Lecture tour of senior citizen homes and meetings to promote health care and Albert Einstein Medical Center Lectures - 1981 to present - series of 3 6 lectures on the East coast tConnecticutt to Alabama) on Agent Orange toxicity along with special lec:ures to the Pennsylvania, New York, West Virginia, Illinois Agent Orange Commissions Lectures - October 1 9 , 1983 and November 1 6 , 1933 "Agent Orange Toxicity" - sponsored by the Pennsylvania Medical Society Lecture - April 28, 1983 - "Agent Orange Effects on Vietnam veterans" - sponsored by the Pennsylvani Health Department *ODOT '’ ’TM TM.ENTS: Internship - St. Agnes Hospital 19 7 3 - '971Medical Residency - University of Pennsylvania Division - P h iladelphia General Hospital l97l-:9 Assistant Chief Admitting Physician - Emergency Room of Philadelphia General Hospital, 1976-1977 St. Agnes M e d i c a l * C e n t e r - Attending Physician 1976-present Methodist Hospital - Attending Physician 1980-present Albert Einstein Daroff Medical Center - 1982-ores Attending Physician Police Surgeon, City of Philadelphia, 1978-presen MEDICAL EXECUTIVE COMMITTEE - St*. Agnes Hospital 1983 UTILISATION REVIEW COMMITTEE - St. Agnes Hospital 1984 and Albert Einstein Hospital (1985-presen PUBLICATIONS: September 1976 - "Stroke" - G o l d b e r g , H. , Codario., R. et ai REGIONAL CEREBRAL BLOOD FLOW IN PATIENTS WITH SEVERE HYPERTENSION FOLLOWING THE ADMINISTRATION OF DIAZOXIDE 13328 R O N A L D A . C O D A p t O , M. D. 1 4 2 .7 S O U T H . B R O A D S T R E E T P H IL A D E L P H IA « P A BOARO C X R T lP IK O IN T IR N A L Januar” , 1 ? 8 l M C O IC IN K PU BLI CA TIO NS 19 147 Agent O r a n g c - 1’y ths and leali tics, X P %’CT ? .y .'" r , , J a n . / 7 ec. page 12 April,. 1982 - REVERSE PHASE HPLC PROFILES OF URINARY PO RP HYRINS IN PATIENTS EXPOSED (19 6 L - 19 7l TO AGENT. OR ANGE AS COMPARED TO HPLC PORPHYRIN PROFILES IN PORPHYRIA, Petryka, Z.J., C o d a r i o , R. t:f ' vt.t "”aîî (cont): April, 1982 - OMENS - "THE CURSE THAT LINGERS" Codario, R. - January, 1983 - Agent Orange Controversy - O M N I . page 16 November, 1982 - STARS AND STRIPES 1 0 6 ( 5 0 : 7 - 1 0 . Point of*View: Agent Orange - The Curse That Ling Codario, R. RELATED ARTICLES/EOOKS/TELEViSION/RADiO PHI LA DELPHIA INQUIRER: O c t o b e r 25, 1981 -Ihvestigat Agent Orange: a d o c t o r ’s personal project. Darryl Sifford PHIL AD EL PH IA JOURNAL: No ve mb er 20, 1981 - Agent O r a n g e Makes South Philly Doc See Red. Bruce Bee CAMDEN COURIER-POST: May 1?, 1982 - Doctor treats Vets but has no answers, Julie Buscy ALUMNI - feature article of the Hahnemann Medical College - Soring, 1982 OMNI - August* 1982 - THE AGENT OR ANGE MYSTERY P am el a Weintraub PH IL AD EL PH IA DAILY NEWS, N o v e m b e r 10, 1932 Battleground - Viet Vets Still Fignting the War Mar ia Gallagher Television October, 1981 - K Y W - T V Special Report on Agent Or October 9, 1982 - PRI ME TIME - feature on my work with Vietnam veterans (WFVI-TV) September 20, 1932 - PEOPLE A R E TALKING - discuss. group on Agent Orange (KYAV-TV) Nov ember 11, 1982 -(Channel 29) - DLL VAL discussion groun on Agent Orange January L, 1985 - EVENING *M AG AZ IN E - (KT.7-T7) feature presentation on Agent Orange June 16 , 1983 - WCAU-TV - discussion on herbicace toxicity with Herb Dennenberg June 1S , 1983 - Niag ar a School of Applied Arts Documentary on Agent Orange Radio July 28, 1983 - WIP People Talk with Michele Iaia featured discussant on Agent Orange September, 1983KSTP News Talk (Minnesota) - The Dick Pomerantz Prog ra m - discussion on Agent Or ange BOOKS WATTING FOR AN ARMY TO D I E , the tragedy of Agent Ora nge by Fred Wilcox, pp. 11L - 125 1332S RONALD A. CODARIO. M. D. I \AZ7 S O U TH BR O A D STREET • P H IL A D E L P H IA . f>A. 1 8 1 4 7 A. ■ BOARO ' C E R T IF IC O IN T E R N A I. «*^<**'¿ KP'-t. ' ► 2 tD .487.3aa3 M E D IC IN E \ ARTICLE S PENDING: ' Review of the Signs and Symptoms of ^00 Vietnam Veterans with Special A t te nt io n to Porph yr in Analysis Case Report: Dying Back Ne ur opathy Due to Dioxin Exposure Case Reports: Review of 10 Liver Biopsies in Vietnam Veterans (exposed to herbicide s) wi th porphyrin disturbances Instructive Manual : Tox ic Herbicide Po is on in g- Dia gn osi s and Management (Sponsored by the Penns yl va ni a Health Dept, anc the Pen nsy l v a n i a Medi ca l Society) LITIGATION EXPERIENCE As a Pollen Surgeon for the City of Ph il adelphia for the past seven years i have been called to testify as an expert witness 5 0 — 50 times in matters related to drivers under the influence of drugs, illness, alcohol; as well as the health ana physical state of police officers injured in the line of duty. I have testified in the disability hearings of the expert witness (treating pr.ysician) I ’'.ave recently finished testi fyi. case. This case dealt with the n to the plaintiff by his exposure (This case was recently won by th 18 patient, as nausea the 5 - :- develoner. •"ri I ’ nave testified at the Veterans several patients (!’ leenam vets an to obtain service ccnnec tea disabCllltv vets; i: ^ c::. e - 'DC-'NAL —„ *-1, 1^ _ — I.y,- p 1/ ^ r * veterans free cf cr.arge and have conducted tne largest independent survey of their health problems ever recorded. ~ o ¿ and This survey is presently being computerised statistical!,v statis anal •.".ted. I have ex," ■" . .n, 13330 A R T H U R I. W . G A L S T O N , P h . D . QUALIFICATIONS Dr. Arthur W. Galston is Eaton Professor of Botany in the Department of Biology, Yale University, New Haven, Connecticut. See attached curriculum vitae. II. SUMMARY OF TESTIMONY Dr. Galston is a plant physiologist and has personally observed the effect of the spraying of Agent Orange on the Vietnam ecosystem, i.e. the devastation of the Vietnamese countryside. Dr. Galston has been in Vietnam on four occasions between 1971 and 1982, and will describe those observations while in Vietnam, with such pictorial evidence as is available Dr. Galston will testify to the potential and actual effects of phenoxy herbicides and their contaminants, both in Vietnam and elsewhere, including the United States and Sweden, and other places. The testimony will include the chemistry and the mechanisms of action of such chemicals on plant life. In addition, Dr. Galston will testify to the fate of Agent Orange and other phenoxy herbicides and their contaminants, especially TCDD, in the environment generally and in Vietnam in particular. Dr. Galston will testify to the persistence of such chemicals on plants, in water, and in soil, such that exposure to the phenoxy herbicides and their contaminants, especially TCDD, by the veterans in sprayed areas in Vietnam is presumed. 13331 I I I . S C I E N T I F I C P R I N C I P L E S A N D A S S U M E D F A C T S See General Summary of Scientific Principles and Assumed Facts. IV SUBSTANCE OF OPINION Dr. Galston will testify to the following opinions: 1. Agent Orange, phenoxy herbicides and their contaminants have had a long-term catastropic effect upon the environ­ ment in Vietnam. 2. 2,3,7,8-TCDD, one contaminant of Agent Orange, persists in the ecosystem for long periods of time. 3. The level of use of Agent Orange in Vietnam exposed servicemen there to significant levels of TCDD. 4. 2,3,7,8-TCDD can enter the human body from a 2,4,5-T treated food chain and can accumulate in the fatty tissues and secretions including milk. 5. The level of use of phenoxy herbicides and the persistence of the herbicides and their contaminants in the environment means that all veterans in sprayed areas in Vietnam can be presumed to have been exposed to the phenoxy herbicides and their contaminants, including TCDD. V. FACTUAL BASIS OF OPINION Dr. Galston's opinion is based upon his personal observations regarding the long-term effects of the use in Vietnam, his knowledge of the persistence of TCDD in the environment, his knowledge as to how TCDD can be transmitted to humans through the food chain and all or part of the following references: 13332 REFERENCES CITED Alien. J. R., D. A. Busotti. J. P. Van Miller. L. J. Abrahamson. and J. J. Lalich. 1977. Morphological changes in monkeys con­ suming a diet containing low levels of 2.3,7.8-teirachlorodibenzo-p-dioxin. Food Cosmet. Toxicol. 15: 401-410. Allen. J. R., and L. A. Carstens. 1967. Light and electron microscopic investigations in Macaca mulatta monkeys fed toxic fat. Am. J. Vet. Res. 28: 1513-1526. Baughman. R.. and M. Meselson. 1973. Ana­ lytical method for detecting TCDD (dioxin): levels of TCDD in samples from Vietnam. Environ. Health Perspect. 5: 27-35. Blair. E. H.. ed. 1973. Chlorodioxins —Origin and Fate. Advances in Chemistrv Series 120, American Chemical Society. Washing­ ton. DC. Clark. D. E.. i. S. Palmer. R. D. Radeleff. H. R. Crookshank. and F. M. Farr. 1975. Residues of chlorophenoxy acid herbicides and their phenolic metabolites in tissues of sheep and cattle. J. Agric. Food Chem. 23(3): 571-578. Crosby, D. G.. and A. S. Wong. 1973. Photodecomposition of 2.4,5-tnchlorophenoxyacetic acid (2,4.5-T) in water. J. Agric. Food Chem. 21(6): 1052-1054. Davis. D. E. 1979. Herbicides in peace and war. BioScience 29:84. 91-94. Dougherty, R. C.. and K. Piotrowska. 1976. Screening by negative chemical ionization mass spectrometry for environmental con­ tamination with toxic residues: application to human unnes. Proc. Hail. Acad. Sci. USA 75(6): 1777-1781. Environmental Health Perspectives. 1973. Experimental Issue No. 5. 1-313. U.S. De­ partment of Health. Education and Wel­ fare. NIEHS. Research Triangle Park. NC. Environmental Protection Agency (EPA). 1978. Rebuttable presumption against registration and continued registration of pesticide products containing 2.4.5-T. Fed. Reg. 43(78): 17116-17157. Epstein. S. 1970. A family likeness. Environ­ ment 12(6): 16-25. Fahmy, O. G.. and M. J. Fahmy. 1954. Cyto­ genetic analysis of the action of carcinogens and tumour inhibitorsin Drosophila melanogaster. II. The mechanism of induction of dominant lethals by 2:4:6--diox­ in residues in bovine fat and milk. J. Assoc. Off. Anal. Chem.. in press. Shadotf. L. A.. R. A. Hummel. L. Lamparsni. and J. H. Davidson. 1979. A search for 2.3.7.8-tetracr.lorodibenzo-p-dioxin (TCDD) in an environment exposed annual­ ly to 2.4.3-tnchlorophenoxyacetic acid es­ ter (2.4,3-T) herbicides. Bull. Environ. Cuntarn. Toxicol., in press. Shank. M. T.. H. C. Sullivan, and H. ! Enos. 1971. A method for determination i low leveis of exposure to 2.4-0 and 2.4.3-T Int. J. Environ. Anal. Chem. 1: 23-33. Sharpee. K. 1973. Microoial Degradation of Phenoxy Herbicides in Culture. Soil, and Aquatic Ecosystems. Ph.D. Thesis. Uni­ versity Microtilms. Ann Arbor. Ml. Smith. R. J. 1978. Dioxins have been present since the advent of fire, says Dow. Science 202: 1166-1167. Stroev. V. S. 1970. The cytogenetic activity of the herbicides atrazine. chloro-iPC and paraquat. Genetika 6: 31-37. Tung. T. T.. T. T. An. N. D. Tam. P. H. Phiet. N. N. Bang. T. T. Bach. H. Van Son. K. D. Son. 1973. Le cancer pnmaire du foie au Viet-nam. Chirurgie 99: 427--36. U.S. Department of Agriculture (USDA). Ag­ ricultural Stabilization and Conservation Service. 1976. The Petticide Review 1973. USDA. Washington. DC. I Ol A A O 0* >3 Van Miller. J. P.. J. J. Laiich. and J. R. Al­ len. 1977. Increased incidence of neoplasms in rats exposed to low concentrations of 2.3,7.8-tetrachlorodibenzo-p-dioxin. Chemosphere 10: 623-632. Westing, A. H. 1973. AAAS Herbicide As­ sessment Commission. Science 179: 12781279. ______ 1976. Ecological Consequences o f the Second Indochina War. Stockholm Inter­ national Peace Research Institute. Almqvist and Wilcsell. Stockholm. Sweden. ______ 1978. Ecological considerations re­ garding massive environmental con­ tamination with 2.3.7,8-tetrachlorodibenzopam-dioxin. Ecoi. Bull (Stockholm) 27: 283-294. Whiteside. T. 1977. A reporter at large. The pendulum and the toxic cloud. New Yorker 23 July: 30-53. _______ 1978. Contaminated. New Yorker 4 Sept.: 34-81. Wiese. A. F.. and R. G. Davis. 1964. Herbi­ cide movement in soil with various amounts of water. Weeds 12(2): 101-103. Wong, A. S.. and D. G. Crosby. 1978. Decon­ tamination of 2J.7.S-letrachlorodibenzo-pdioxin (TCDD) by photochemical action. In F. Cattabeni. A. CavaiJaro. and G. GaJIi, eds. Dioxin: Toxicological and Chemical Aspects. S. P. Medical and Scientific Books. New York. Wuu. K. D., and W. F. Grant. 1966. Morpho­ logical and somatic chromosomal aber­ rations induced by pesticides in barley (Hordeum vulqare). Can. J. Genet. Cytol. 8: 481-501. ______ 1967. Chromosomal aberrations in­ duced by pesticides in meiotic cells of bar­ ley. Cytoloigia 32: 31-41. 126-12-7122 BIOGRAPHICAL SKETCHES ARTHUR ¥. GALSTUN. Ph.D., Eaton Professor of Botany, Department of Biology, Tale University Born April 21, 1920, New York City. Married, 2 children. B;S. Cornell University 1940; M.S. University of Illinois 1942; Ph.D. University of Illinois 1943. U.S. Navy, 1944-46; Agriculture Officer, U.S.N. Military Government, Okinawa, 1945-46. Elected to Phi Beta Kappa, Phi Kappa Phi, Sigma li, American Academy of Arts and Sciences; National Sigma Ii Lecturer, 1966; National Phi Beta Kappa Visiting Scholar, 1972-3. Award of the New York Academy of Sciences, 1979. Honorary LL.D., 1980, Iona. Plant Physiologist, Emergency Rubber Project, California Institute of Technology 1943-44; Instructor in Botany, Yale University, 1946-47; Senior Research Fellow, California Institute of Technology, 1947-50; Associate Professor of Biology, California Institute of Technology, 1951-1955. Professor of Plant Physiology, Department of Botany, Yale University 1955— 61; Chairman, Department of Botany, 1961—62; Director, Division of Biological Sciences, Yale University, 1965-66; Professor of Biology, 1962-73; Eaton Professor of Botany, 1973Fellow of the John Simon Gngenheim Memorial Foundation, Stockholm and Sheffield, 1950— 51; Fulbright Fellow, Canberra, Australia, 1960-61; National Science Foundation Faculty Fellow, London, 1967-68; Albert Einstein Fellow and Visiting Professor, Hebrew University of Jerusalem, 1980. Visiting Fellow, Yolfson College, Cambridge, England, 1983. Secretary, American Society of Plant Physiologists, -1955-57; Vice President, 1957-58:.President, 1962-63. Secretary-Treasurer, International Association for Plant Physiology, 1962-67. VicePresident, Botanical Society of America, 1967-68; President, 1968-69; Merit Award, 1970. Formerly Council, Federation of American Scientists; President, Society for Social Responsibility in Science; Board Member, Scientists' Institute for Public Information. Member, Committee on Space Biology and Medicine, National Research Council. Editorial Board Member: Journal of Plant Growth Regulation. Pesticide Phvs iology and Biochemistry. Environment. Formerly Chemical and Engineering News. Science Year. Plant Physiology, Phytochemistry. American Journal of Botany. Llovdia. Formerly regular columnist, Natnral History magazine. Former member: Metabolic and Regulatory Biology Panels, Nation Science Foundation; Executive Committee, Growth Society; and Governing Boards, Biological Sciences Curriculum Study, Commission on Undergraduate Eduation in the Biological Sciences and American Institute of Biological Sciences. First American scientist to visit the People’s Republic of China, 1971. Metnrn visits to Far East, 1972, 1975, 1977. 1980. Books: 'Principles of Plant Physiology' (with J. Bonner). Freeman, 1952. 'Life of the Green Plant'. Prentice-Hall, 1961, 2nd Edn., 1964, 3rd Page 26 a oO S a l «ton. A r thur T. 126-12-7122 Edn. . 1980 (with. P.J. Davies and B.L. Setter). 'Control Mechanisms in Plant Development', (with P.J. Paries), Prentice Hall. 1970. 'Daily Life in People'» China', Crowell, 1973; Simon and Schuster, 1975. 'Green Visdom' Basic Books, Inc. NT, 1981. Arthur f. Galston Publications (1979-1983) A. In Press Eaur— Sawhney, R. and A.V. Galston. 1983. The culture of oat protoplasts and tissues. In: Evans, D.A., T.R. Sharp, P.V. Aoairato and 7. Tamada (eds.) 'Protoplast and Tissue Culture Methods for Crop Iaproveaent,' MacMillan Publications on Plant Tissue Culture, Morristown, New Jersey. Shekhavat, N.S. and A.V. Galston. 1983. Isolation, culture and regeneration of noth bean Vigna aconitifolia leaf protoplasts. Plant Sci. Lett. Slocum, R.D., J.J. Gaynor and A.f. Galston. 1984. Experiments on plants grown in space: Cytological and ultrastrnctural studies on root tissues. Ann. Bot. Young, N.D. and A.V. Galston. peas? Plant Physiol. 1983. B. Are polyaaines transported in etiolated Published Britz, S.J. and A.V. Galston. 1983. Physiology of movements in the stems of seedlings Pisua sat ivum L. cv. Alaska. III. Phototropism in relation to gravitropism, nutation, and growth. Plant Physiol. 71: 313-318. Duraortier, F.M., H.E. Flores, N.S. Shekhawat and A.V. Galston. 1983. Gradients of polyaaines and their biosynthetic enzymes in coleoptiles and r o o t s of corn. Plant P h y s i o l . 72: 915-918. Galston, A.V. 1983 . Polyaaines as modulators of plant development. Science 33: 382-388. Bio Gaynor, J.J. and A.V. Galston. 1983. Purification and characterization of amyloplasts from etiolated epicotyls of Pisua sativum. Plant and Cell Physiol. 24: 411-421. Goballe, G.T. and A.V. Galston. 1983. Vound-induced lignin formation and resistance to cellulase in oat leaves. Phytopathology 73: 619-623. ( Racusen, R.H. and A.V. Galston. 1983. Developmental significance of light' ----mediated electrical responses in plant tissue. JLn Photomorphogenesis. Edited by V. Shropshire, Jr. and H. Mohr. Encyclopedia of Plant Physiology 16: 687-703. Springer-Verlag, Berlin, Heidelberg, New York, Tokyo. Shekhavat, N.S. and A.V. Galston. 1983. Kesophyll protoplasts of Fenugreek (Trigonella foenuagraecum) : Isolation, cultnre and shoot regeneration. Plant Cell Report« 2: 119-121. Young, N.D. and A.V. Galston. 1983. Pntrescine and acid stress. Induction of arginine decarboxyl ate activity and pntrescine accnlation by lev pH. Page 27 13238 12.6-12-7122 Plant Physiol. 71: 767-771. 1983. Britz, S.J. and A.V. Galston. 1982. Physiology of movements in items of seedling Pisnm sativnm L. cv. Alaska. I. Plant Physiol. 70: 264-271. Britz, S.J. and A.?. Gal »ton. 1982. Physiology of movements interns of seedling Pisnm sativnm L. cv. Alaska. II. The role of the ajfcal hook and of auxin in nntation. Plant Physiol. 70: 1401-1404. Britz, S.J. and A.V. Galston. 1982. Light-enhanced perception of gravity in stems of intact pea seedlings. Planta 134: 189-192. Dai, Y . , R. ranr-Savhney and A.V. Galston. 1982. Promotion by giSberellic acid of polyamine biosynthesis in internodes of light-grown dnrf peas. Plant Physiol. 69: 103-106. Flores, H.E. and A.V. Galston. 1982. Analysis of polyamines in Mgher plants by high performance liquid performance. Plant Physiol. 69: 701-706. Flores, H.E. and A.V. Galston. 1982. Polyamines and plant stress; Activation of pntrescine biosynthesis by osmotic shock. Scieace 217: 1259-1261. Flores, H.E., A. Thier and A.V. Galston. 1982. In vitro cnltnreif grain and vegetable amaranths (Amaranthns Spp.) Amer. J. Bot. 69: 109-1054. Führer, J. , R. Raur— Sawhney, L.M. Shih and A.V. Galston. 1982. BXects of exogenous 1 ,3-diaminopropane and spermidine on senescence of sat leaves. II. Inhibition of ethylene biosynthesis and possible mode of iction. PI. Physiol. 70: 1597-1600. Galston, A.V. and R. Raur-Sawhney. 1982. Polyamines: Are they anew class of plant growth regulators? Plant Growth Substances 1982. Aademic Press, pp. 451-461. Galston, A.V., H.E. Flores and R. laur-Sawhney. 1982. Polyamine formation by arginine decarboxylase as a transducer of hormonal, environmental and stress stimuli in higher plants. The Physiologist 25 (6): SS7-138. Geballe, G.T. and A.V. Galston. 1982. Vound-indnced resistance taeellulase in oat leaves. Plant Physiol. 70: 781-787. Geballe, G.T. and A.V. Galston. 1982. Ethylene as an effector oiseundinduced resistance to cellulose in oat leaves. Plant Physiol..70: 788-790. Goren, R . , N. Palavan and A.V. Galston. 1982. Seperating phytochasae effects on arginine decarboxylase activity from its effect on growth. J. Plant Growth Regnl. 1: 61-73. Goren, R . , N. Palavan, H. Flores and A.V. Galston. 1982. ChangesS> polyamine titer in etiolated pea seedlings following red light treatment. Plant and Cell Physiol. 23: 19-26. Raur-Sawhney, R . , L.X. Shih and A.V. Galston. 1982. Relation of jqiyamine biosynthesis to the initiation of sprooting in potato tubers, üant Physiol. 69: 411-415. a o C'Q Page 28 *•' Eaur-Sawhney, R. , L.X. Shih, T. Cegielska and A.F. Galston. 1982. Inhibition of protease activity by polyamines. Relevance for control of leaf senescence. FEBS Lett. 145: 345-349. Raur-Savhney, R. , L.X. Shih, H.E. Flores and A.F. Galston. 1982. Relation of polyamine synthesis and titer to aging and senescence in oat leaves. Plant Physiol. 69: 405-410. Palavan, N. and A.F. Galston. 1982. Polyamine biosynthesis and titer during various developmental stages of Phaseolns vulgaris. Physiol. Plant 55: 438-444. Shih, L.X. , 2. Ranr-Savhney, J. Führer, S. Samanta and A.F. Gals to*. 1982. Effects of exogenous 1 ,3-diaminopropane and spermidine on senescence of oat leaves. I. Inhibition of protease activity, ethylene production, and chlorophyll loss as related to polyamine content. Plant Zhysiol. 70; 1592- 1596. Slocum, R.D. and A.F. Galston. 1982. A comparative study of monocat and dicot root development in normal (earth) and hypogravity (space) environments. The Physiologist 25(6): S131-132. Racusen, E.H. and A.F. Galston. 1981. Phytochrome modifies blue-lightinduced electrical changes in corn coleoptiles. Plant Physiol. 66: 534-535 Dai, Y. and A.F. Galston. 1981. Simultaneous phytochrome— controlled promotion and inhibition of arginine decarboxylase activity in buds and epicotyls of etiolated pea*. Plant Physiol. 67: 266-269. Flores, H.E., R. Ranr— Sawhnoy and A.F. Galston. 1981. Protoplasts as vehicles for plant propagation and improvement. in R. Maramorosch (ed). Advances in Cell Culture 1: 241-279. Academic Press, N.Y. Raur— Sawhney, R. and A.F. Galston. 1981. On the physiological sipdficance of polyamines in higher plants. Recent Developments in Plant Sciences, pp. 129-144. Raur— Savhney, R. , H.E. Flores and A.F. Galston. oat leaves: A cell vall-localized enzyme. 1981. Polyamine cxidase in Plant Physiol. 63: 494-498. Satter, R.L. and A.F. Galston. 1981. Xechanisms of control of leaf movements. Ann. Rev. Plant Physiol. 32: 83-110. Satter, R.L., S.E. Guggino, T.A. Lonergan and A.F. Galston. 1981. The effoct* of blue and far red light on rhythmic leaflet movements in Sananea and Albixxia. Plant Physiol. 67: 965-968. Flores, H.E. and A.F. Galston. 1980. Tissue culture of Amarsnth: Initial results and prospects. JLn Proceedings of the Second Amsrsnth inference, 1979. Rodale Press, Inc., pp. 105-108. “« Galston, A.F. 1980. Circumnntstion. rhythms and light-regulated scfeaents in plants. JLn Plant Grovth Substances 1979. Ed. by F. Shoog. Proceedings of the 10th International Conference on Plant Grovth Substances, Xadison, Tisconsin. July 22-26. Springor-Verlag, Berlin Heidelberg, N«v York pp. Page 29 13340 437-443. Galston, A.f. 1980. Herbicides. _in Academic American Encyclopedia. Arete Pnbliahin* Co., Inc., Princeton Forrestal Center., Princeton. N.J. Galston, A.f. and R. tanr-Sawhney. 1980. New in Plant Physiology 11: 5-8. Polyaaines and plant cells. That's Kaur-Sawhney, R., H.E. Flores and A.f. Galston. 1980. Polyamine-indnced DNA synthesis and mitosis in oat leaf protoplasts. Plant Physiol.* 65: 368-371. Galston, A.f. 1979. Herbicides: A mixed blessing. Galston, A.f. and C.L. Slayman. 1979. American Scientist 67: 337-344. Bio.Science 29: 85-90. The not-so secret life of plants. Galston, A.f., R. lanr-Sawhney, A. Altman and H. Flores. 1979. Polyamines, macromolecular syntheses and the problem of cereal protoplast regeneration. la Advances in Protoplast Research. Proceedings of the 5th International Protoplast Symposinm, Szeged, Hungary, July 9-14. Aiademiai Hi ado pp. 485-497. Kaur-Savhney, R. and A.f. Galston. 1979. Interaction of polyamines and light on biochemical processes involved in leaf senescence. Plant, Cell and Environment 2: 189-196. 1979 Galston, A. W. Herbicides: A mixed blessing. (3): 85-90, 1979. Page 30 3I0SCIEJCE Vol. 20 CONTINUED BIBLIOGRAPHY OF ARTHUR W. GALSTON 1977 Racusen, R. H. and A. W. Galston. Electrical evidence for rhythmic changes in the cotransport of sucrose and hydrogen ions in Samanea pulvini. PLANTA (BERL) 134(1): 57-62. 1977. Satter, Ruth L., Martin Schrempf, Javade Chaudhri and Arthur W. Galston. (Dep. Biol., Yale Univ., New Haven, Conn. 06520, USA.) Phytochrome and circadian clocks in Samanea: Rhythmic redistribution of potassium and potassium and chloride within the pulvinus during long dark periods. PLANT PHYSIOL (BETHESDA) 59(2): 231-235. 1977. Rancillac, Michael, Ravindar Kaur-Sawhney, Brian Staskawicz and and Arthur W. Galston. Effects of cycloheximide and kinetin pretreatments on responses of susceptible and resistant Avena leaf protoplasts to the phytotoxin victorin. PLANT CELL PHYSIOL 17(5): 987-995. 1976. Simon, Satter, and Arthur W. Galston. Circadian rhythmicity in excised Samanea pulvini: II. Resetting the clock by phytochrome conversion. PLANT PHYSIOL (BETHESDA) 58(3): 421-425. 1976. Fuchs and Arthur W. Galston. Macromolecular synthesis in oat leaf protoplasts. PLANT CELL PHYSIOL 17(3): 475-482. 1976. Schrempf, Satter and Arthur W. Galston. Potassium-linked chloride fluxes during rhythmic leaf movement of Albizzia julibrissin. PLANT PHYSIOL (BETHESDA) 58(2): 190-192. 1976. 1976 Kaur-Sawhney, Rancillac, Staskawicz, Adams and Arthur W. Galston. Effect of cycloheximide and kinetin on yield, integrity and metabolic activity of oat leaf protoplasts. PLANT SCI LETT 7(1): 57-67. 1976. Satter, Applewhite, Chaudhri and Arthur W. Galston. Pfr phytochrome and sucrose requirement for rhythmic leaflet movement in Albizzia. PHOTOCHEM PH0T0BI0L 23(2) : 107-112. 1976. Reid and Arthur W. Galston. Experiments on the isolation and cultivation of protop Lasts and calli from agriculturally important plants: II. Soybean(Glycine max L.) BIOCHEM PHYSIOL PFLANZ (BPP) 168(5.6): 473-482. 1975[recd. 1976.] Brenneman and Arthur W. Galston. Experiments on the cultivation of protoplasts and calli of agriculturally important plants: I. Oat (Avena sativa L.) Biochem Physiol Pflanz (BPP) 1968(5/6): 453-457. 1975[reed. 1976]. 4 AO A Lisansky and Arthur W. Galston. Phytochrome stability in vitro: II. A low molecular weight protective factor. PLANT PHYSIOL 57(2): 188-191. Ulus. 1976. 1975 Novak and Arthur W. Galston. Control of in vivo protein synthesis and peroxidase formation by DNA-containing extracts of noraal and crown gall tissues. PHYTOCHEMISTRY (OXF) 14(1): 49-56. Ulus. 1975. Satter, Gebalie, Applewhite and A. W. Galston. Potassium flux and leaf movement in Samanea Saman: I. Rhythmic movement. J GEN PHYSIOL 64(4): 413-430. Ulus. 1974. Satter, Gebalie and A. W. Galston. Potassium flux and leaf movement in Samanea Saman: II. Phytochrome controlled movement. J GEN PHYSIOL 64(4): 431-442. Ulus. 1974. Satter, Applewhite and Arthur W. Galston. Rhythmic potassium flux in Albizia: Effect of animophylline, cations, and inhibitors of respiration. PLANT PHYSIOL 54(3): 280-285, Illus. 1974. 1974 Whitney R., Jr. and Arthur W. Galston. Differential effects of ethylene on pith peroxidase of intact tobacco plants aari excised tissue. PLANT PHYSIOL 53(6): 1931-933. Illus. 1974. Lisansky and A. W. Galston. Phytochrome stability in vitro: I. Effect of metal ions. PLANT PHYSIOL 53(3): 352-359. Illus. 1974. Applewhite, Satter and A. W. Galston. Protein synthesis doting endogenous rhythmic leaflet movement in Albizia. J GEN PKESIOL 62(6): 707-713. Illus. 1973. Satter, Applewhite, Kreis and A. W. Galston. Rhythmic lealet movement in Albizia julibrissin: Effect of electrolytes aed temperature alteration. PLANT PHYSIOL 52(3): 202-207. Illas. 1973. Satter, A. W. Galston. Leaf movements: Rosetta stone of plant behavior? BIOSCIENCE 23(7): 407-417. Illus. 1973. 1973 Satter, Applewhite and A. W. Galston. Phytochrome-controDed nyctinasty in Albizzi julibrissin: V. Evidence against acetycholine participation. PLANT PHYSIOL 50(4): 523-525. 1972. JOHN A. GAROFALO, M.D. I. QUALIFICATIONS See attached curriculum vitae. II. SUBJECT MATTER The subject matter of Dr. G a r o f a l o ' s testimony will per­ tain to the field of immunology. that Agent Orange III. (dioxin) He will elaborate on the effect can have on the immune system. GENERAL SCIENTIFIC PRINCIPLES The field of immunology involves the study of how the body responds to antigenic (foreign) lymphocytes are made up of B-cells; stimulation. T-cells; Peripheral blood and T cell subsets (also referred to as the immunoregulatory cells of the immune system). During the past two decades, the field of immunology has recorded a number of dramatic advances. The most significant of whic h have been the recognition of the various classes of T and B lymphocytes, hybridoma technology (provides a reliable and consis tent method for providing large quantities of monoclonal antibodies directed against specific cell surface antigens) the technological advances in flow cytometry. (65-85% of lymphocytes) and T lymphocytes are responsible for a spectrum of immune responses referred to as cell-mediated immunity which in­ clude delayed hypersensitivity; allograph rejection; tumor cyto­ toxicity, whereby they destroy host cells bearing foreign anti­ gens; and cell-mediated resistance to infectious agents viruses, and intracellular faculative bacteria). (fungi, Two functionally 133 distinct subsets of T cells have been defined with monoclonal T4+ antibodies. cells represent the helper/inducer population 38-53%) whereas T8+ cells represent the suppressor/cytotoxic pop­ ulation (18-30%) of T cells, (cytotoxic refers to the major effector functions the capacity to kill specific cells to which they are sensit i z e d ) . T4+ (helper/inducer) cells regulate the immune re­ sponse by means of cell-cell interactions as well as by producing biologically potent regulatory molecules. cer function in T-T cell T4+ cells provide indu­ (required for optimal development of cy­ totoxicity by the T8+ c e l l s ) ; T-B cell (induces B cells to pro­ liferate and differentiateinto immunoglobulin containing p l a s m a ) ; and T-macrophage interactions. T4+ cells produce humoral factors such as lymphocyte mitogenic factor, which induces proliferation of all major lymphocyte subclasses. Antigen stimulated T4+ cells produce helper factors that modulate erythroid stem-cell production and are important in hematopietic differentiation. tain cells with suppressor/cytotoxic functions. T8+ cells con­ This subset suppresses B cell immunoglobulin synthesis and has the capacity to kill cells to which they are sensitized. B lymphocytes are cells coded to product immunoglobulins, which are proteins found in blood and various secretions. major g o r u p s : B cells product Ig which belong to four IgG - responsible for defense against bacterial infections i.e. pneumonia and strep throat; IgM - responsible for the defense against anerobic bacterial infections i.e. bowel pathogens; IgA - defends us against viral infections and is found in large quantities in our secretions; defense against allergens. - 2- IgE - responsible for our HYBRIDOMA TECHNOLOGY — The advent of hybridome technology has p r o ­ vided a new approach to immunology research. With its application monoclonal antibodies capable of recognizing with precision the functional components of the immune system provide the medical community with highly specific reagents for the study of T lympho­ cyte maturation and for the identification of T lymphocyte sybpopulations. ORTHO SPECTRUM III utilizes the observation that human lymphocytes, monocytes and granulocytes posses different light scattering characteristics. Cells undergoing analysis travel in single file through a quartz cuvette where they intersect a n ar­ rowly focused 488nm wavelength beam of light from an argon-ion laser. The illuminated cells scatter the light in all directions. A s o 1 i d - s t i n t n s e n s o r m l l e e r s l o w .i ruj ln f o r w a r d s c a t t e r t o d i s c r i m ­ inate size of cells, and a photomultiplier tube (PMT) set at 90°. These signals produce a histogram of cells counted based on in­ tensity of green fluorescence. Analysis of peripheral blood samples is performed using whole blood. direct immunofluorescence, The cells are labeled by in which the monoclonal antibody directed against the desired cell surface antigen is conjugated with a flourescent dye, or by indirect immunofluorescence, monoclonal antibody, in which the having been found to the cell surface, is visualized with a second fluoresceinated antibody directed against the monoclonal immunoglobulin. i Q q * .C J V Xj In the evaluation of lymphocyte populations both p e r ­ centages and absolute values are taken into consideration. The mechanism of how abnormal lymphocyte populations affects the im- mune response will be set out. The basic theorem is that changes in lymphocyte populations are suggestive of disease processer and often but not universally relate to dysfunction. of this litigation, For the purposes it is important to distinguish between immune deficiencies and immuno-suppression. Suppression referring to an acquired immune deficiency that can be the result of exposure to chemical toxins. Dr. Garofalo has had particular clinical experience rele­ vant to this litigation. about thirty-five He has, since December, 1983, examined (35) Vietnam veterans for Agent Orange-related immune abberations. To the best of his knowledge, the published literature does not contain any reports of data comparable to that which he has acquired. A general review of his date indicates that the Vietnam veterans exposed to Agent Orange have slightly elevated levels of lymphocytes, with particular reference to T helper cells. There is even some elevation of suppressor T cells. IV. SUBSTANCE OF OPINIONS 1. Agent Orange can affect the immune system by produ­ cing changes in the numbers and distribution of T cells, cells, and T suppressors cells, T helper though it is much more likely that it has its effect through changes in the latter two types of cells. 2. The effect on helper T cells may result in a h e i g h ­ tened immune response, leading to the formation of auto-immune diseases. These in turn may lead to excess cancer formation, arthritis, and nerve damage, the latter including both central -4- 1XS'0-' . ¿w * nerve damage and peripheral neuropathy, of which the "dying back" variant is typical. 3. Agent Orange can cause an excess of T8+ cells (suppressor/ c y t o t o x i c ) . This may represent an increase in either the suppressor population which in turn can interfere with helper T cell and B cell function or the cytotoxic cell population which have the capacity to kill specific cells to which they are sensi­ tized . 4. Agent Orange may act as an antigen bound to body tissues resulting in the formation of autoantibodies and cytotoxic cells directed against the sensitized tissue. Auto Antibody: "Auto" refers to self; "Antibody" refers to a protein formed by the immune system in a response to antigen exposure. An autoantibody is thus an antibody that is formed within a person against their own tissues, cells, platelers, 5. nerve tissue, i.e., red blood skin). Individual opinions concerning the representative plaintiffs are contained in their individual reports. V. GROUNDS FOR OPINIONS Dr. Garofalo will rely upon his own experience in the evaluation of other veterans he has evaluated in the past or whom he will evaluate in the future, list of articles. -5- and upon the attached ARTICLES UPON WHICH DR. GAROFALO MAY RELY IN WHOLE, OR IN PART, ARE: J. Hopkins Dioxin: Carcinogenicity FD. COSMET. TOXICOL. 1980 Voi. 18, pp. 739-741 J. Hopkins, P. Cooper Dioxin Dangers to Man FD. COSMET. TOXICOL. 1980 Vol. 18, pp. 541-546 J. E. Huff, J. A. Moore, R. Caracci and L. Tomatis Long-Term Hazards of Polychlorinated Dibenzodioxins and P o lychlor­ inated Dibenzofurans ENVIRONMENTAL HEALTH PERSPECTIVES 1980 Vol. 36, pp. 221-240 David Païen & Edward Glover Our Promotion by O in Skin of HRS/J Hairless Mice MACMILLAN JOURNAL November 18, 1982 Vol. 300, pp. 271-273 G. Reggiani, F. Hoffmann Acute Human Exposure to TCDD in Seveso Italy JOURNALOF TOXICOLOGY AND ENVIRONMENTAL HEALTH 1980 Vol. 6, pp. 27-43 Michael I. Luster, Gary A. Boorman, Jack H. Dean, Martha W. Harris, Robert W. Luebke, M a rtin L. Padarathsingh and John A. Moore Examination of Bone Marrow, Immunologic Parameters and Host Susceptibility Following Pre- and Postnatal Exposure to 2,3,7,8Tetrachlorodibenzo-p-Diox in (TCDD) INT. J. IMMUNOPHARMACY 1980 Vol. 2, pp. 301-310 Willi a m G. Dunagin, M.D. Dioxin Effects on Human Health MISSOURI M E D I C I N E March, 1983 Vol. 80, No. 3, pp. 127-131 19348 - 6 - R. P. Sharma, P. J. Gehring Effects of 2,3, 7 , 8-Tetrachlorodibenzo-p-Dioxin (TCDD) On Splenic Lymphocyte Transformation in Mice After Single and Repeated Exposures ANNALS NEW YORK ACADEMY OF SCIENCES 1979 pp. 487-497 S. J. Stohs, M.Q. Hassan and W. J. Murray Lipid Peroxidation as a Possible Cause of TCDD Toxicity BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS March 29, 1983 Volume 111, No. 3, 1984, pp. 854-859 David A. Clark, Jack Gauldie, Myron R. Szewczuk and George Sweeney Enhanced Supressor Cell Activity as a Mechanism of Immunosuppres­ sion by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (41275) PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE 19 81 pp. 290-299 Graziella Filippini, M.D., Bianca Bordo, M.D., Paolo Crenna, M.D., Nicoletta Massetto, M.D., Massimo Musicco, M.D., Renato Boeri, M.D. Relationship Between Clinical and Electrophysiological Findings and Indicators of Heavy Exposure to 2,3,7,8-Tetrachlorodibenxodioxin SCAND J WORK ENVIRON HEALTH 1981 Voi. 7, pp. 257-262 C. M. Bishop, A. H. Jones Non-Hodgkin's Lymphoma of the Scalp in Workers Exposed to Dioxins THE LANCET August 15, 1981 p . 369 Jana P a z d e r o v a - V e j l u p k o v a , M.D., Marcela Nemcova, Ph.D., Jane Pickova, Ph.D., Lubor Jirasek, Ph.D., Edgar Lukas, Ph.D. The Development and Prognosis of Chronic Intoxication by Tetrachlordibenzo-p-dioxin in Men ARCHIVES OF ENVIRONMENTAL HEALTH J a n u a r y / F e b r u a r y , 1981 Vol. 36, No. 1, pp. 5-11 -7- Henry C. Pitot, Thomas Goldsworthy, H. A. Campbell, and Alan Poland Quantitative Evaluation of the Promotion by 2,3,7,8,-Tetrachlorodibenzo-p-dioxin of Hepatocarcinogenesis from Diethylnitrosamine CANCER RESEARCH October, 1980 Vol. 40, p p . 3316-3620 J. G. Vos, J. G. K r e e f t e n b e r g , H. W. B. Engle, A. Minderhoud and L. M. Van Noorle Jansen Studies on 2,3,7,8-Tetrachlorodibenzo-p-Dioxin-Induced Immune Suppression and Decreased Resistance to Infection: Endotoxin Hypersensitivity, Serum Zinc Concentrations and Effect of Thymosin Treatment TOXICOLOGY 1978 V o l . 9, pp. 75-86 Michael I. Luster, Robert E. Faith and George Clark Laboratory Studies on the Immune Effects of Halogenated Aromatics ANNALS NEW YORK ACADEMY OF SCIENCES 1979 pp. 473-483 Ralph R. Cook Dioxin, Chloracne, THE LANCET March 14, 1981 and Soft Tissue Sarcoma A. Mantovani, A. Vecchi, W. L u i n i , M. sironi, G. P. C a n d i a n i , F. Spreafico and S. Farattini Effect of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin on M a c r ophage and Natural Killer Cell-Mediated Cytotoxicity in Mice BIOMEDICINE 1980 Vol. 32, pp. 200-204 Michael I. Luster and Robert E. Faith Assessment of Immunologic Alterations Caused by Halogenated Aromatic Hydrocarbons ANNALS NEW YORK ACADEMY OF SCIENCES 1979 pp. 572-577 i 1 3 3 ru x-i - 8- John A. Garofalo, M.D. 847 Old Lancaster Road Bryn Mawr, PA 19010 Date of Birth: August 15, 1946 SPECIALTY: Hematology - Oncology - Immunology AFFILIATIONS : Assistant Professor of Medicine Thomas Jefferson University Hospital Philadelphia, Pennsylvania Assistant Attending Department of Medicine Bryn Mawr Hospital Bryn Mawr, Pennsylvania EDUCATION: 1977-1980 1977-1980 1976-1977 1975-1976 Clinical Fellow - Immunology - Oncology Memorial Sloan Kettering Cancer Center New York, New York. Research Fellow - Immunobiology Memorial Sloan Kettering Cancer Center New York, New York. Medical Resident - Pennsylvania Hospital, Philadelphia, Pennsylvania. Medical Intern, Philadelphia General Hospital Philadelphia, Pennsylvania. 1974-1975 Research Fellow - Immunobiology, Memorial Sloan Kettering Cancer Center New York, New York. 1969-1974 University of Rome, Faculty of Medicine. 1964-1969 Oklahoma State University, Stillwater, Oklahoma - Bachelor of Science in Physiology. 1983 Medical Director - Home Cancer Care, INC. Home Health Care Agency Medical Director - Immunodiagnostics Clinical Laboratories, INC., Reference Immunology Laboratory. 1983 BIBLIOGRAPHY John A. G arofalo I. L it e r s to the E d ito r 1. AHJTI, F . , GAROFALO, J . A . : Rectal irr.n'.ur.og 1obul in syn th esis in u lc e ra ­ tive c o l i t i s . To The E d ito r: New Ennland Journal of Medicine vol 287, Na. 22, 1151 , 1972. ------------------------------------------- 2. GSvQFALO, J . A . , STRONG, £ ., GOOD, R. A. : Zinc and in te s tin a l bypass procedures. To the E d ito r: Annals of In te rn a l M edicine, June 1979. II. Abstracts li G/aût-ALû, « iA,, CiiNrli^Nufii'.i, i-K!jfjwLi-.A, S chloride on lymphocyte transform ation ih viirò-iffnets nf zinc Fed. Proc. 37( 6) , 31 54, 1978. 2. GSSFALO, J . A . , STRONG, E . , CUNNINGMAM-RUNDLES, S . , ERLANDSON, E . , KESENDEZ-BOTET, C ., SCHWARTZ, M ., GOOD, R . A . : Serum zinc ir, p a tien ts with epidermoid cancer of the head and ~eck. Fed. Proc. 38( 3) , 2561. 3. CUHINGHAM-RUNDLES, C ., CUN.NINGKAM-RUNDL ES, $ ., GAROFALO, J . , IWATA, T ., INCEFY, G ., TWOMEY, J . , GOOD, R. A. : Increased T lymphocyte func­ tion and thymonoietin fo llo w in g zin c replacement in man. Fed. P ro c. 38(3), 5259, 1979. 4. CUKINGHAM-RUNDLES, S . , CUNNINGHAM-RUNDLES , C . , GAROFALO, J., DUPONT, B ., GOOD, R . A . : E f f e c t of zin c on human B c e ll a c tiv a tio n . Fed. Pro c. 33(2), 3735, 1979. 5 . ’ GAJSfALO, J . A . _et a_l_.: Serum zinc and copper and the Cu/Zu r a t io in patients w ith can cer. AACR/ASCG, 733, 1980. 11. Publications 1. AUm , F . , LACAVA, V ., GAROFALO, J . A . , 0 *AMELIO, ■R . , D‘ASERO, C .: Surface markers on human lymphocytes: Studies of normal su b je cts and of patients w ith primary im m unodeficiencies. C l i n . Ex p . Immunol. 15: 43-52, 1973. 2. AILTI, F . , CIARLA, K . V . , D1ASERO, C ., 0 'AMELIO, R ., GAROFALO, J . A . : Surface markers on lymphocytes of p a tie n ts w ith in fe c tio u s d ise a se s. Infection and Immunity 8(1 ) , 110-117 , 1973. 3. A lim , F . , PAPA, G ., LACAVA, V ., CIARLA, M. V. , D*AMELIO, R ., GAROFALO, J . : Lymphocyte membrane markers in acute lym phoblastic leukem ia. B r i t . J . Baem, 27, 635, 1974. 4 CUHINGHAM-RUNDLES, S., DE SOUSA, M ., GAROFALO, J.A., BOGNACKI, J.J., LEE, 5.J., DUPONT, B., GOOD, R.A.: D iff e r e n t ia l a n a ly sis of spontaneous uptake of thymidine and t r a n s fe r r in by mononuclear c e lls in v it r o in Hodîkin's d ise a s e . 13th In te rn a tio n a l Leukocyte Con;erence, 1979. 13353 5. SCHLOEN, L.H., FERNANDES, G., GAROFALO, J.A., GOOD, R.A.: Nutrition, Immunity and Cancer - A Review, Part II. Clinical Bulletin, 9, #2, 1979. 6. GAROFALO, J.A., CUNNINGHAM-RUNDLES, S., BRAUN, D.W., GOOD, R.A. : In Vitro Effect, of Zn’r"r on Peripheral Blood Lymphocytes in Patients with Cancer. Inter. J. of Immunopharmacology, 2, 37-44, 1980. 7. GAROFALO, J.A., ASHIKARI, K., LESSER, M., MENENDEZ-BOTET, C., CUNNINGKAM-RUNDLES, S., SCHWARTZ, M.K., GOOD, R.A.: Serum Zinc, Copper and the Cu/Zn Ratio in Patients with Benign and Malignant Breast Lesions. Cancer, 46, 2, 26S2-2685, 1980. 8. GAROFALO, J.A., ERLANDSON, E ., STRONG, E., LESSER, M ., GEROLD, F., SPIRO, R. , SCHWARTZ, M . , GOOD, R.A.: SErum Zinc, Serum Copper and the Cu/Zn Ratio in Patients with Epidermoid Cancer of the Head and Neck. J. of Surgical Oncology, Vol. 15, issue 4, 381-386, 1980. 9. SCKULOF, R.S., GAROFALO, J.A., GOOD, R.A., GUPTA, S.: Concanavalin A Induced Suppressor Ceil Activity for T Cell Proliferative Responses: Autologous and Allogenic Suppression in Aging Humans. Cellular Immunoloqv, 56, 80-88, 1980. 10. GOOD, R.A., FERNANDES, G., CUNNINGHAM-RUNDLES, C., C'JNNINGHAM-RUNDLES, S., GAROFALO, J.A., RAO, K., INCEFY, G.S., IWATA, T.: The Relation of Zinc Deficiency to Immunologic Function in Animals and Man. In Pr imary Immunodeficiencies, Inserm Symposium No. 16, 223-234, Editors: M. Seiigmann and W.K. Hitzig, Biomedical Press, 1980 . 11. GOOD, R.A., FERNANDES, G., GARCFAL^, ...A., CUNNINGHAMRUNDLES, C., IWATA, T., WEST, A.: Zinc ana Immunity. In: International Conference on Cxi icai and Public Health Significance of Trace Minerals in tr.e World Population, Detroit, 1980; Proceedings (A.S. Prasad, ed.), New York, Alan R. Liss. 13354 L I. E N N A R T H A R D E L L , M . D . , P h . D . QUALIFICATIONS Dr. Hardell is employed by the University Hospital in its Department of Oncology in Umea, Sweden, where he specializes in intern medicine and oncology. His work includes diagnosis, evaluation of possible causes of cancer, students. treatment, and and education of medical His Curriculum Vitae is attached. A list of seminars is also attached. II. Subject Matter Dr. Hardell will testify to several epidemiological studies which he and his colleagues have conducted in Sweden. This research includes investigations concerning the relationship between the risk for different types of cancer and exposure to phenoxy herbicides and chlorophenols. The research has been published in the medical and scientific literature. These studies utilized the case-control study as t h e vehicle for investigation. of cases, Certain methodological aspects, selection of controls, assessment of exposure, and statistical methods, were considered; and then utilizatioa was based upon thoroughly considered aspects of bias, controlled. such as selection all of which sere well 13355 Dr. Hardell has also seen in his clinical practice basal cell carcinoma of persons previously exposed to phenoxy herbicides, with no other known confounding variables. III. Scientific Principles See General Statement of Scientific Principles and Assumed Facts attached. Dr. Hardell will use as a factual base for his testimony his hands-on diagnoses and treatment of various cancer victims as well as his review of the medical records and examinations of cases involved in his epidemiological studies. His additional clinical experiences also form a factual basis for his testimony, especially those patients with basal cell carcinoma. Dr. Hardell will also review the medical records of George Ewalt, Danny Ford, and David Lambiotte for the opinions which he will express regarding the causation (in the legal sense) their exposure to Agent Orange and basal cell carcinoma, sarcoma (form of soft tissue sarcoma) and rhabdomyo­ and malignant lymphocytic lymphoma. 13358 IV. Substance of Opinions A. Specifically, Dr. Hardell's studies, four in number, involved soft tissue sarcomas, malignant lymphomas, cancer. and colon Highly statistically significant risks of soft tissue sarcomas and malignant lymphoma were found, whereas no association was found for colon cancer. In point of fact, the negative finding for colon cancer strongly supports the statistical significance of the increased risk demonstrated for soft tissue sarcomas and malignant lymphomas, and that there exists a presumed causal relationship between exposure to phenoxy herbicides and human cancer, particularly of soft tissue sarcoma and malignant lymphoma. B. With respect to those cases with soft tissue sarcoma, malignant lymphoma, and basal cell carcinomas, Dr. Hardell will testify that the presumed exposure to Agent Orange caused, in significant part, V. such neoplastic processes. Grounds for Each Opinion A. General The bases for Dr. Hardell's testimony as to various facts and opinions include: training, and experience; educational background, professional diagnosis and treatment of patients, review of the applicable medical and scientific literature; personal research; and a review of the pertinent medical data of the relevant representative plaintiffs. B . S p 1. e c i f i c Soft tissue sarcomas and malignant lymphoma References : Cook RR (1981): Dioxin, Lancet i. 618-619. chloracne, and soft-tissue sarcoma. Eriksson M, Hardell L, Berg NO, Moller T, Axelson 0 (1981): Soft-tissue sarcomas and exposure to chemical substances; a case-reference study. Br J Ind Med 38: 27-33. Hardell L (1979): Malignant lymphoma of histiocytic type and exposure to phenoxyacetic acids or chloropheno1s . Lancet i: 55-56. Hardell L (1981): Relation of soft-tissue sarcoma, malignant lymphoma and colon cancer to phenoxy acids, chloropheno1s and other agents. Scand J Work Environ Health 7: 119-130. Hardell, L, Sandstrom A (1979): Case-control study; softtissue sarcomas and exposure to phenoxyacetic acids or chlorophenols. Br J Cancer 39: 711-717. Hardell L, Eriksson J, Lenner P, Lundgren E (1981): Malignant lymphom.' and exposure to chemicals, especially organic solvents, chlorophenols and phenoxy acids; a case-control study. Br J Cancer 43: 169-176 Honchar PA, Kalperin WE (1981): 2,4,5-T trichlorophenol, soft tissue sarcoma. Lancet i: 268-269. and Johnson F E , Kugler M A , Brown SM (1981): soft-tissue sarcomas and chlorinated phenols. Lancet I: 1370. Moses M, Selikoff IJ (1981): soft-tissue sarcomas, phenoxy herbicides and chlorinated phenols. Lancet i: 1370 Pitot HC, Golds wo rthyT, Poland H (1980): Promotion by 2,3, 7 ,8-tetrachlorodibenzo-p-dioxin of hepatocarcinogenesis from diethylnitrosamine. Cancer Res 40: 3616-3620. Poland A, Palen D, Glover E (1982): Tumour promotion by TCDD in skin of HRS/J hairless mice. Nature 300: 271-273. Sarma PR, Jacobs J (1982) Thoracic soft-tissue sarcoma, in Vietnam veterans exposed to agent orange. N. Engl J. Med 306: 1109 13358 2. Basal Cell Carcinoma Case history: Woman born in 1946. ovaries. In 1964 operated for a cyst on one of her No other diseases. In the end of the 1960's she developed a blister on her left shoulder and in the 1970's several ones on her back. In June 1977, two basal cell carcinomas were surgically removed from her back. In September 1977 nine more and in December 1977, two more basal cell carcinomas were excised from her back. In January 1983 one basal cell carcinoma on her shoulder and another on her back were cured by radiotherapy. In October 1983 five tumors were removed from her back; two basal cell carcinomas and three basal cell carcinomas in situ. During summertime in 1959, 1960, and 1961 the patient afforested for one month each summer. The seedlings were treated with DDT. Moreover, she carried water for the dilution of phenoxy acids used by back pack sprayers. She walker in newly sprayed areas. In 1960 she used to basal bark spray for six weeks and in 1961 for two weeks. The chemical used was a combination of 2,4,5-T and 2,4,-D. She was thereby stripped to her waist but for a brassiere. She used no gloves . The patient reported no heredity for basal cell carcinoma. She had not used any special drugs or been exposed to arsenic. i X w 0 0 0 Curriculum Vitae Lennart Hardell M. D. , Ph. D. Department of Oncology, U n iv e rs ity Hospi t al , S-901 85 UMEA, Sweden Born in October 18, 1944. Medical degree from U n iv e rs ity of Upsala, Sweden October 27, 1971. A utho rizatio n to p ra c tic e the. medical p ro fe ssio n , National Board of Health and W eifar^ S^ cirhoTnvflkJvem ber 5, 1971. S p e cia lize d in in te rn a l medicine October 18, 1976. S p e cia lize d in oncology, June 20, 1979. Medical d is s e rta tio n U n iv e rs ity of Umeâ, May 15, 1981. D ire c t testimony before the United S ta te s Environmental Pro tectio n Agency in the matter of the hearing of 2 , 4 , 5 - T and S i l v e x , Washington DC, September 29-30 1980 and February 9, 1981. R eceiver of the Fernstrom Award, U n iv e rs ity of Umeâ, October 9, 1982. D elivered by the King Carl XVI G ustaf of Sweden. Member of "Expert Panel on Dioxin Documents", United S ta te s Environmental P ro te ctio n Agency, C in c in n a ti, Ohio, J u ly 27-29, 1983. Q u a lifie d fo r A sso ciate P ro fe sso r of oncology, U n iv e rs ity of Umeâ, December 9, 1983. Member of the Swedish Medical A sso cia tio n . Member of Nordic Radiotherapy Club Member of Swedish A sso ciatio n of Radiotherapy Member of Swedish A sso ciatio n of Oncology Member of Swedish Epidem iological A sso ciatio n 123P.Q Appointments by Or Lennart H ardell A fte r au th o rizatio n worked a s: General p r a c t it io n e r , Prim ary Health Centre, Haparanda, November 1 1971 - August 31 1972. Ju n io r r e g is t r a r , Department of P s y c h ia try , County H o sp ita l, K ristineh am n , September 1-30, 1972. Ju n io r r e g is t r a r , Department of October 1 - December 31 1972. P s y c h ia try , County H o sp ita l, Boden, From January 1 1973 to August 31 1976 vario us appointments as Ju n io r r e g is t r a r , Senior r e g is t r a r and co nsu ltant at the Department of In te rn a l Medicine, County H o sp ita l, Boden. From September 1 1976 vario us appointments as a Ju n io r r e g is t r a r , Senior r e g is t r a r and co nsu ltant at the Department of Oncology, U n iv e rs ity H o sp ita l, Umea. September 1 - December 31 1983 Head and co n su lta n t, Centre of Oncology, U n iv e rs ity H o sp ita l, Umea. For the moment appointed as co nsu ltant at the Department of Oncology, U n iv e rs ity H o sp ita l, Umea, Sweden. 13361 COURSES tN WHICH DR LENNART HARDELL HAS PARTICIPATED Cardiology U n iv e rs ity of Lund A p ril 2-6 1973 Hypertonia, hypotonia and blood vessel diseases Regional H ospital of Malmo November 5-9 19/ Lung d ise a se s, e s p e c ia lly astma, autoimmune and work re la te d lung diseases U n iv e rs ity of Upsala March 11-15 197^ Gastroenterology and liv e r diseases U n iv e rs ity of Gothenburg May 13-17 1974 Acute medicine Regional H ospital of Örebro November 18-22 1 Hematology, nephrology U n iv e rs ity of Linköping A p ril 7-11 1975 Course in endocrinology K a ro lin sk a In s t it u t e , Stockholm November 3-7 197 In tra th o ra c a l tumours Regional H ospital Huddinge February 23-27 11 In fe c tio u s d iseases and a n t ib io tic therapy U n iv e rs ity of Gothenburg February 15-19 1: Cancer epidemiology, cancer s t a t i s t ic s and e a rly diagnoses of cancer K a ro lin sk a I n s t it u t e , Stockholm October 11-15 19. Postgraduate course in c lin ic a l oncology, so ft tis s u e sarcomas, plasma c e ll tumours, cancer of the esophagus and stomach Royal Marsden H o sp ita l, The Chester B eatty Research I n s t it u t e , London November 14-18 19- B io lo g ic a l and medical e ffe c ts of ir r a d ia t io n , course fo r oncolog ists K a ro lin sk a I n s t it u t e , Stockholm May 2-6 1977 B io s ta t ic s in epidemiology, methods and a p p lic a b i1it y U n iv e rs ity of Umea March 11-18 1978 Therapy with c y t o s ta t ic drugs and hormones of malignant tumours and o rie n ta tio n about progress in tumour immunology K a ro lin sk a I n s t it u t e , Stockholm May 8-12 1978 Cancer epidemiology IARC, Lyon, France J u ly 31-August 11 Radiation physics fo r o nco lo g ists K a ro lin sk a In s t it u t e , Stockholm October 2-6 1978 1 0, o ^ Clinical oncology II and radiation therapy University of Lund October 16-20 1 Cl in ic a l oncology I U n iv e rs ity of Umeâ March 19-23 197! Course on epidem iological approach to occupational cancer • IARC, Lyon, France March 17-21 198' Methods of epidemiology U n iv e rs ity of Umea Course fo r threr weeks June 1980. P u b iications 1. H ardell L . Maligna mesenkymala mjukdelstumörer och expo sitio n fo r fe n o xi- syro r - en k l i n i s k o b servatio n . Läkartidningen 71 ( 1977 ) 2753-2754. (In Swedish, English summary) 2. H ardell L . Kemiska substanser och maligna mesenkymala tumorer. Svensk fö r e n in g fö r medicinsk r a d io lo g i. Fdrhandlingar nr 9 (1978) 18-21. (In Sw edish). 3. Hardell L , Sandström A. Case-control S tu d ie : Maligna mesenkymala m jukdels­ tumörer och exp o sitio n fö r fe n o x is y ro r e l l e r k lo rfe n o le r. Läkartidningen 75 (1978) 3535-3536. (In Sw edish). 4. Hardell L , Sandström A. Case-control stud y: S o ft- tis s u e sarcomas and exposure to phenoxyacetic acid s or chlo ro pheno ls. Paper presented at the conference on p e stic id e s and human h e a lth . S o cie ty fo r Occupational and Environmental H ealth , Washington O. C. , USA December 10-13, 1978. 5. H ardell L . Malignant lymphoma of h is t io c y t ic type and exposure to phenoxy a c e tic acids or chlorophenols. Lancet i (1979) 55-56. 6. Hardell L , Sandström A. Case-control stud y: S o ft- tis s u e sarcomas and exposure to phenoxy acid s or chloro pheno ls. B r. J . Cancer 39 (1979) 711-717. 7. Eriksso n M, H ardell L , Berg NO, M öljer T , Axelson 0. Case-control Studie over maligna mesenkymala mjukdelstumörer och e xp o sitio n fo r kemiska su b stan se r. Läkartidningen 76 (1979) 3872-3875. (In Sw edish). 8. Hardell L . Cancer epidemiology in northern Sweden. Nordic Council A rc t . Med. Res. Rep. No. 26 (1980) 94-97. 9. H ardell L . The c lo fib r a t e problem: A d iffe re n c t view po int. Lancet i i (1980) 1081-1082. 10. H ardell L . Case-control s tu d ie s : S o ft- tis s u e sarcomas and m alignant lympho­ mas and exposure to phenoxy a cid s o r chlo ro pheno ls. In : Progress in Mutation Research, V ol. 2, £d. Koppas. E lse v ie r/N o rth -H o lla n d . Biomedical P re s s , pp. 105-108, 1981. 11. Hardell L . D ire ct testim ony before the United States Environmental Protection Agency. Washington DC. E x ih ib it No. 762, September 29-30, 1980. 12. Hardell L, Eriksson M, tenner P. En f a ll- k o n t r o ll stu d ie : Maligna lymfom och exposition fo r kemiska substanser, s a r s k ilt organiska losningsmedel, k io rfe n o le r och fe n o x is y ro r. Lakartidningen 77 (1980) 208-210. (In Swedish). 13. H ardell L , Eriksson M, Lenner P. (Hodgkins sjukdom - en ko m p letterin g ). Rep 1ik Lakartidningen 77 (1980) 983. (In Swedish). 14. H ardell L . R elatio n of s o ft - t is s u e sarcoma, malignant lymphoma and colon cancer to phenoxy a c id s , chlorophenols and other agents. Scand. J . Work. E n viro n . Health 7 (1981) 119-130. 15. H ardell L , Eriksso n M. S o ft- tis s u e sarcomas, phenoxy h e rb icid e s and c h lo ­ rin ated phenols. Lancet i i (1981) 250. 16. H ardell L . Epidem iological stu d ie s on s o ft- tis s u e sarcoma and malignant lymphoma and t h e ir re la tio n to phenoxy acid or chlorophenol exposure. Umea U n iv e rs ity Medical D is s e r ta tio n s . New S e rie s No 65 - ISSN 0346-6612. 1981. 17. H ardell L . D ire c t testim ony before the United States Environmental Pro­ te ctio n Agency. Washington D.C. E x ih ib it No 956, February 9, 1981. 18. H ardell L , Eriksso n M, Lenner P, Lundgren E. Malignant lymphoma and expo­ sure to chem icals, e s p e c ia lly organic so lv e n ts, chlorophenols and phenoxy a c id s : A case-con trol stu d y. B r. J . Cancer 43 (1981) 169-176. 19. H ardell L , Eriksso n M. F e n o x isy ro r, k io rfe n o le r och ca n ce r. Lakartidningen 78 (1981) 2862-2863. (In Sw edish). 20. Axelson 0, Flodin U, H ardell L. A comment on the re fe re n ce s e rie s with regard to m u ltip le exposure evalu atio n in a c a se -re fe re n t study. Scand. J . Work. En viro n. Health 8 (1982) suppl. 1, 15t 19. 1 ci 21. Eriksson M, H ardell L, Berg NO, M öller T, Axelson 0. S o ft- tis s u e sarcomas and exposure to chemical substances: a c a se -re fe re n t study. B r. J . Ind. Med. 38 (1981) 27-33. 22. Hardell L . F a ll- k o n t r o ll s t u d ie r : Maligna mesenkymala mjukdelstumörer, maligna lymfom och exponering fo r fe n o xisyro r e l l e r k lo rfe n o le r. N JF-serm inar 12-13 november 1980. Nordisk jo rd b ru ksfo rskn ing 1 (1981) 58-59. (In Sw edish). 23. Osterman B, H ardell L , Holm J , Lenner P, Lindholm C, Wahl in A. E rfa re n h e te r av in te n siv cyto statikab ehan d ling vid akut myeloisk leukem i. Läkartidningen 79 (1982) 2107-2109. (In Swedish). 24. Sandahl C, H ardell L . K o ststu d ie vid onkologisk k l i n i k . D e lstu d ie . Maten pä sju kh u set. I . P a tie n t- och I I . personalsynpunkter. N äringsforskning 27 (1983) 14-21. (In Swedish, En g lish summary). 25. Hardell L . Cancer. K ap ite l i lärobok i invärtesm edicin fö r sju k sk b 'te rsk o r. (1982), 263-268. (In Sw edish). 26. Hardell L , Axelson 0. S o ft- tis s u e sarcoma, malignant lymphoma and exposure to phenoxy acids or chlorophenols. Lancet i (1982) 1408-1409. 27. H ardell L , Johansson B, Axelson 0 . Epidem iological study on nasal cancer and nasopharyngeal cancer and t h e ir re la tio n to phenoxy acid or chlorophenol exposure. Am. J . Ind. Med. 3 (1982) 247-257. 28. H ardell L . Exposure to chlorophenols and phenoxy h e rb icid e s in the working environment. A b stract before the 13th In te rn a tio n a l Cancer Congress. September 8-15, 1982. S e a tt le , Washington USA. 29. H ardell L . Exposure to p o lychlo rin ated dibenzo-p-dioxins and dibenzofurans in the environment. In : 13th In te rn a tio n a l Cancer Congress, Part E . Cancer Management. Eds. Mirand, Hutchinson, M ihich. 1983. Alan R L is s , New York, pp. 357-369, 30. H ardell L , Eriksso n M, Lenner P, Lundgren E. Malignant lymphoma and ex­ posure to chem icals, e s p e c ia lly organic s o lv e n ts , chlorophenols, and phenoxy a c id s : A case-co n tro l study. Poster at the 13th In te rn a tio n a l Cancer Congress, September 8-15, 1982. S e a tt le , Washington USA. 31. H ardell L . Epidem iological stu d ie s on s o ft - tis s u e sarcoma, malignant lymphoma, n a s a l, and nasopharyngeal cancer and t h e ir re la tio n to phenoxy acid or chlorophenol exposure. In : C h lo rinated D ioxins and Dibenzofurans in the Total Environment. Eds. Choudhary, K e ith , Rappe. Butterworth P u b lis h e rs , Boston, pp. 367-374, 1983. 32. Bengtsson NO, H ardell L , E riksso n M. Asbestos exposure and malignant lymphoma. Lancet i i (1982) 1463. 33. H ardell L , Bengtsson NO. Ep idem iological study o f socioeconomic fa c to rs and c lin ic a l fin d in g s in Hodgkin's d ise a s e , and re a n a ly s is of previous data regarding chemical exposure. B r . J . Cancer 48 (1983) 217-225. 34. Sandahl, Ronnlund U, H ardell L . K o ststu d ie vid onkologisk k l i n i k . N u tritio n s s ta tu s hos radioterapibehandlade head- och n e ck p a tie n te r. Ume£ U n iv e rs ite t 1983. (In Sw edish). 35. H ardell L . Epidem iological stu d ie s on s o f t - t is s u e sarcoma, m alignant lym­ phoma, n a s a l, and nasopharyngeal cancer and t h e ir re la tio n to phenoxy acid or chlorophenol exposure. A b stra ct before D ivid sio n o f Environmental Chem istry, American Chemical S o c ie ty , Kansas C it y , M iss o u ri, September 15-16, 1982. 36. D ire c t testim ony of Dr. Lennart H a rd e ll, "The Herbicide Court Case", Nova S c o tia , Canada, May 1983 (presented by Dr. M. E rik s s o n ). 37. H ardell L . Axelson 0, Rappe C. Nasal cancer and chlorophenols. Lancet i (1983) 1167. 38. Sandahl C, Ronnlund U, H ardell L . B a ttre n arin g sstatu s hos ca n ce rp a tie n te r med h ja lp av n utritio n sg ru p p och kostombud? Lakartidningen 80 (1983) 2234-2235. (In Sw edish). JL 39. Domellof L . Hansson M. H ardell L . Nygren M. Rappe C. Le ve ls of p o lych lo rin ate d dibenzodioxins (PCDDs) and dibenzofurans (PCDFs) in f a t tis s u e from ca n cerp atien ts and c o n tro ls . A b stract before the AACR annual meeting May 9-12, 1984, Toronto, O n tario , Canada. H A R D E L L , L e n n a r t 1. Conference organized by the Swedish Society of Medical Radiology (Invited speaker) 2. Conference by the Finnish Medical Association; Duodecim and Medical Faculty 3. Malignant Tumors and Chemical Risk Sectors in the Environment (Invited speaker) A. Meeting on Phenoxy Acids; The Committee on Agriculture of Swedish Parliment (Invited speaker) 5. Soft-tissue Sarcoma and Exposure to Phenoxy Acids or Chlorophenols; Meeting by the Swedish Pharmaceptical Association in UmeS (Invited speaker) 6. Conference on Pesticides and Human Health - Society for Occupational and Environmental Health (Invited speaker) 7. Symposium by Nordic Counsel on Arctic Medical Research (Invited speaker) 8. Seminar by Umeâ University Before The Swedish Work Environmental Fund; Chemical Substances in the Environment (Invited speaker) V Umeâ, Sweden September 23-24, 1977 Oulu, Finland Oulu, Finland February 22-23, 1978 Stockholm, Sweden October 17, 1978 Umeâ, Sweden November 9, 1978 Washington, D.C. December 10-13, 1978 Leykgavik, Iceland June 29-30, 1979 Umeâ, Sweden September 11-12, 1979 9. Seminar on the Work with Pesticides and Associated Risk; The National Swedish Environmental Protection Board (Invited to participate) 10. Seminar on the Use of Phenoxy Acids in the Agriculture; Swedish National Board of Occupational Safety and Health (Invited to participate) 11. Conference on the Use of Pesticides in Forestries - Swedish Association of Churches (Invited speaker) 12. Conference by the Swedish Association of Pesticide Manufacturers; Phenoxy Acids and Cancer (Invited speaker) 13. Committee on the Use of Pesticides in Forestry and Agriculture The Swedish Parliment (Invited speaker) 14. Conference on Use and Regulation of Pesticides - Nordic Counsel of Workers in Agriculture and Horticulture; Health Effects of Phenoxy Acids (Invited speaker) 15. Tenth Annual Meeting of European Environmental Mutagen; Society on Environmental Mutagenisis (Invited speaker) 16. Seminar on Demands Made by the Society for Registration and Use of PesticidesAssociation of Nordic Agricultural Research (Invited speaker) Stockholm, Sweden September 20, 1979 Stockholm, Sweden October 3, 1979 Sodrahoka, Sweden November 6, 1979 Stockholm, Sweden November 27, 1979 Stockholm, Sweden February 20, ]980 Istab, Sweden September 1-5, 1980 Athens, Greece September 14-19, 1980 Helleiud, Norway November 3.2—13 , 1980 4 17. Seminar on Phenoxy Adics and Cancer; Institute of Occupational Health (Invited speaker) 18. international Symposium on Prevention of Occupational Cancer; Institute of Occupational Health, Helsinki, Finland;: and International Labor Office and World Health Organization 19. Staff Meeting - University Hospital, Linköping, Sweden; Phenoxy Acids or Soft-tissue sarcoma and Malignant Lymphoma (Invited speaker) 20. Thirteenth International Cancer Congress; The Environment and Cancer; Recent Epidemiologic Developments (Invited speaker) 21. Symposium on Chlorinated Dioxins and Dibenzo Phurons in the Total Environment; The 184th American Chemical Society Meeting (Invited speaker) 22. Seminar on Pesticides - of Benefit or Environmental Pollutant; County Hospital at Karlshamn (Invited speaker) 23. Expert Panel on Dioxon Documents; United States Environmental Protection Agency (Invited member) 24. Symposium on the Swedish Cancer Registry; Yesterday, Today and Tomorrow (Invited speaker) H e l s i n k i , F i n l a n d D e c e m b e r 1 2 , 1 9 8 0 Helsinki, Finland April 21-24, 1981 Linköping, Sweden October 22, 1981 Seattle, Washington September 8-15, 1982 Kansas City, Missouri September 12-17, 1982 Karlshamn, Sweden March 11, 1983 Cincinnati, Ohio July 27-29, 1983 Liding, Sweden November 11, 1983 25. Seminar on Drugs and Pesticides; The Swedish Branch of Friends of Earth International ((nvited speaker) Conference on Biological Mechanisms of Dioxin Action Symposium on Toxicology; Swedish and Finnish Association of Toxicology (Invited speaker - unable to attend) Symposium on Leukemia and Related Diseases; International Association for Comparative Research (Invited speaker - unable to attend) Internation Symposium on Herbicides and Defoliants in War; The Long-Term Effects on Man and Nature (Invited speaker - unable to attend) Symposium on Public Health and Risks of Chlorinated Dioxins (Invited speaker - unable to attend) Congress on the Scientific and Social Response from Exposure to Dioxins and Related Material; Association of Occupational and Environmental Health (Invited speaker - unable to attend) v Biskopnarno, Sweden November 26-27, 1983 Banbury Center, NY April 1-4, 1984 Stockholm, Sweden May 16, 1981 Los Angeles, CA August 31-September 4, 1981 Ho Chi Minh City, Vietnam January 13-20, 1983 Rockefeller University New York October 19-20, 1983 Arlington, Virginia December 6-7, 1983 M I. A U R E E N C . H A T C H , P h . D . Qualifications Dr. Hatch is Assistant Professor Of Epidemiology at Columbia University, School of Public Health, in New York City. Her Curriculum Vitae and an Addendum listing non-scientific work experience and scientific meetings attended are attached. II. Subject Matter The subject matter about which Dr. Hatch will testify is reproductive epidemiology and toxicology, and theirspecific applicability to miscarriages and congenital malformations (birth defects) in the wives and children of Vietnam veterans. Dr. Hatch will testify at length to the data collected in Vietnam regarding untoward pregnancy outcomes. Dr. Hatch is one of two investigators who are to publish that portion of the International Symposium held in Ho Chi Minh City in January, 1983 having to do with reproductive problems as a result of exposure to Agent Orange and other phenoxy herbicide spraying in Vietnam. I l l . S c i e n t i f i c P r i n c i p l e s See General Statement of Scientific Principles and Assumed Facts attached. IV. Substance of Opinions A. That exposure to Agent Orange in Vietnam has resulted in certain epidemiological data showing a statistically significant increase in certain congenital malformations, limb deformaties, and anencephaly, e.g. cleft palate, as a result of paternal mediated reproductive effects where only the fathers were exposed to Agent Orange. B. That animal experiments confirm the epidemiological data in that TCDD exposure of the male has shown reproductive toxicity. V. Grounds for each Opinion A. General Review of applicable medical and scientific literature; personal research; seminars; attendance and/or participation at various education and training. 13373 R E F E R E N C E S C I T E D Allen JR, Carstons LA. Light and electron microscopic observations in Macaca mulatta monkeys fed toxic fat. Am J Vet Res 28:1513-1526, 1967. Constable J, Hatch M. Herbicide exposure and reproductive outcome. In: Herbicides in War: The Long-term Effects of Man and Nature, AW Westing, ed. New York: Taylor & Francis, 1984 (in press). Khera KS, Ruddick JA. Polychlorodibenzoistar-p-dioxins: Perinatal effects and the dominant lethal test in Wistar rata. In: Chlorodioxins - Origin and Fate, EH Blaire, ed. Washington DC: American Chemical Society, 1973, pp 70-84. Kociba RJ, Keeler PA< Park CN, Gehring PJ. 2,3,7,8tetrachlorodibenzo-p-dioxin (TCDD): Results of a 13-week oral toxicity study in rats. Toxicol Appl Pharmacol 35:553-575, 1976. McConnell EE< Moore JA< Haseman JK, Harris MW> The comparative toxicity of chlorinated dibenzo-p-dioxins in mice and guinea pigs. Toxicol Appl Pharmacol 44:335-356, 1978. Mattison DR, Thorgeirsson SS. Gonadal aryl hydrocarbon hydroxylase in rats and mice. Cancer Res 38:1368-1373, 1978. Norback DH, Allen JR. Biological responses of the nonhuinan primate, chicken and rat to chlorinated dibenzo-p-dioxin ingestion. Environ Health Perspect 5:233-240, 1973. Peterson, R. Hormonal changes and "wasting" observed in moderately-high-dose animal experiments. Presented at the Symposium on Public Health Risks of the Dioxins, The Rockefeller University, October 19-20, 1983. (Proceedings in press, Alan R. Liss Inc.) Poland A, Knutson JC. 2,3,7,8-tetrachlorodibenzo-p-dioxin and related aromatic hydrocarbons: Examination of the mechnanism of toxicity. Ann Rev Pharmacol Toxicol 22:517-554, 1982. Tofilon PJ, Piper WN. 2,3,7,8-tetrachlorodibenzo-p-dioxinmediated depression of rat testicular heme synthesis and microsomal cytochrome P-450. Biochem Pharmacol 31:3663-3666, 1982. 1 M a u r e e n C . H 2 a t c h RELEVANT EMPLOYMENT: Curriculum Vitae MAUREEN C. HATCH 412 Mountain View Road Englewood, New Jersey 07631 Home: (201) 569-4139 Business: (212) 694-3944 Born: 26 March, 1942 SS # 054-34-6077 EDUCATION: B.A., 1963: Manhattanville College, Purchase, N.Y. Graduate studies in urban planning, 1965-67: Hunter College, N.Y.C. M.P.H., Epidemiology, 1979: Columbia Unversity School of Public Health, N.Y.C. Ph.D., Epidemiology, 1983: Columbia University Graduate School of Arts and Sciences, N.Y.C. Thesis Topic: Paternal Risk Factors for Spontaneous Abortion. HONORS: 1977-79: N.I.C.H.D. Fellowship, Epidemiology of Mental Retardation and Other Developmental Disorders 1978: Selected for the Society for Epidemiologic Research Student Workshop PROFESSIONAL SOCIETIES: Society for Epidemiologic Research, Committee Occupational Reproductive Hazards COMPUTER SKILLS: Computer languages: Wylbur, UC360 Statistical software: SAS, SPSS, CROSSTABS M a u r e e n C . H a t c h 3 Hatch, M., Kline, J. Epidemiology Studies: Spontaneous Abortion and Exposure to the Herbicide 2,4,5-T. U.S. Environmental Protection Agency, Washington, D.C., 1981 (EPA 560/6-81-006). Stein, Z., Hatch, M., Kline, J., Shrout, P., Warburton, D. Epidemiologic Considerations in Assessing Health Effects at Toxic Waste Sites. In: Assessment of Health Effects at Chemical Disposal Sites, William W. Lowrance, Ed. The Rockefeller University, New York City, 1981. Edmonds, L., Hatch, M., Holmes, L., Kline, J., Letz, G., Levin, B., Miller, R., Shrout, P., Stein, Z., Warburton, D., Weinstock, M., Whorton, D., Wyrobek, A. Report of Panel II: Guidelines for Reproductive Studies in Exposed Human Populations. In: Guidelines for Studies of Human Populations Exposed to Mutagenic and Repro­ ductive Hazards, Arthur D. Bloom, Ed. March of Dimes Birth Defects Foundation, 1981. Kline, J., Stein, Z., Hatch, M., Strobino, B. The Role of Spontaneous Abortion Studies in Environmental Research. EPA Technical Report, 1983 (in press). Kline, J., Stein, Z., Hatch, M., Hutzler, M., Lai, A., Pantel-Silverman, J. Surveillance of Parental Occupational and Spontaneous Abortion. NIOSH Technical Report, 1983 (in press). Hatch, M. Occupational and environmental hazards to human reproduc­ tion. In: Double Exposure: Women's Health Hazards on the Job and at Home, Wendy Chavkin, Ed., Monthly Review Press, 1984 (in press). Stein, Z., Hatch, M. Outcomes of occupational exposures: Antenatal and postnatal impairment. In: Review of Occupational Ha­ zards to Reproductive Health, World Health Organization, Geneva, Switzerland, 1983, pp 79-91. Constable, J., Hatch, M. Herbicide exposure and reproductive outcome- an overview. In: Herbicides in War: The Long-term Effects on Man and Nature, A.W. Westing, Ed., New York: Taylor & Francis, Pubs., 1983 (in press). Hatch, M. Parental occupation and cytogenetic findings in abortuses. In: Reproduction: The New Frontier in Occupational Health, James Lockey, Grace Lemasters, William Keye, Eds., New York: Alan R. Liss, Inc., 1984 (in press). Hatch, M. Reproductive effects of the chlorinated dioxins. In: Public Health Risks of the Dioxins, William W. Lowrance, Ed., The Rockefeller University, New York City, 1984 (in press). -T> 1 i i ;/ M a u r e e n C . H a t c h A PRESENTATIONS: Hatch, M. Testing Clusters of Reproductive Anomalies to Screen for New Teratogens. Presented at the Society for Epidemiologic Research, Student Workshop on Epidemiologic Methods, Iowa City, Iowa, June 1978. Hatch, M. Environmental Hazards to Human Reproduction. Presented at the March of Dimes Nursing Symposium, New York City, March 1981. Hatch, M. Social Context, Concepts of Safety, and Occupational Epidemiology. Presented at the Conference on Work and Health, Case Western Reserve University, Cleveland, Ohio, April 1981. Hatch, M. Spontaneous Abortion as an Endpoint in Environmental Research. Presented at the Latin American Course on Genetic Toxicology, Mexico City, August 1981. Hatch, M. Reproductive Hazards in the Workplace: Research Findings, Research Issues. Presented at the New Jersey Family Planning League Symposium on Occupational Hazards and Reproductive Health, Clark, New Jersey, October 1981. Hatch, M., Kline, J., Stein, Z., Hutzler, M., Silverman, J . , Lai, A. Parental Employment and Spontaneous Abortion. Presented at the American Public Health Association Meetings, Montreal, November 1982. Hatch, M., Kline, J., Stein, Z., Hutzler, M., Lai, A., PantelSilverman, J., Parental Employment and Spontaneous Abortion. Presented at the Conference on Reproductive Health Studies in Industry, East Millstone, New Jersey, December 1982. Hatch, M. Reproductive Effects of Herbicide Exposure in Humans. Presented at the International Symposium on Herbicides and Defoliants in War: The Long-term Effects on Man and Nature, Ho Chi Minh City, Vietnam, January 1983. Hatch, M. Agent Orange and the Herbicide 2,4,5-T. Presented at the American Chemical Society Conference on Dioxins, Old Westbury, May 1983. Hatch, M. Environmental Influences on Reproduction. Medical Department Seminar, Brookhaven National Laboratory, Upton, Long Island, September 1983. Hatch, M. Environmental Agents and Aneuploidy in Human Spontaneous Abortions. Presented at the Environmental Protection Agency Workshop on Approaches for Assessing the Risk of Aneuploidy Induction by Chemicals, Washington, D.C., October 1983. Hatch, M. Reproductive Epidemiology. Presented as part of the University of Ottawa refresher course, Recent Advances in Occupational and Environmental Health, Ottawa, Ontario, October 1983. M a u r e e n C . H a t c h 5 CONSULTING EXPERIENCE: Council on Environmental Quality: Scientific advisory report entitled "Chemical Hazards to Reproduction." panel for Environmental Protection Agency: Reviewer for study by Dow Chemical Co. on the reproductive effects of occupational exposure to chlorinated dioxins. National Opinion Research Center: Reviewer for reproductive portion of survey instrument developed for the Air Force study of herbicide-exposed personnel. TEACHING EXPERIENCE: Coordinator for Columbia core course in epidemiology for public health students. Teaching Assistant and section leader for courses in epidemiology cancer epidemiology for public health and medical students. and A D D E N D U M Nonscientific Work Experience: 1963-64 Harper & Row Publishers: designed brochures , wrote jacket copy. 1964-68 Architects' Renewal Committee in Harlem, administrative assistant, junior planner. 1968-69 Model Cities Program, Hoboken, NJ: Planner. 1970-73 C. Richard Hatch Associates, Inc.: conceived and wrote educational materials on urban planning and ecology. 1973-76 Parttime freelance editing for such firms as Harry Abrams, Inc. and World Publishing Co. Scientific promotional Inc.: Meetings Attended in Addition to Those on CV: . Society for Epidemiologic Research, Iowa City, 6/78 . Society for Epidemiologic Research, New Haven, 6/79 or 6/80 . Birth Defects Symposium X: Human Embryonic and Fetal Death, Albany, 9/79 . Birth Defects Symposium XI: Human Mutation, Albany, 9/80 . American Public Health Association Meetings, New York City 1980 (?) . First Annual Symposium on Environmental Epidemiology, Pittsburgh, 4/80 . Changing Risk of Disease University, 10/81 in Women, Johns Hopkins Please note also that the last two papers mentioned on p.3 of the attached CV were originally presented at scientific meetings whose proceedings are currently in press; Reproduction: The New Frontier..., a symposium at the Rocky Mountain Center for Occupational and Environmental Health of the University of Utah, Park City, 4/83, and Public Health Risks of the Dioxins, a symposium at The Rockefeller University, 10/83.I I also attended an allegedly impartial scientific meeting on 2,4,5-T convened in June, 1980 (?) by Dr. Frederick Coulston, at which there were many Dow scientists whose names had not appeared on t original list of conferees. ALASTAIR W. M. HAY, Ph.D. I. QUALIFICATIONS Dr. Hay is a lecturer on Chemical Pathology, Department of Chemical Pathology, Old Medical School, University of Leeds, Leeds, England. His Curriculum Vitae is attached. A list of seminars, meetings and awards is also attached. II. SUBJECT MATTER Dr. Hay will provide background testimony on a broad range of matters relating to Agent Orange, phenoxy herbicides, and their contaminants, including 2, 3, 7, 8-TCDD. Dr. Hay will discuss in detail his knowledge of the various phenoxy herbicides and their contaminants, including but not limited to the various aspects of: chemistry; biochemistry; manufacture and/or production; fate in the environment, animals, and humans; modes of exposure, i.e. absorption, ingestion and in­ halation, specifically by the veterans who served in Vietnam; toxicity; and the state of the medical and scientific literature at various times since at least 1957 forward. Dr. Hay's testimony regarding the medical and scientific literature will include an exposition of the definitions and explanations, and their applicability to the troops exposed in Vietnam, of the phenoxy herbicides and their contaminants, in the following areas: plant physiology; toxicology; neuro-toxi- cology, both neurological and psychological; epidemiology; immunology; mutagenicity; teratology; embryotoxicity; reproductive toxicology; and carcinogenicity. III. SCIENTIFIC PRINCIPLES See General Statement of Scientific Principles and Assumed Facts attached. IV. SUBSTANCE OF OPINION* 1 Dr. Hay will testify to the following opinions: A. That phenoxy herbicides, including Agent Orange, and 2, 4, 5-T, and their contaminants, especially TCDD, are: 1. Highly toxic 2. Neurotoxic 3. Immunosuppressive 4. Teratogenic and Embryotoxic 5. Potentially Mutagenic 6. Carcinogenic. B. That there is no "minimum effect" level for 2, 3, 7, 8-TCDD and all other dioxins or, in other words, there is no known "safe level" for any human intake of 2, 3, 7, 8-TCDD and all other dioxins. V. GROUNDS FOR EACH OPINION A. General The medical and scientific literature, attendance and participation in various symposia, review of various documents of certain defendants, personal research, and experience form the bases of whatever facts and opinions to which Dr. Hay will testify. B. More specifically, the phenoxy herbicides, including Agent Orange, 2,4,-D and 2,4,5-T and their contaminants, including dioxin, especially TCDD, are: 1. Highly toxic McConnell, E.E., et al. Toxicology & Applied Pharmacology 44, 355-356 (1978); Schwetz, B.A., et al. Advances in Chemistry Series, ed. E. H. Blair, 120 55-69 (1973); Greig, J.B., et al. Food & Cosmetics Toxicology, 11,585-595 (1973); 2. Neurotoxic Kimmig, J. & Schultz, K. H. Dermatologica 115, 540-546 (1957); Bauer, et al. Archiv. Fuer Gewerbepathology un Gewerbehygin, 18,538-55 (1961) 3. Immunosuppressive Vos, J.G., & Moore, J.A. Internal Archives of Allergy and Applied Immunology 47,777-794 (1974); Faith, R.E., and Luster, M.I. Annals of The N.Y. Acad, of Sciences, 320, 564-571 (1979) 13383 4. Teratogenic and Embryotoxic Neubert, D., and Dillmann, I. Naunym Schmiedebergs Archives and Pharmacology (Berlin) 272 (3), 243-264 (1972) Neubert, D. Environmental Health Perspectives 5, 67-79 (1973); Courtney, K.D., and Moore, J.A. Toxicology and Applied Pharmacology, 20, 396-403 (1971); Courtney, K.D. Bulletin of Environmental Contamination and Toxicology, 16, 674-681 (1976); Smith, F.A., et al. Toxicology and Applied Pharmacology 38, 517-523 (1976) ; Moore, J.A., et a l . E n v iron­ mental Health Perspectives 5, 81-85 (1973); Sparschu, G.L., et a l . Food and Cosmetic Toxicology, 9, 405-412 (1971); Roll, R. Food and Cosmetic Toxicology, 9,671-676 (1971) 5. Potentially Mutagenic Rogers, A . M . , et a l ., Mutation Research 105, 445-449 (1982); Bronzetti, G., et a l . in Chlorinated Dioxins and Related Compounds: Impact on the Environment (pergamon Press, Oxford, NY (1982) pp 429-436; Hay, A. in The Chemical Scythe (Plenum Press, 1982) pp. 43 6. Carcinogenic Allen, et al., Chemosphere, 9,537-544 (1977) ; Kociba, R.J., et a l . T o x i ­ cology and Applied Pharmacology. 46, 279-303 (1978); Anonymous. Bioassay of 2,3,7,8-tetrachlorodibenzo-p-dioxin for possible carcino­ genicity (gavage study), National Cancer Institute DHHS Publication No. (NIH) 80-1757 (1980); Toth, K.S., et al. Nature (London) 278,548-549 (1979); Anonymous. National Cancer Institute Technical Report Series No. 123 (1979); Anonymous. Bioassay of a mixture of 1,2,3,6,7,8and 1,2,3,7,8,9-hexachlorodibenzo-pdioxin for possible carcinogenicity (gavage study), National Cancer Institute, Technical Report Series No. 198 (1980); Anonymous. Bioassay of a mixture of 1/2/3/6/7/8- and 1/2/3/7/8/9hexachlorodibenzo-p-dioxin for possible carcinogenicity (dermal study), National Cancer Institute, Technical Report Series No. 202 (1980) 1338 Dr. Hay will testify to examples of the grounds which support the above, including: knowledge of spraying Agent Orange, especially its effect on the Vietnamese countryside; the purpose and historical tracing of the animal studies; historical tracing of the human data, including the various industrial incidents since 1949 (Hay, A. The Chemical Scythe, Plenum, N.Y. (1982) pp 95-146); references to specific documents such as the EPA Dioxin document (presently in draft form); various cancer epidemiology; (Hardell, L. & Sandstrom, A. British Journal of Cancer, _39/ 711-717 (1979) ; Hardell, et al. British Journal of Cancer, 4_3, 169-176 (1981); Honchor, P.A. and Halperin, W.E. Lancet, I. 268-269 (1981); and Cook, R.R., Lancet, I. 618-619 (1981); pertinent teratology epidemiology (Hanity, J.A., et al., Science, 212, 349-351 (1981); Field, B., and Kerr, C. Lancet I. 1341-1342 (1979)); various studies of the Vietnamese (Tung, T.T., LaRevue de Medicine, 1_4 , 653-657 (1977)); especially reproduction toxicology (Constable, J. Report of the Workshop on Reproductive epidemiology. International Sym­ posium on Herbicides and Defoliants in War: The long term effects on Man and Nature. Ho Chi Minh City 13-20 January 1983; to be published in Herbicides in War. Ed. A.H. Westing, SIPRI); and those reports of the symptoms and diagnoses of the U. S. Vietnam veterans. C. The above will be relied upon to show that the is no "minimum effect" level for 2,3,7,8-TCDD or other dioxins. I33B 5 Name: Alastair Watt Macir.tyre HAY D.Q.B.: 2 1 Apr:1 19 47 Marital Status: Married Chi 1crer.: 1 son (Tom) Place of Birth: Glasgow, Scotland. Nationality: British Degrees: B.Sc.(Hons), Chemistry IIA - London 1969 Ph.D.. Biochemistry, London 1973 Home Address: School House, Arthington Lane, Arthington, Leeds LS21 1PE England. Work Address: Department of Chemical Pathology, Old Medical School, University of Leeds, Leeds LS2 9NL England. Place of Secondary Education: Gifford Technical High School, Bulowavo, Zimbabwe (formerly Rhodesia) Present Appointment: University lecturer in Chemical Pathology since April 1979 (University of Leeds) Leeds, England. Former Appointments: Research Fellow - Zoological Soc. of London September 1972 - November 1977 A Research Fellow - University of Leeds, Department of Animal Physiology and Nutrition December 1977 - March 1979 Societies: Biochemical Society Nutrition Society Expert Committees: 1983 EPA Review Panel on Dioxins for Environmental Criteria and Assessment Office. PUBLICATIONS : 4r Books 1. The Chemical Scythe: Lessons of 2,4,5-T Alastair Hay. Plenum Press. 265 pp. August 1982. and Dioxin. 2- Sean Murphy, Alastair Hay and Steven Rose. No Fire:- No Thunder. The threat of chemical and biological warfare. Pluto Press. (To be published in January 1984). 135pp. I> 1 V.. 1. Sjr.cioir, A. J., Fiennes. R.N.T.W., Hay, A.W.M., Watson. G., Crawford, M.A.. & Hart, M.G. Linolenic acic deprivation in Capuchin monkeys. Proc. Nutr. Soc., _33, 49A (1974). 2. Hay.A.W.M., Sinclair, A.J., & Ray, W.G. Some useful techmaues in thin laver chromatoaraphy. J. Lab. Pract. 483-484 (1974). ' ’ A simple macrotome. 73 3. Hay, A.W.M. & Ray, W.G. 24. 35 (1975). J. Lab. Pract. 4. Hay, A.W.M. Comparative aspects of vitamin D transport. In: Calcium Regulating Hormones (Excerpta Medica, Amsterdam). The Proc. of the 5th Parathyroid Conference, Oxford. pp 405407 (1975). 5. Hay, A.W.M. & Watson, G. Binding of 25-hydroxyvitamin to plasma protein in New World monkeys. Nature, 256, 150 (1975). 6. Hay, A.W.M. The transport of 25-hydroxycholecalciferol in a New World monkey. Biochem. J. 151, 193-196 (1975). 7. Hay, A.W.M. & Watson-, G. The plasma transport proteins of 25-hydroxycholecalciferol in mammals. Comp. Biochem. Bhysiol. 53B, 163-166 (1976). 8. Hay, A.W.M. & Watson, G. The plasma transportprotein of 25-hydroxychclecalciferol in fish, amphibia, reptiles and birds. Comp. Biochem. Physiol. 53B, 167-172 (1976). 9. Hay, A.W.M. The transport of vitamin D in the Giant Panda. Trans. Zool. Soc. Lone., _33_,■ 139-140. (1976). 10. Hay,A.W.M. Vitamin D transport in vertebrates. Soc. J. Anat. 121, 195 (1976). 11. Hay, A.W.M. A possible role for vitamin D. in vertebrate evolution. Proc. of the 2nd Internation Workshop on Calcified Tissues. (Abstract) . Isr. J. Med. Sci. _1_2, 31-32 (1976) . 12. Hay, A.W.M. & Watson, G. The binding of 25-hydroxycholecalcifer and 25-hydroxyergocalciferol to tissue binding proteins in a New World and an Old World primate. Comp. Biochem. Physiol. (1977). 56B, 131-134 13. Hay, A.W.M., & Watson, G. Vitamin D~ in vertebrate evolution. (1977). Comp . Biochem. Physiol. 56 B, 375-380 14. Hay, A.W.M. & Watson, G. Binding properties of serum vitamin D transport proteins in vertebrates for 24R, 2 5 -hydroxycholecalcif and 24S, 25-hydroxycholecalciferol in vitro. Comp. Biochem. Physiol. 58B, 42-48 (1977).. Proc. Anat. 13387 15. Hay, A.K..'-:. ' Viats on, G. Evolution o /itamir D serum transport pi-teins in vitamin D; Biochemical, Chemical and Clinical Aspects related to Calcium Metabolism (Ec. by Norman, A.W. et al) Walter de Gruvter," Berlin & New York (1977) pp 483-4S9. 16 . Hay , A..W.M. Vitamin D at Asi lomar. Report of 3rd Workshop on Vitamin D. Nature 266, 17- 18 (1977). 17. Hay , A.W.M. Combatting rickets. Nature 270, 289 (1977) 19. Hay, A.W.M., Darling, M. & Watson, G. Rickets and vitamin D metabolism in primates. Proc. Nutr. Soc. .37., 42A. (1978) . 20. Hay, A.W.M. Tetrachlorodibenzo-p-dioxin release at Seveso. Disasters 1(4) 289-308 (1977). 21. Hay, A.W.M. (1977) . Identifying carcinogens. Nature, 269, 468-470 22. Hay, A.W.M. (1978) . Seveso: No answers yet. Disasters 2., 163-168 23. Hay, A.W.M. Vitamin D transport (Review). series in Nutrition and Food (in press) . 24. Hay, A.W.M. Resurgence of Vitamin D. 426-427 (1978). 25. Hay, A.W.M. Halogenated Hydrocarbon Effects. 533-534. (1978). 26. Hay, A.W.M. & Jones, G. metabolites on Sephadex (1979) . 27. Hay, A.W.M. Accidents in trichlorophenol plants: a need for realistic surveys to ascertain risk to health. Proc. of N.Y. Acad. of Sci. 320, 321-324 (1979). 28. Rivers, J.P.W., Frankel, T.L., Juttla, S-, & Hay, A.W.M. Vitamin D in the Nutrition of the Cat. Proc. Nutr. Soc. 38., 36A (1979) . 29. Hay, A.W.M., Hassam, A.G., Crawford, M.A., Stevens, P.A., Mawer, E.B. & Case, L. The ability of la,25-dihydroxycholecalciferol to alter the fatty acid composition of phosphoglyceric in rat intestinal mucosa and smooth muscle in Vitamin D Basic Research and its Clinical Application (Ed. by Norman, A.W., et al). Walter de Gruyter, Berlin, & N.Y. (1979). r— 4 00 Hay , A.W.M. Vitamin D^ metabolism in New World prima tes. Proc. of the 3rd International Workshop on Calcified Tissues, Israel 6-9th March 1978 (in press). C.R.C. Handbook Nature, 273, Nature, 274, The elution profile of vitamin D 2 LH20. Clin. Chem. 25, 473-475 13388 - 30. Care. A.D., lckard, D.W., *1 - Ross, R.. I. A.W.M., Garel, j .m . & Reoel, J. A comparison of the effects of 25, 26-dihyd roxychclecalciferol (25,26-DHCC) and 24.25-DHCC on calcitonin secretion rate m vitamin D depleted pics. J. Endocrinology 85.. (2), 5 4p-55p (1980). 31. Fleming , J. Cooper, E.H., Hay, A.W.M., Morgan, D.B., and Tarapia, L. Tubul oprotei n u n a in Cancer Chemotherapy. La Ricerca Clin Lab. j_0, 135-141 (1980). 32. Hay. A. Nature, 33. Hay, A.W.M. Essential fatty acid restriction inhibits vitamin D dependent Calcium absorption. Lipids. 15, 251-4 (1980). 34. Intestinal, la. 25-dihydroxycholecaleiferol-dependent calcium absorption inhibited by essential fatty acid restriction. Proceedings of Nutri. Soc. .39., 89A (1980). 35. Halogenated hydrocarbon. of Science & Technology. 36. Hay, A.W.M. Exposure to TCDD: the health risks. Chlorinated dioxins and related compounds. Impact on the Environment. O. Hutzinger, et al. Pergamon Press, Oxford, N.Y. (1982) . 37. Fleming, J.J., Child, J.A., Cooper, E.H., Hay, A.M., Morgan, D.B. & Parapia, L. Renal tubular damage without glomeular damage after cytotoxic drugs and aminoglycoside Biomedicine J3_3, 251-254 (1980). 38. Hay, Alastair. New pathways for chlorinated dioxins. Nature. 294. 514-515 (1981). 39. Hay, A.W.M., Mawer, E.B., Hassan, A.G., Crawford, M.A. & Stevens, P.A. The Role of essential fatty acids in vitamin D dependent calcium absorption in the intestine. Proc. of 5th vitamin D workshop. Williamsburg, U.S.A. New in Vitamin D, chemical biochemical and clinical endocrinology of calcium metabolism. Walter de Guyter. Berlin, N.Y. (1982) pp309-311. 40. Hay, Alastair. Vitamin D: sunlight and precursors. Nature. 297, 364 (1982) . 41. Sheltawy, M., Hay, A.W.M., Hullin, R.P., and Morgan, D.B. Vitamin D 2 and D 3 in the nutrition of elderly. Clin. Sci. 6 2, 15-16 (1982) (abstract). 42. Hay, A. Herbicides, trichlorophenols and soft tissue sarcomas. Lancet I, 1240 (1982). Complecation of vitamin D metabolism still increasino 2 7s‘ . 509-510 (1979). Hay, A.W.M. McGraw-Hill in 1981 EST Yearbook ppl98-200. • '07 133C ) , - 5- 4 i. hay, A. It kills weeds, but what, about people? hew Scientist. j?4_, No. 1314 pplSS-161 (1982) 44. Hay, A., Murphy, S., Robinson, J.P. Sr Rose, S. The poison cloud hanging over Europe. New Scientist 93, No. 1296 ppe 30-6 25 (1982) 45. Hay, A. Experimental Toxicology and cytogenetics: an overview. Ir. "Herbicides and War" to be published by Stockholm International Peace Research Institute 1984 A. Vies ting. Edit. 46. Hay, A. The Mutagenic Properties of 2«3,7,8 -Tetrachlorodiben p-dioxin in "Chlorinated Dioxins and Dibenzofurans in the Total Environment. Vol II. Edit, by Keith, L.H. et al to be published in 1984. 47. Jones, C., Hay, A.W.M., Morgan, D.B., and Hullin, R.P. Response of the serum 25-hvdroxy vitamin D to minimal exposure to sunshin in patients in a long stay mental hospital. (abstract) To be published in November 1983 Proceedings of the UK Bone and Tooth Society. 48. Sheltawy, M., Newton, H., Hay, A., and Morgan, D.B. and Hull, R.P. The contribution of diet and sunlight to the plasma 25-hydroxy vitamin D. (abstract) to be published in November 1983. Proceedings of UK Bone and Tooth Society. 49. Feely, M., Hay, A., Clarke, N., Price, D., and Cooke, J. "mini-Dose" Phenobarbitone : A useful marker of compliance submitted to IUPH.AR 9th International Congress of Pharmacology 50. Sheltawy, M., Newton, H., Hay, A., Morgan, D.B., and Hullin, The contribution of dietary vitamin D and sunlight to the plasma 25-hvdroxy vitamin D in the elderly. Submitted to Clin:Leal Nutri Other■ Scientific Ar 1. Hay, Alastair. (1976) . 2 . Hay, Alastair. 270 (1976) 3. Hay, Alastair. (1976) 4. Hay, Alas tair. 310 (1976) . 5. Hay, Alastair. (1976) 6 . Hay, Alastair. 13390 Seven months on. 265, Nature, 490 (1977). 1 r \ . Ala s t a i r Hay, Sevesc: Dioxin damage. Nature 2 6 6 .7-8 (1977) . 8. Hay, Alastair. Zoo story. 9. Hay, Italy: 10 . Hay, Alastair. (1977) Seves o solicit u d e . 11 . Hay, Alastair. 571- 572 (1977) An aid to deve l o p m e n t ? Natu re, 12 . Hay, Roche's 267, 13. Hay, A l a s t a i r . (1977) . 90 Twelve months after Seveso. 14 . Hay, Alastair. Seveso Row. 15. Hay, Alastair. Timely delay. 16. Hay, Alastair. (1977). Informing on 2,4,5-T. 17. Hay, Alastair. 91-93(1977). Health and safety 3 years on. Nature, 270, 18 . Hay, Alastair. Combatting rickets. 2 70, 289 (1977) . 19. Hay, Alastair. 101-2 (1978) . Science Key to Vietnams Recovery, Nature 271, 20. Hay, Alastair. 271, 101-102 Science helps to rebuild Vietnam. (1978). Nature, 21. Kay, Alastair. Dioxin meeting recommends cancer study. Nature. 271, 202 (1978) . 22 . Hay Alastair. (1978) . Vietnams Dioxin Problem. 23. Hay, Alastair. 94-95 (1978). Vietnam calls its scientists to arms. 24 . Hay, Alastair. Israel's Scientist-President Resigns. 273, 93 (1978) . 25. Hay, Alastair. Vietnam extends scientific links. 273, 419 (1978) . 26 . Hay, Alastair. Commonwealth Science Council Coordinates approach to UNCSTD. Nature, 273, 697-698 (1978). 27. Hay, Alastair. Company's claim sparks fresh controversy over Seveso. Nature, 274, 108 (1978). Alastair. Alastair. Nature 267, Distant d r u m s . reply. 94-95 Natur e Nature. Nature, Nature, 267, 26 7, 30 1 (1977) 384-385 267, 74 9 (1977) Na ture, 268, 395 Nature, (1977). 268 (1977) 269, 279 (1977). Nature, 26 9, 749-^-750 Nature, Nature, 271, 597-598 273, Nature, Nature. 13391 i Hay. Alastair. Neurotcxins ir.av go unrecoonised. 274, 206 (1978). Dioxin source is 'safe'. Nature. 29. Hay, Alastair. (1578) . 30. Hay, Alastair. Vietnam still looking for foreign aid. Nature, 275, 6-7 (1978) 31. Hay, Alastair. Vietnam's scientists wait for books and equipment. Nature, 276, 203 (1978). 32. Hay, Alastair. Dioxin workshop. 33. Hay Alastair. Nature, 226, Health and safety research gets underway. 435-437 (1978). 34. Hay, Alastair. Switzerland to consider revised guidelines. Nature, 277, 341-342 (1979). 35. Hay, Alastair. Italian Commission covered up Seveso delays. Nature, 277, 588-589 (1979), 36. Hay, Alastair. Dioxin: the 10 year battle that began with Agent Orange. Nature, 278, 108-110 (1979) . 37. Hay, Alastair. UK ministry gives green light to 2,4,5-T. Nature, 278, 388 (1979). 38. Hay, Alastair. Complexities of vitamin D metabolism still increasing. Nature, 278, 509-510 (1979). 39. Hay, Alastair. Critics challenge data that led to 2,4,5-T ban. Nature, 279, 3 (1979). 40. Hay, Alastair. 41. Hay, Alastair. US Defense Department destroys evidence of Vietnam devastation. Nature, 279, 662 (1979). 42. Hay, Alastair. What caused the Seveso explosion? 273, 582-583 (1979). 43. Hay, Alastair. US scientists to join Italians in dioxin study. Nature, 221 338 (1979). 44. Hay, Alastair. Rickets under control again in UK. 279. 749 (1979). 45. Hay, Alastair. Vietnam veterans studied for herbicide exposure. Nature, 279. 667. (1979). 46. Hay, Alastair. (1979) . Skin toxicology. Nature, Nature, 276, 304 Nature, 279, 375 Handle us with care. 274, 526 (1978). (1979). Nature, Nature, Nature, 280, 8-9 13392 8 47 . Hay, Alastair. M a l f or ma ti on s at birth increased last year. . Nature, 2 8 0 , 184 (1979). 48 . Hay, 2S0, 49 . Hay, Alastair. Asbestos: 28 1. 172 (1979) . 50 Alastair. Press 623 (1979), banned from conference. killer dust, in Seveso Nature, says book. Nature, .Hav, Alastair. Seveso: the crucial questi on of reactor safety Nature. 28JL* 521 (1979). 51. Hay, Alastair. D i s pu te over Dow Chemicals traces. Nature, 2 8 1 , 619-620 (1979). 52. Hay, 282, 53. Hay, Alastair. EPA panel recommends p o s t p o n e m e n t of 2,4,5-T hearings. Nature. 282, 124 (1979). 54. Hay, Alastair. Short term tests can p r e di ct potential carcinogens, says study. Nature, 2 8 2 , 664 (1979). 55. Hay, Alastair. Dioxin as a health hazard. Nature, 2 8 3 , 229-230 (1980). 56. Hay, Alastair. Health m o n i to ri ng enda ng er ed at Seveso. Nature, 2 8 3 , 237 (1980). 57. Hay, Alastair. 58. Hay, Alastair. Study finds m a l nu tr it io n in Nature, 2 8 3 , 612 (1980) . 7 % of elderly. 59 Hay, Alastair. Ch em ic al company study shows hazard. Nature, 2 3 3 , 613 (1980). no dioxin 60. Hay, Alastair. Nature, 2 8 4 , 2 dioxin report. 61. Hay, Alastair. Dioxi n and 2,4,5-T: Nature, 2 8 4 . Ill (1980). 62. Hay, Alastair. (1980) . The CIA's 63 . Hay, Alastair. (1980) . Coalite health su rvey talks. 64 . Red faces Hay, Alastair. Nature, 2 8 6 , 97 (1980). 65 . Hay, Alastair. (1980) . Alastair. UK 5 (1979) . to tighten asbestos Dioxin detection. theory of dioxin controls. Nature, Book Review. 2 8 3 , 426 Ch emical company suppresses (1980) . A plea what are toxic agents. Nature, (1980). the risks? Nature, (and hot tempers) for 2,4,5-T. Nature, 2 8 4 , 296 Nature, 284, on 2,4,5-T. 2 8 7 , 659-570 13393 66 . H a y , A l a s f ■r . H e r b i c i d e safety: 4 - 5 (1931) . Bi. cure, Nature, of Health. " ' D C 67. Hay, Alas tai r . (193 1) - 68 . Hay, Alastai r . C h l o r i n a t e d diox in s and the environment. Nature. 289, 351-352, (1981). 69 . Hay, Alastair. Seveso: the intrigue and the infighting. Book Review. Nature, 2 9 0 , 71-72 (1981). 70'. Hay, Alastair. D i s p o s i n g of dioxins by oxidation. Nature, 290, 294, (1981). 71 . Hay, Alastair. (1981) . 72. Hay, A., Murphy, S., Robinson, Nature, ¿94, 204 (1981) . 73. Hay, Alastair. Spot the potential carcinogen. 296 , 100, (1982) . 74. Hay, Alastair. R e l a t i n g to halen at ed hydrocarbons. Nature, 296, 688 (1982). 75 . Hay, Alastair. (1982) . 76 . Hay, Alastair. The official's book of risky business. Book Review. Nature, 301, 640 (1983). 77. Hay, Alastair. De f o l i a n t s in Vietnam: Nature, ¿02, 208-209 (1983). 78 . Hay, Alastair. Empow er ed Nature, 305. 77 (1983) . 79 . Hay, A l a s t a i r . . .and its control. 305, 486 (1983) . 80 . Hay, Alastair. Fresh support for apian origin. 306. 8 (1983).1 Rickets at bay. Nature. S e c re cy at Coalite. J.P. Ch e m i s t r y at War. 289, Nature, 113 2 9 0 , 729, On Chemical War. Nature, the to set standards. Nature, 2 9 8 , 205-206 long term effects. Book review. Journal Review. Nature. Nature. 1 OOtfS i oa H A Y , A l a s t a i r W . M . Additional Papers 1. Paper: "Relationship between Sex Hormones and Fructose Metabolisms in Rat Liver"; Presented at Nutrition Society, London, December 7, 1972. 2. Participant: International Agency for Research on Cancer, NIEHS/IARC Working Group on the Coordination of Epidemiological Studies on the Long-Term Hazards of Chlorinated Dibenzo Dioxins-Chlorinated Dibenzo Phurons; Lyon, Lyon, France, January 10-11, 1978. 3. Member: Panel on Human Observation of the Consequences of Dioxon Exposure; Meeting: International Symposium on Chlorinated Dioxins and Related Compounds, Arlington, Virginia, October, 1981. 4. Paper: "The Role of Membrane Lipids in the Expression of Vitamin D Function in the Intestinal Nucosal Cell"; Presented at the Biochemical Society, London, December, 1981. 5. Paper: "The Manufacture of 2,4,5-Trichlorophenol and its Social Consequences"; Presented at the Royal Society of Chemistry, Education Division Meeting, Leeds, England, September, 1981. 6. Presentation: "Renal Toxicity to the Yorkshire Regional Health Authority Meeting on Aspects of Pathology:; Harigat, January, 1980. 7. Paper: "TCDD Mutagenic Property"; Presented at the International Symposium on Herbicides and Defoliants in War; Long-Term Effects on Man and Nature; held in Ho Chi Minh City, Vietnam; Also, repertoire of working group on experimental toxicology and cytogentics at this Conference. H E R B E R T I. K A Y E , P h . D . QUALIFICATIONS Dr. Herbert Kaye, Ph.D., is a psychologist in the Department of Psychology at the State University of New York at Stoneybrook, Long Island and a visiting Associate Professor in the Department of Psychiatry at New York University Medical Center. II. See attached curriculum vitae. SUBJECT MATTER OF TESTIMONY Dr. Kaye will testify concerning the significance of a battery of quantitative neurophysiological tests called neurometries which will be performed on various plaintiffs. The procedures were developed in part by Dr. Kaye in conjunction with medical and psychological researchers from this and other countries. He will testify that neurometries, on which he has written extensively, is a sophisticated battery of electrical tests in use for about fifty years, which are highly efficient in the determining cortical EEG and evoked responses. Dr. Kaye will explain the model used in the computerization against which the test results are compared and will explain how deviations from normal produce certain effects. Dr. Kaye will also discuss the mechanism by which toxins produce these altered responses, and what effect those altered responses have upon the individual veterans at present, and the prognosis for any additional changes or deterioration in the future based upon an assumed bioaccumulation of the toxic materials in the system. In doing so, he will rely on his experience in diagnosing many Vietnam veterans exposed to Agent Orange. I I I . G E N E R A L S C I E N T I F I C P R I N C I P L E S R E L E V A N T T O A R E A : The scientific principles arise from three general disciplines: neurophysiology, mathematics, and neuropsychology. The area of neurophysiology includes the work on neuro-anatomy, neurochemistry, neuropharmacology, and applied or clinical electrophysiology. The work in mathematics represents multivariate statistics. The work in neuropsychology includes direct and indirect brain-behavior research and clinical diagnostics. The neurophysiological basis of the development of neurometries is presented in Volumes I and II of Functional Neurosciences, published in 1977 by Lawrence Erlbaum Associates, publishers, Hillside, New Jersey. However, this work represents an integration of research and applications in the neurosciences over a period four decades, initiated with the seminal EEG work of Gibbs (see, for example, Atlas of Electroencephalography, Cambridge, Massachusetts, Addison-Wesley) W. Gray Walter (see, for example, Electronic Engineering, 1943, 16, pp. 9-13) and going through the specific and extensive quantitative work of Matousek and Peterson (Automation of Clinical Electroencephalography, New York, Raven Press, 1973, pp. 75-102) and current work by quantitative electrophysiologists such as A. S. Gevins, C. Shagass, Theodore Gasser, Enoch Calloway, T. M. Itil, L. Goldstein, and others. (See, for example, Neuro-psychopharmacology, Proceedings of the Tenth Congress of the Collegium Internationale Neuro-psycho-psychopharmacologicum, eighth relevant norm. (See John, et al., Science, Volume 210, 1980). Neuropsychological literature represents the third strand. This represents the melding of brain electrophysiology and other neurophysiological techniques with those of psychology, or the study of mental and behavioral processes. There is a huge literature in the area, and recent work by such researchers as Gevins, Galin, Tucker, Thatcher, Needleman, and others, as well as those studies of Dr. Kaye and his students and colleagues indicate that quantitative electrophysiology is valuable in diagnosing underlying cortical processes serving certain behaviors. IV. SUBSTANCE OF OPINION 1. Agent Orange represents a neurotoxic agent that works indirectly by affecting liver function and the liver's production of heme; and in doing so makes an individual, so affected, vulne^ible to neurohvpoxia. 2. Agent Orange may also work at a local level on enzymes relevant to the production and mobilizations of neurotransmitters. 3. Agent Orange, which is lipid, soluable, is likely to be stored in myelin and other fatty material and is collectively "time released" under "stress". 4. Storage is likely to be greater in the long fiber tracts, such as the major pathways from spinal cord to peripheral cutaneous receptors, pathways from frontal cortical regions to the thalimus and in spinal cortical motor pathways. 5. Changes in cortical functioning, represented by each EEG's slowing, represent breakdown of neural metabolic function occurring as a result of progressive neurotoxic assault. 6. Changes in cortical functioning represented by inter-hemispheric asymmetries and wave-shape incoherence represent the disruption of neural -4- timing either through the breakdown of cortical pacers, or through the failure of transcortical communication via the corpus collosum. 7. The occurrence of sharp-wave activity is caused by disruption of inhibitory neurotransmicters and represents a mechanism that can partially account for mood lability, which along with selective suppression of frontal lobe function would provide the basis for behavioral discontrol. V. GROUNDS FOR MY OPINION' A recent study by Needleman (Acta Psychiatrica-Scandinavica, 1983, Supplement No. 303, pp. 26-37) indicates the ability to utilize simple quantitative EEC spectral measures along with the pa chological measures to classify children from the "normal" population to have high and low lead levels (using Jentvne lead levels). The disreiminating variables for the EEC were the variables associated in our and inconventional EEG work with abnormalities; that is, excessive slow wave energy. Recent work in our evaluation unit has examined the abnormality profiles of thirty-two Vietnam veterans. In summary, approximately fifty percent showed spectral abnormalities, fifty percent showed power asymmetries, fifty percent showed wave-shape incoherence, and fifty percent showed sharp wave activity. In all, eighty-four percent showed some significant degree of abnormality. Correlation of these patients' neurometries profiles with other behavioral and physiological data is progressing. Specific correlation of neurometries profiles and behavioral reports of individual patients who were exposed to herbicides while engaged in non-military activities is also proceeding. Finally, there is a growing body of data relating research with people who were exposed to low levels of toxic material and who show the range of effects present in the Vietnam veterans exposed to Agent Orange. In particular, research on the mechanisms underlying heavy metal toxicity (such as with lead and wiih methyl mercury) suggests possible mechanisms for both neurotoxic and genetic effects. (See, for example, Chang, L.W. "Pathogenetic Mechanisms of the Neurotoxicity of Methyl Mercury" in Mechanism of Actions of Neurotoxic Substances, edited by K.N. Prasad and A. Vernagakis, Raven Press, New York, 1982; and, Egan, et al., "Experimental Design for Animal Toxicity Studies" in Experimental and Clinical Neurotoxicology, edited by P.S. Spenser and H.H. Schaumberg, Williams and Wilkins, Baltimore, 1980. 13400 -6- 1‘ Cinnicuhm l’Ita - HeA.be/iZ: Kaye. Vote Binth and Binthplace: Hay 23, 193 5, Hew Hon.li City Manital Status ■ Hannled, one child Fuslness Addness: Psychology Vepantment S.U.H.V. at. Stony Bnook Stony Snook, Hew Yank 1179C Phone.: (516) 246-7632 Clinic Addness: Heunometnlcs Evaluation Unit Hauppaugc Pno Sessional Puilding 111 Smithtown Bypass Hauppauge, Hew Honk 11717 Education: Rennslean Po.tytech. Institute., finom 9/53 to 1/56, faield: englneenlng Hunten College, £nom 1/56 to 6/56 Columbia Uni.ventity, {¡nom 7/56 to 7/60 B.S.C. (1/60), psychology Bnown University, 9/60 to 6/62, M.S.C. (6/ 62) , psychology Bnown Univensity, 9/62 to 6/64, Ph.V. [6/64], psychology Pnofaessionai Expe/Uence: Bnown Univensity, 7/64 to 1/66 Reseanch Associate, Vepantment Oq Psychology Emony Univensity, 9/66 to 6/67 Assistant PnoWesson, (joint position) Gnaduate School cft Psychology and In the Medical School, the Vepantment o£ Cbstetnlcs and Gynecology Emony Univensity, 7/67 to 3/71 Associate Pno^esson, (joint appointment] Gnaduate School o/ Psychology and In the Medical School, the Vepantments o^ Cbstetnlcs and Gynecology State Univensity o¡$ Hew Yank at Stony Pnook., 4/71 to pnesent Associate PnoWesson o$ Psychology Hew Yank Univensity Medical Centen, Vept. o P s y c h i a t n y Bnain Reseanch Labonatonles, 1977 to pnesent Visiting Associate Pno Wesson -1- 13401 »■’ * ' p A c fe is io n a l S qa . v a . c c . (7) Llyiivensity: ”.iAeetoA Institute for ReseoAch in Learning and Instruction: (i?77-7974) ViieetoA Vevelcpmaital Psychology pA.cgAam: f 797 7- 7976/ 7977 ;7 97g*;1 9%1-pAesent) Pe.paAtme.yit Executive Committee IS of 12 years th A o u g h 19S3-4 Academic year) VepaAim.ent Graduate Committee 12years) , department Undergraduate Committee [Z years) ViA.eci.oA. of Undergraduate Psychology PAcgAam (7°75-6} University Special Committees: (a) Peh.avioA.al M e d icin e (b) Chair Tenure Committee: Kenneth Code (c) Chair Special Education Committee Id) Pay Care (e.J Undergraduate Studies ( fj University Awards .Program of SJ'.M.V. ( 192?-S3) Vepaatment Special Committees: la) Applied Child and Family Concentration (hj Setting of S.C.V.C. on South Campus (c) Vay Care Vissentations and Theses: la) Ph.v's: 5 Students (6) Master's: 12 Stud eats (cj T huve been on about 15 disseAtaticn committees of students other than my own. ( Z} Outside University: Consulting EditCA: (a) Journal of ExpeAimertal Child Tsyeholugij {1967-1974) lb) Vevelopment Psychology 11969-1974) (c) J o u A n a l cf I n f a n t Behavior and Vevelopment ( 1976- fonward . ] Id) JouAnal o(J LeaAning Visabilities 11977-forward) (e) Child Vevelofoment 11977-1910; 19S5-forivard) Associate EditoA: JouAnal of LeaAning disabilities; Game's Application: Guest EditoA la) Science ( b) JouAnal Ayiim.al P.ehavicA (cj Psychological Review (d) S.R.C.V. Monograph ( G] Human. Vevelopment ( f ) P eh avicA P.eseaAch. Methods and 1 n stn u m en ta ticn (g) JouAnal exp. Child Psychology M. l.H. Member of, Clinical and. VcAScnality Fellowship Review-Committee ( 1970-75) N. S.F. Curst Reviewer of Research Grants 11°S2) A.C.I..P. /N.l.N.C.V.S 5 year SuppoAt Priorities Subcommittee 11971) (3) Outside Consultant Activities: Uacted. Motions VeveiopvienCTrogr.om (7 976-fcAwaAd) WoAid. Health Organization, Pan American Health. Organization (7 °7 l-l 910) Jamaica Ministry of Education and Mitrestry of Social Security 11979-1910) 14) Outside Committee Activities: 13402' Committee for Research' in Infancy lone of the founding members, 1°63) The VAazelton Infant PehavicA Seale (committee on use for pAematuAe infants, 1977.) Committee fcA Research in Infancy iRccoAd.ing secActary 1967; coorganizer of meet. -7- & B.O.C.E.S., I T I , Committee on Student Adjustment. CentcA, (Jhave seAved cu an occasional irembe.t $c a szv zao X s e k e d dlstAlats in Suffolk County in helping tc develop S p e d a i Fdetention f a c i l i t i e s . ! (I (¡ave s za v ed as an ou tside evaluation fcA tenute and/on /yiomction d z d s io r s qoa. pxcfes si orals a t 7 univzAsi.ti.es: Einstein. UnivcAsitu; C.H.d.Y.; PatgeAS Univttsily; UniveAslty of Connecticut; University of Ala Fama; University cf Illinois; and University cf Chicago.) dembzAship in PAofessiona l Asse dations: ' Sigma XI American Psychology A,i>soda.tien did Atlantic Asioc.ia.tLon cf Vevzlcpmzrtal Psychologists SLtffolk County Psycho logical Assentation JtitzA.nati.onal Conference fea Truant Studies Committee {¡OA PzseoAch in Infancy S c d c X y for Peseatch in Child Development d m Yo a Ii dento pi i Jeliological GAoup Infancy Ga o up of Mew YeAt d m Yca !z Academy cf Sdeners InteAnalicnal deuAcpsycholcgical S o d c i y S o d z t y fen the Kennesciences (pending) dationcJ. Academy of deuAopsychology (pending) JnteAnaiional S o d z t y fon the Study o¿ Infant Peh.avicA H cucas Ä.P.A. F ell ov:,V.Lv.csion 7, 1914 A.P.A. division 1 Candidate fen CAedentials Committee dZ/tAltl-PalmzA Annual Heeling: Keynote SpeakzA, 1972 Association of Childten with Lcanning Pisa b-il!ties : Special Pa z s entallo n: (1916-1c Association of ChlidAcn with Leatning disabilities ¡dolio nal Institute of d cuno loe and. Communicable Piscases and StAcke Special Ccmmltte.c on PeseoAch PKionitizu fOA Gov eAnment SuppcAt (1972) Pan American Health CAganizatlcn JnteAnaiional Workshop Participant.: Ejects of U.ateAnal dulAiticn on Jurants Health, Pandjachel, Guatemala, (1 979) GAants on ('.'kick J Was P d n d p l e Juves tig atoa qa Co-pAlndple Investigatea : d. J.CJT.D. Ïnfant VehavscA (1966-1 970) McCandless Fund: Early Language development (1967-1969) d.J.E. Hale/Female Differences In F.tee Wo Ad Associations (Ia69-70) S.U.H.Y. Biomedical Fund: Jnfant BehavloA (1972-1973] d.S.F./P.A.d.d. : Erain-Eekavion Pel alio ns hips (1971 -73; 73-76; 76-79) d.J.C.H.P. Jn^ant BehavlcA (197F-7S) Office of Education, E.E.H. (d.V.U. Hed. Centzn.) Brain function and Pemcdlatlon c Leatning P-Lsabltitles (1976-21) A^llllatlcn to Other GAants: U.d.P.P. datx.bbean~J!utJiiticnot. and. Jurant. High Pis!- Longitudinal Study H.ajcn Jnvited LectuAes (last 2 y ears) : &J".”17lAgsrja~Clfe SpdrTVevetejment Cenfietence: Pialectic AppAoach.es to Development Hethods (1976) S.P.C.V. CcnveAsaticn Holla, on Physiology Heosllaementó (1922) A.P.A. Conversation Holla with H. Kaye (1976) S.P.C.V. JntAoductoAy Speo.ker at Symposium: Ju ra n t Conditioning and Pevelop. (197 Hinnesota Sumpcsium en Development: Bacìi : Funatlcn in J dfancy (1 976) J.d.S. (Etiropean Division) CcmputzA Applicatiom in Heure psycho leg y (Jtaly, 1920] Hid-A.H. Pevel.opmcndtal Psychological Heelings (1921) A.C.L.V./d.J.d.C.P.S. ( 797S] 13403. ì Joint U.S.S.P-.-'.'.S. A. Ccná ca enee.: TheoAetlcal. Conceptuallzatloni o{) ExpeAlmental Methodology; U.P.: H.t (enfasi, (1QEC) S a c e l l i B oa . d n c d a l l e r , V ie tn a m V e tcA a n H ( s t a n i m i r i d i l o n; Su a v I vcah S y m p o n lu r , J 911 198? Ve.teAa.iu Acj e r i charge Victimó Anno e . (In v it e d V o A t l d p a n t , 1952) ( I have given about 30 leduAeA to local ¿chcol gaoupn, S p e d a i Education PaAentTea.ch.eAH Anne elation*,, and local. lnt.eA.eHt gA.oup¿ In the lant 5 yeoAH. ) V ie tn a m 13404 -4- TuXUaticns: "Developmental changes in the olfactony threshold of the. neonate" . Child. Vevetpm., 1965, 34_, 571-376. [with Lips-itt, L.P. and Engen, T.) "Two alter:]otS tc demonstnate tonal suppnession of non-nutnit.ive suck-uig in neonates." Pencep-t. Hot. Stull*, 1963, 1J_, 521-522. (with Levin, G.P.j "Conditioned sucLing in the. human newboAH." 29-3C, (with Lipsitt, L.P. J Psyehon. S e c . , 1963, 1, » "Clfaetcny nespenses and adaptation in ike. human neonate.." J. ccmp. physiol. Psychol., 56_, 1964, 73-77. (with Engen, T. and Lipsitt, L.PT1 "Skin Conduc-tance in ike Human Slecnate." Child. Vevelpm., 1964, 35, 1297-1305 "The relation of eteetxono.etu.al thAcs hold to basal skin conductance in the human neonate, Child Develpn., 1964, 35, 1307-1312. (with Lipsitt, L.P. "Hcn-nuinitive sucking by human neoiiate." (with Levin, G.R.) Child V evetpn., 1964, 35_, 4 79-755. "rnimany and seccndany punishment o f toe sue king in the infant nhesus monkey." Psychol. Sei., 1965, 3_, 73-74. (with Cox, J., Eosack, P., and A ndenson, K.) "Change in neonatat Acsponse to optimizing and non-optimizing ¿ueking ¿timiiation." Psyeh.cn. Sii..,1965, l, 221-222. [with Lipsitt, L.P.) "The eaiditioned Pafcfc.cn response in human new hen ns." 287-228 Psyehon.Sci., 1965, 2, "Qpenant Avoidance, in an infant nhesus within the finst month of life." Psyehon. Sei., 1965, 3, 371-372 "Reacting cf M. S'ulatta fnom binth." 16, 176-486. Labonatoni' Animat Cane Panel, 1966, "Enhancemetut cf neonatat ¿ueking through. Aeinfcncemcut." 1966, 163-168. (with Lipsitt, L.P. and Eosaek, T . ) J. Exp. Child Psychol. "Sucking behavicA in the kun:an infant: An evaluation of tie pAoeess aid its modification." Advances in_Child Development and Eeluivion, 1967, Til, 1-50. "The effects of feeding and tonal s-timu.lati.on on non-nu.tA.ltive su.ck.ing in the human nCwbonn." J. Exp. Child Psychol., 1966, 5, 146-154. (with Levin, G.P..) "Wonk decAemcnt and nest ncccveny cuning ncn-nutniti.ve sucking in the human neonate." J. Exp. Child Psychol., 1966, 3_, 146-154. (with Levin, G.P.) "Sensony Pnocesses in Infancy." In Reese, H. and Lipsitt., L.P. (eds.) Expenimeivtal. Child Psychology, Slew Vonk- Academic nness, 1969, l/cl. 3 "Agneemovt among Subjects in choosing .tAigAa.m. labels fon nandom shapes." Amen, J c u a . of Psychol., Dot. 83, Mo. 1, Stanch, 1970. "Effects of vaniatlcn of anal expedience upon suckle." In Posma, J. Qnal 13405 Publication!: (Coni’d.) Semotion and PcAcc.pid.cn, I'cl. 3, C. C. Thomas, H. V., 1973. "Feedback u o¿ ncunoivct-tlc cvaAuatlcniIn chlidncn. In: A P.othcnbcAç)Çfi {Ed.), Vcv etc ¡n:enti In deuA.oA.cg y, VaA. 6, 1983, pp. 11-31 :Eli evict Elom edlauí Pne¿¿ : Amitcndam. John, E . P.., Eaiton, P . , Pnlchep, L., Ahn, H., Kaye, H., and Poind, P. NeuA.ometA.lc geatuAei o & -chlldAen with. vanloiu cognitive, fiunctloni ofl imutcloglcaA. d.i&ofud.ifu. In: A. Pothenbengen ( F a . ) , VeveAcpmenti In NeuAoiogy, VoA. 6, pp 389-403. E-ti evict PlcmecLical P n H Z : Jmiictdojr.. B i b l i o g r a p h y Herbert Kaye, Ph.D. Baird, H.W., John, E.R., Ahn, H., and Maisel, E. Neurometric evaluation of epileptic children who do well and poorly in school. Electroencephalography and Clinical Neurophysiology, 1980, 48, 683-693. Bear, D.M. Temporal lobe epilepsy: Cortex, 1979, 15, 357-384. A syndrome of sensory-limbic hyperconnection. Bear, D.M., and Tedio, P. Quantitative analysis of interictal behavior in temporal lobe epilepsy. Arch. Neurol., 1977, 21» 454-467. Buchsbaum, Monte, S. The middle evoked response conponents and schizophrenia. Schizophrenia Bulletin, 1977, 2» 93-104. Carrie, J.R.G. The detection and quantification of transient and paroxysmal EEG abnormalities. In P. Kellaway and I. Petersen (Eds.), Automation of clinical electroencephalography. New York: Raven Press, 1973, 217-234. Chang, L.W. Pathogenetic mechanisms of the neurotoxicity of methylmercury. In K.N. Prosad and A. Vernadakis (Eds.), Mechanisms of Actions of Neurotoxic Substances. New York: Raven Press, 1982. Cohen, R., and Nardini, J. The correlation of bilateral occipital slow activity in the human EEG with certain disorders of behavior. Am. J. Psychiat., 1958, 115, 44-54. Duffy, T.E., and Plum, F. Hepatic encephalopathy. In I. Arias, H. Popper, D. Schachter, and D.A. Shafritz (Eds.), The Liver: Biology and pathobiology. New York: Raven Press, 1982. Dwyer, J.H., Karoly, Toth, and Epstein, S.S. Cancer clinical epidemiology in Viet Nam: Phenoxy Herbicides, primary hepatic carcinoma, and toxic neurasthenia. In A.H. Westing (Ed.), Herbicides in War: The long-term effects on man and nature. Stockholm: in press, 1984. Flor-Henry, P., Koles, L.J., Bo-Lassen, P., and Yendall, L.T. Studies of the functional psychoses: Power spectral EEG analysis. IRCS Medical Science: Biomedical Technology, Neurology and Neurosurgery: Psychiatry and Clinical Psychology, 1975, 2» 87. Gasser, T., Backer, P., and Mochs, J. Transformations toward the normal distri­ bution of broad band spectral parameters of the EEG. Electroencephalography and Clinical Neurophysiology, 1982, 52, 119-124. Gevins, A.S. Quantitative aspects of electroencephalography. In Michael Aminoff (Ed.), Electro-diagnosis in clinical neurology, 1981, 118-160. Gloor, P., Ball, G., and Schaul, N. Brain lesions that produce delta waves in the EEG. Neurology, 1977, 21_, 326-333. 134C8 Gotman, J., Skuce, D.R., Thompson, C.J., Gloor, P., Ives, J.R., and Ray, W.F. Clinical applications of spectral analysis and extraction of features from electroencephalograms with slow waves in adult patients. Electroenceph. Clin. Neurophysiol., 1973, 35^, 225-235. Giannitrapani, D. EEG average frequency and intelligence. Neurophysiol., 1969, 27_, 480-486. EEG and Clinical Girgis, M., and Kiloh, L.G. Limbic epilepsy and the dyscontrol syndrome. Amsterdam: Elsevier, 1980. Hecaen, H., and Albert, M.L. Human neuropsychology. New York: Wiley, 1978. Heifel, J., and Bohman, M. Benign epilepsy in children with centrotemporal EEG foci: Intelligence, behavioral, and school adjustment. Epilepsia (Vol. 6 ). New York: Raven Press, 1975, 679-687. Hodgson, E., Bend, J.R., and Philpot, R.M. New York: Elsevier Biomedical, 1982. Reviews in biochemical toxicology. Hoyumpa, A.M., Jr., and Schenker, S. Perspectives in hepatic encephalopathy. J. Lab. Clin. Med., V.100, 1982, 477-487. Ingemar Petersen, K.G., and Sellden, N. On the need to collect EEG data from so-called normal individuals. Clinical Neuropsychology. John, E.R. Functional Neuroscience, Vol. II, Neurometries: Clinical applications of quantitative electrophysiology. Hillsdale, NJ: L.E.A. Publishers, 1977. John, E.R., Easton, P., Prichep. L, Ahn, H., and Baird, H. Neurometric features of children with various cognitive functions or neurological disorders. In A. Rothenberger (Ed.), Developments in Neurology, Vol. 6 , 1983, 389-403. John, E.R., Kaye, H., Friedman, J., Prichep, L., and Ahn, H. and limitations of neurometries evaluations of children. (Ed.), Developments in Neurology, Vol. 6 , 1983, 11-33. Validity, utility In A. Rothenberger John, E.R. Prichep, L., Ahn, H., Easton, P., Friedman, J., and Kaye, H. Neurometric evaluation of cognitive dysfunctions and neurological disorders in children. Prog, in Neurobiology, Vol. 21, 1983, 239-290. Kamp, A., Schrijer, C.F.M., and Storm Van Leeuwen, W. Occurrence of "Beta bursts" in human frontal cortex related to psychological parameters. Electroenceph. Clin. Neurophysiol., 1972, 33_, 257-267. Kellaway, P., and Petersen, I. 'Quantitative analytic.studies in epilepsy. New York: Raven Press, 1976. Kiloh, L.G., McComas, A.J., and Osselton, J.W. Epilepsy. Clinical Electro­ encephalography (3rd Edition). London: Butterworths, 1977, 71-108. Koshino, Y., and Niedermeyer, E. in the electroencephalogram. The clinical significance of small sharp spikes Clinical Electroencephalography, 1975, 6^, 131-140. IS4C9 -2- Kulig, B.M., Meinardi, H., and Stores, G. (Eds.), Epilepsy and behavior '79. Proceedings of WOPSASSEPY I The first workshop on the Psychological Assess­ ment of Persons with Epilepsy, 1980, 132-139, 30-35, 90-97. Lockhard, J.S., and Ward, A. A. (Eds.), New York: Raven Press, 1980. Epilepsy; A window to brain mechanisms. Lopes De Silva, F.H., Van Hulten, K., Lommen, J.G., Storm Vein Leeeuwen, W. , Van Veelen, C.W.M., and Vlieganthart, W. Automatic detection and localization of epileptic foci. Electroencephalography and Clinical Neurophysiology, 1977, 43, 1-13. Luria, A.R. Higher cortical functions in man. New York: Basic Books, 1980. Mailman, R.B. Biochemical toxicology of the central nervous system. In E. Hodgson and F.E. Guthrie (Eds.), Introduction to biochemical toxicology. New York: Elsevier, 1980. Manzo, L. , Liery, N., LaCasse, Y., and Roche, L. New York: Pergamon Press, 1980. Advances in neurotoxicology. Matthis, P., Schiffner, D., and Benninger, C. Spectral analysis of the EEG: comparison of various spectral parameters. Electroencephalography and Clinical Neurophysiology, 1981, 52_, 218-221. Milner, B. Hemispheric specialization: Scope and limits. In F.O. Schmitt and F.G. Warden (Eds.), The Neurosciences: Third study program. Cambridge, Mass.: MIT Press, 1974, 75-89. Mirsky, A.F. Epilepsy, attentiveness and consciousness: Recent contributions from behavioral and physiological investigations. A summary and commentary. Contemporary Clinical Neurophysiology (EEG Suppl.), 1978, 34[, 269-275. New York State Department of Health. Dioxin Exposure: Report to the Governer and Legislature, April 1982. Article 24-B, Public Health Law. Nicholson, W.J., and Moore, J.A. Health effects of halogenated aromatic hydro­ carbons. Annals of the New York Academy of Sciences, Vol. 320, 1979. Nowak, S.M., and Marczynski, T.J. Trait anxiety is reflected in EEG alpha response to stress. Electroencephalography and Clinical Neurophysiology, 1981, 52, 175-191. Penry, J.K., and Daly, D.D. (Eds.), Complex partial seizures and their treatment. Advances in Neurology, Vol. II. New York: Raven Press, 1975. Perry, N.W., Jr., McCoy, J.G., Cunningham, J.C., Falgout, J.C., and Street, W.J. Multivariate visual evoked response correlates of.intelligence. Psycho­ physiology , 1976, 13, 323-329. Poland, A., and Knutson, J.C. 2, 3, 7, 8-Tetrachlorodibenzo p-dioxin and related halogenated aromatic hydrocarbons: Examination of the mechanism of toxicity. Annual Review of Pharmacology and Toxicology, 1982, Vol. 22, 517-554. -3 - Prasad, K.N., and Vernadakis, A. Mechanisms of action of neurotoxic substances. New York: Raven Press, 1982. Read, A.E. The EEG in liver disease. Butterworth, 1967. In A.E. Read (Ed.), The Liver. London: Rhodes, L.E., Dustman, R.E., and Beck, E.C. comparison of bright and dull children. physiology, 1969, 3_, 364-372. The visual evoked response: A Electroencephalography and Neuro­ Riley, T.L., and Massey, E.W. The syndrome of aphasia, headaches, and left temporal spikes. Headache, 1980, 20_(2) , 90-92. Riley, T., and Niedermeyer, E. Rage attacks and episodic violent behavior: Electroencephalographic findings and general considerations. Clinical Electroencephalography, 1978, £, 131-139. Shagans, C., Gershen, S., and Friedhoff, A.J. New York: Raven Press, 1977. Psychopathology and brain dysfunctic Shukla, G.D., Srivastava, O.N., Katiyor, B.C., Joshi, V. , and Mohan, P.K. Psychiatric manifestations in temporal lobe epilepsy: A controlled study. British Journal of Psychiatry, 1979, 135, 411-417. Simon, 0., Mullner, E., and Heinemann, U. Relationship between background activity and subclinical seizure pattern. Electroencephalography and Clinical Neuro­ physiology, 1976, 40, 449-455. v Sittenfeld, P., Budzynski, T., and Stoyva, J. Differential shaping of EEG theta rhythms. Biofeedback and Self-Regulation, 1976, 1_, 31-46. Survillo, W.W. Interhemispheric EEG differences in relation to short term memory. Percept, and Motor Skills, Vol. 31, 1971, 246-253. Sutton, S., Tueting, P., Zubin, J., and John, E.R. Information delivery and the sensory evoked potential. Science, 1966, 155, 1436-1439. Thatcher, R.W. Electrophysiological correlates of animal and human memory. In R.D. Terry and S. Gershon (Eds.), Neurobiology of Aging. New York: Raven Press, 1976. Thatcher, R.W., and John, E.R. Functional neurosciences: Vol. I, Foundations of cognitive processes. Hillsdale, NJ: L.E.A. Publishers, 1977. Thatcher, R.W. , McAlaster, R. , Lester, M.L. , Horst, R.L., and Cantor,. D.S. Hemispheric EEG asymmetries related to cognitive functioning in children. Publications of the Applied Neurosciences Laboratories, University of Maryland Medical School, 1983. Towe, A.L. Electrophysiology of the cerebral cortex: Consciousness in neuro­ physiology. J.C. Ruth, H.D. Patton, J.W. Woodbury, and A.L. Towe, Eds. W.B. Saunders Co., 1968, 455-464. 13411 -4 - Tucker, D.M., Stenlie, C.E., Roth, R.S., and Shearer, S.L.. Right frontal lobe activation and right hemisphere performance decrement during a depressed mood. Archives General Psychiatry, in press, 1983, 1-35. Wagner, S.L. Clinical toxicology of agricultural chemicals. Park Ridge, New Jersey: Noyes Data Corp., 1983. Walsh, K.W. Neuropsychology. Edinburgh: Churchill Livingstone, 1978. Walter, G. Intrinsic rhythms of the brain. In J. Field, H.W. Magoun and V.E. Hall (Eds.), Handbook of physiology, Vol. I. Washington; Am. Physiol. Soc. , 1959, 279-298. Ward, A.A., Penry, J.K., and Purpura, D.P. Epilepsy: Research publications: A.R.N.M.D., Vol. 61. New York: Raven Press, 1983. Waxman, S.G., and Geschivind, N. The interictal behavior syndrome of temporal lobe epilepsy. Archives General Psychiatry, 1975, 32./ 1580-1586. Wexler, B.E. Cerebral laterality and psychiatry: A review of literature. American Journal of Psychiatry, 1980, 137:3, 279-291. 13412 R I. O N A L D H . K E R M A N , P h . D . Qualifications Dr. Kerman is Associate Professor, and Chief, Cellular Immunology, Clinical Immunology Laboratories, the University of Texas Medical School at Houston. His Curriculum Vitae is attached. 11. Subject Matter Dr. Kerman will testify that the special scientific discipline involved is immuno-toxicology which has been defined as "the undesirable effects of an inappropriate response of the immune system". Dr. Kerman will discuss the following in his testimony: the immune system, with its organic, cellular, and hesroral components - most especially with regard to the latter, T-helper cells, 3-cells, immune response, plasma cells and immunoglobulin prodaition; both beneficial and harmful; the various experimental studies, particularly those demonstratin'.!! atrophy of the thymus, weight loss, depletion of lymphoid orpns, lymphopenia, thickness) cutaneous type delayed hypersensitivity jskin and altered bacterial immunity. I I I . S c i e n t i f i c P r i n c i p l e s See General Statement of Scientific Principles and Assumed Facts attached. IV . Substance of Opinions A. That TCDD is immunosuppressive- B. That a person exposed to TCDD might have increased predisposition to increased infection, neoplasm (cancer), V. and other diseases. Grounds for each opinion A. General The bases for the facts and opinions to which Dr. Kerman will testify include a review of the applicable medical and scientific literature, his educational and professional background, and his work in connection with the Texas Agent Orange Study. 13414 B. Specif ic As indicated above, Dr. Kerman will testify that 2,3, 7,8-TCDD in particular causes, among others, immuno-suppressive effects, as reported in the literature regarding the various animal species studies. Specifically, TCDD has been demonstrated to suppress T-cell mediated immunity in such species. effect likewise has been demonstrated This in humans by Bekesi, specifically an alteration of mature T-cells. A mort complete exposition of the substance and grounds for Dr. Kerman's opinions is set forth below. B e t w e e n 1 9 6 1 a n d 1 9 7 1 , t h e U n i t e d S t a t e s A i r F o r c e dropped more than 100 million pounds of herbicides is Vietnam to defoliate certain forest regions. Chief among the herbicidal agents used was "Agent Orange" which is a mixture of equal parts of 2,4-dichlorophenol (2,4,5-T). (2,4-D) and 2,4,5 trichloropheno 1 Agent Orange contains a toxic contaminant, 2 ,3 ,7 ,8 - 1 et r ach lo rod ib en z o - p-d iox in (variously referred to as TCDD or dioxin), which has been called by some authorities "the most potent small-molecule toxin known" (1 - 2 ). TCDD produces toxic effects in various mammalian species; the toxic manifestations often depend on the species. Guinea pigs are very sensitive to the toxic effects pf TCDD, the single LD50 dose for this chemical being less thaa 1 ug/kg body weight. about 100 ug/kg. The LD50 value for mice and rabits is The toxic effects of the chemical include hepatic damages, thymic atrophy, hematological alterations and teratological effects in various species (3-7). A consistent toxic effect of TCDD in various test animals is damage to the thymus gland. hymocytes A dose-related depletion of from this organ leading to cortical atrophy and hymic involution has been described in various species. Buu-Hoi et al (4) were first to suggest that sublethal doses of TCDD produced thymus atrophy and proposed that the thymus, liver and heart were the target organs of dioxin toxicity. Single or repeated toxic doses of TCDD caused a decrease in b o H $ Q "7 £ s weight and several vital organs and often reduced organ: body weight ratios. TCDD has been reported to cause a reduction of body weight rabbits and monkeys in guinea pigs, rats, mice, (as reviewed in 8 ). In all species, a consistent reduction in thymus weight was seen. This is often associated with atrophy of the thymic cortex subse­ quent to the gradual depletion of lymphocytes in this area at low doses of TCDD. Vos and co-workers (6 ) reported the effects of TCDD on the immune system of guinea pigs, rats and mice. Several tests were employed in these three species and the authors con­ cluded that the Effect of TCDD was primarily on cell mediated immune mechanisms of these animals. Guinea pigs treated with 1 ug/kg of TCDD per week either died or were moribund after 4 doses. At this dose and also at smaller doses 0.04 and 0.2 ug/kg), (0.008, guinea pigs showed severe loss of body weight, depleting of lymphoid organs, particularly the thymus and lymphopenia. primarily on the thymus. At sublethal doses the effects were In selected experiments, the treated and control animals were challenged with a subcutaneous dose of tetanus toxoid or an oil suspension of killed mycobacterium tuberculosis. One and two weeks after a second challenge 7 dose, the TCDD animals had significantly lower tetanus antitoxin titers. Similarly, TCDD animals displayed deceased skin thickness reactions when tested for delayed type hypersensitivity to intradermal tuberculin injections. Female albino rats treated orally with TCDD once a week for 6 weeks displayed reduced body and thumus weights (The relative thymus weight of TCDD treated vas about half of the controls). On the basis of these experiments Vos et al (6 ) concluded that TCDD suppressed the ce11-mediated immunity in guinea pigs, mice and rats. humoral immunity (antibody response) The in guinea pigs Vas also slightly suppressed. Thigpen et al (9) challenged groups of mice treated orally with TCDD to either Salmonella born or Herpesvirus suis. Treatment of mice with TCDD reduced the time of death, after bacterial challenge and also increased the mortality to S.bern. The influence of challenge to similar animals with H. suis influenced neither the period of death nor mortality rate. The conclusion was that treatment with TCDD had ¿i differential effect on bacterial vs. viral challenge. The possibility of alterations in phagocytic c e 11 - j uact ion or in the interaction of T-cells with phagocytic cells vas suggested. In similar experiments Dean et al (10) reported that mice treated pre and post natally with TCDD displayed decreased host resistance and increased susceptibility to bacterial challenge Additionally, (listeria monocytogenes). these mice were more susceptible to tusor for­ mation following challenge with PYBG tumor cells froa syngeneic transplantable tumors. Finally, these mice displayed depressed lymphoproliferative responses to PHA which correlated with the decreased host resistance. Sharma et al (11) reported that rabbits orally exposed to TCDD for 8 weeks and then innoculated with tetanus toxoid displayed depressed thymus and popliteal lymph node «eights. Serumantitetanus titers showed a decrease starting from 0.1 ug/kg. at treatmist levels Similarly, a significant decrease in the number of plasma cells in popliteal nodes was observed. Skin reactivity to tuberculin was depressed at all TCDD levels. These results were somehwat comparable to those reported in mice by Sharma and Gehring (12) using a similar protocol. It may be concluded that treatment of animals with TCDD produced effects on cell-mediated immune reactions at very low doses, whereas the effect on humoral immunity was observed at high dose levels. The effect on humoral immune responses may be an in­ direct one, produced by an initial suppression of T cells involved in such mechanisms. Recently, Clark et al (13) reported on the chronic immunocoxic effects of TCDD in mice. doses of 1 0 0 Total ug/kg or greater produced cellular depletion in thymus, spleen and lymph nodes and the animals appeared sick. The antibody response to sheep red blood cells was impaired following 40 ug/kg TCDD, the delayed hypersensitivity response to oxazolone was impaired by 4 ug/kg and the generation of allo-antieen specific cytotoxid T-cells to as little °.004 ug/kg TCDD. (CTL) was sensitive In vitro analysis of the mechan­ ism of suppression indicated generation of cells capable of suppressing CTL generation in vitro following TCDD. Several studies have been reported where exposure of animals to TCDD has been shown to decrease the responsiveness of lymphocytes to various mitogens in culture. Exposure of rats to various doses of TCDD, pre and postnatally through maternal treatments decreased the synthesis of DNA by splenic and thymic lymphocytes when cultured in the presence of PHA (14). The decreased responsiveness of thymus cells to mitogens, together with the fact that there was depletion of cells in the thymus, suggest a strong immunosuppressive effect of TCDD. A similar effect to that described above for rats was observed in mice and rabbits when these animals were challenged with an appropriate antigen (tetanus toxoid). The effects of a single dose of TCDD in suppressing mitogen responsiveness was most marked in younger animals (1 0 ). The influence of direct addition of TCDD to mouse splenic cultures was reported by Sharma and Gehring (12). TCDD decreased the unstimulated DNA synthesis in lymphocytes at concentrations as low as 10 -9 M. The relative effect of mitogens such as PHA and PWM was also reduced. Luster and co­ workers exposed spleen cells to TCDD and reported DNA, RNA and protein synthesis in spleens were inhibited. In man several episodes of accidental or purposeful exposure to TCDD have occurred including 1) Sevese, Italy, 1976 where a transient decrease in lymphocytes was reported (15); 2) Monsanto incident, communications) 1949 (Bekesi, personal reporting alterations in mature T cells and 3) the United Kingdom incident at Coalite in a Transcript (reported out from EPA Cancellation Hearings on 2,4,5-T and Silvex (November 14, 1980) wherein the highly exposed group was observed to display depressed PHA response and IgM and IgD immunoglobulin levels. This brief review (as cited above) TCDD is a potent immunosuppressive. indicates that What is most distressing and of greatest concern is the data reflecting decreased immunocompétence following TCDD exposure leading to increased susceptibility to infection and/or possible tumor challenge in experimental animals. inbalance in immunoregu 1 ation. It indicates a fundamental R E F E R E N C E S 1. Poland, A. and Glover, E.: 2 ,3,7 ,8 -Tetrachlorodibenzo-p-dioxin; a potent inducer of aminolevulinic acid synthetase. Science, 179: A 7 6 , 1973 . 2. McConnell, EE, and McKinney, J.D.: Exquisite toxicity in the guinea pig to structurally similar halogenated dioxins, furans, biphenyls and naphthalenes. Toxicol. Appl. Pharmacol. 45: 298, 1978. 3. Gupta, B.N., Vos, J.G., Moore, J.A., Zinkl, J.G., and Bullock, B.C.: Pathologic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in laboratory animals. Environ. Health Perspect. 5:125, 1973 4. Buu-Hoi, N.P., Chanh, P.H., Sesque, G., Azum-Gelade, M.C., and Saint-Ruf, G.: Organs as targets of dioxin intoxication. Naturwissenschaften. 59: 174, 1972 5. Vos, J.G., Moore, J.A., and Zinkl, J.G.: the Immune System of Laboratory Animals. Perspect. 5:149, 1973. Effect of TCDD on Environ. Health 6 . Zinkl, J.G., Vos, J.G., Moore, J.A. and Gupta, B.N.: Hematological and clinical chemistry effects of TCDD. Environ. Health Perspect. 5, 111, 1973 7. Courtney, K.D. and Moore, J.A.: Teratology studies with 2,4,5-T and TCDD. Toxicol. Appl. Pharmacol. 20: 396, 1971 8 . Sharma , R.P.: Effects of TCDD on immunologic systems, in Immunologic Considerations in Toxicology (R.P. Sharma, ed) pg. 89, CRC Press, Inc., Boca Raton, Florida 9. Thigpen, J.E., Farth, R.E., McConnell, E.E. and Moore, J.A.: Increased susceptibility to bacterial infection as a sequela of exposure to an environmental contaminant TCDD. Infect. Immun. 12: 1319, 1975. 10. Dean, J.H., Luster, M.I., Boorman, G.A., Padarathsingh , M.L., Luebke, R.W. and Clements, M.E.: Host resistance models as endpoints for assessing immune alterations following chemical exposure: Studies with Diethy1stilbest jo 1, cyclophosphamide and 2,3,7 ,8 - 1 etrachlorodibenzo-p-dioxin in Biological Relevance of Immune Suppression as induced by genetic, therapeutic and environmental factors, (Dean, J.H. and Padarasthingh, M.D., eds), Pg. 233, Van Nostrand Reinhold Co., New York Sharma, R.P., Kociba, R.J. and Gehring, P.J.: Immunotoxicologica1 effects of TCDD in mice and rabbits. J. Environ Pathol. Toxicol. (In Press). Sharma, R.P. and Gehring, P.J.: Effects of TCDD on Splenic Lymphocyte transformation in Mice after Single and Repeated Exposures. Ann N.Y. Acad. Sci. 320: 487, 1979 Clark, D., Gauldie, J., Szewczuk, M.R. and Sweeney, G.: Enhanced suppressor cell activity as a mechanism of Immuno­ suppression by TCDD. Proc. Soc. Expt.l. Biol. Med. 168: 290, 1981. V o o , J.G. and Moore, J.D. : Suppression of cellular immunity in rats and mice by maternal treatment with TCDD. Int. Arch. Allergy 47: 777, 1974 Reggiani, G.: Medical problems raised by TCDD contamination in Seveso, Italy. Arch. Toxicol. 40: 161, 1978. CURRICULUM VITAE Ronald H. Kerman, Ph.D. DATE OF BIRTH: June 10, 1943 PLACE OF BERTH: Chicago, Illinois NATIONALITY: U.S. Citizen SEX: Male EDUCATION: 1965 1967 1969 University of Illinois, B.S. (with Honors) University of Illinois, M.S. University of Illinois, Ph.D. in Immunology HONORS: 1965 1967-1969 1967 1969-1971 1970 Bachelor of Science with General Honors in the College Recipient of Public Health Service Predoctoral Traineeship Phi Sigma National Biological Honorary Recipient of Public Health Service Postdoctoral Traineeship Society of Sigma Xi RESEARCH AND PROFESSIONAL EXPERIENCE: 1983- 1981- 1977-1980 1974-1977 1973-1977 1972-1973 1969-1971 Associate Professor Department of Pathology, and Chief, Cellular Im­ munology, Clinical Immunology Laboratories, The Uni­ versity of Texas Medical School at Houston Associate Professor Department of Surgery, and Head, Histocompatibility and Immune Evaluation Laboratories, Division of Organ Transplantation, The University of Texas Medical School at Houston Member, Program in Immunology, Graduate School of Bio­ medical Sciences, The University of Texas Health Science Center at Houston Assistant Professor Department of Surgery, and Head, Histocompatibility and Immune Evaluation Laboratories, Division of Organ Transplantation, The University of Texas Medical School at Houston Assistant Professor Department of Surgery, Loyola University Sritch School of Medicine, Maywood, Illinois Research Immunologist Chief, Immunobiology Research Laboratory, Research Service, V. A. Hospital, Hines, Illinois Assistant Professor Department of Microbiology, Jefferson Merfeal College Postdoctoral Fellow, (Immunology) Children's Hospital of Philadelphia and The University of Pennsylvania School of Medicine Curriculum Vit.ie Ronald H. 1\ormati. Ph.D. 2 PROFESSIONAL SOCIETIES: The Transplantation Society (Editorial Board, Trans­ plantation and Member, Symposium Committee) American Association of Immunologists American Association for Cancer Research New York Academy of Sciences American Society of Transplant Physicians (Kember, and Vice Chairman, Scientific Studies Committee) Society for Experimental Biology and Medicine International Society for Heart Transplantation American Association for the Advancement of Science American Society for Histocompatibility and Immunogenetics (Chairman, Finance and Audit Committee, and Member, Laboratory Accreditation Committee) RESEARCH INTERESTS: Immunologic response to allotransplantation and malignancy Evaluation of immunocompetency RESEARCH SUPPORT: 1974-1978 1976-1979 1976- 1980 1977- 1973 197719771983-1984 OTHER ACTIVITIES: Co-principal Investigator: Bronchogenic Carcinoma: Immu­ nologic Profile, Radio and Immunotherapy - V.A. Medical Research Grant No. MRIS-8121-08. $213,009 Co-principal Investigator: Immunotherapy Adjuvant to Radiotheraoy of Head and Neck Cancer - VTA. Medical Research Grant No. MRIS-8121-06. $78,814 Co-principal Investigator: Factors Influencing Immuno­ compétence in Human Transplantation - V„A. .Medical Research Grant No. MRIS-3068. $68,770 Principal Investigator: Functional and Surface Receptor Differences of Human T-lymphocyte Subocpulations General Research Support Funds, The Diversity of Texas Medical School at Houston. $5,000 Principal Investigator: The Role of HLA Typing in Renal Transplantation, ESRD Program, No. 4500S& $377,400 (last year) Principal Investigator: Immune Monitoring for tbe Diagnosis of Renal Allograft Rejection, ESRD Program, No. 450068. $544,800 (last year) Principal Investigator: Immune Evaluation d Veterans Exposed to Agent Orange. Texas Veterans Agent Orange Assistance Program, IAC(83-84)1266. $93,3$ï Special Consultant in Immunology to the Epideaiology and Disease Control Study Section, NIH Consultant in Immunology and Histocompatibility Testing to the Department of Laboratory Medicine, .’O . Anderson Hospital and Tumor Institute Consulting Immunologist to the Upjohn and S®ebz Pharma­ ceutical Companies Editorial Board, Transplantation Review of manuscripts for the journal Human fcnmunology Review of manuscripts for the journal Transpiration Review of manuscripts for the journal Heart Transplantation Book reviewer for Journal of American MedicaSJssociation Literature Reviewer for The American Ansjciation of Clinical Histocompatibility Testing — AACBSion News Curriculum Vitae Ronuld 11. Kerman, Ph.D. 3 Grant Reviewer for the Kidney Foundation of Canada Grant Reviewer in Transplantation Immundbgy for The March of Dimes - Birth Defects Foundation Outside Reviewer of Research Proposals in Iramunology for the Research and Development Committee, The Vet­ erans Administration Research Service Invited Participant (as a testing laboratory) in The Third American HLA Workshop Invited Participant (as a testing laboratory) in The Eighth International Histocompatibility Workshop "Relevance of DR typing to renal allograft survival" Invited Participant (as a testing laboratory) » The Inter­ national Transfusion and Transplantation Wsekshop Invited Participant (as a testing laboratory) i>r the Ninth International Histocompatibility Workshop Invited Presenter at an Nil! Workshop, ”716 Biological Relevance of Immune Suppression as induced by Genetic, Therapeutic and Environmental Factors" Invited Participant (as a testing laboratory) in the Inter­ national Collaborative Transplant Study Laboratory Inspector for Clinical Laboratory Accreditation in Histocompatibility for The American Soeiety for His­ tocompatibility and Immunogenetics and Tbe College of American Pathologists Chairman, Finance and Audit Committee for "Rte American Society for Histocompatibility and Immunofsnetics Member, Symposium and Affiliations C osaittee, The Transplantation Society Member and Vice-Chairman, Scientific StudiesCommittee, American Society of Transplant Physiciuns Member, Acquired Immune Deficiency Synskome (AIDS) Working Group for the Houston Area Chairman, Organizing Committee and Host for The Fourth International Immune Monitoring Symposium: Im­ munological Evaluation and Monitoring of Transplant Recipient (1983) Member, Organizing Committee for the International Sym­ posium on Relevant Immunological Factors in Clinical Kidney Transplantation, Heidelberg, West Germany, 1985 Member, UTMSH Admissions Interview Committee Member, UTMSH Admissions Committee Member, Medical Review Board, Organ TrasDlantation Center, UTMSH Member. Committee on Subject Selection for T> University of Texas System Agent Orange Study Member, Steering Committee, Program in Immunology, UT-GSBS Chairman. Bv-Laws Committee, Program in feimunolojy, UT-GSBS" Course Director, "Methods in Cellular Immuiwkgy," a Pro­ gram in Immunology Course, UT-GSBS BIBLIOGRAPHY Ronald II. Kerman, Ph.D. Publications 1. Kerman. R., Segre, D. and Myers, W.L.: Altered response to pneumococcal polysaccharide in offspring of immunologically paralyzed mice. Science 156:1514, 1967. 2. Kerman. R., Segre, D. and Myers, W.L.: The role of immune and natural specific antibodies in immunologic paralysis and immunity of mice to pneumococcal polysac­ charide Type III. J. Immunol. 104:655, 1970. 3. Kerman, R. and Segre, D.: Anti-pneumococcal polysaccharide Type III hemolytic plaques in mice: Cellular response in immunity and immunologic paralysis. J. Immunol. _104:1262, 1970. 4. Kerman. R. and Harris, T.N.: Resistance to dénaturation by periodate of a diaiyzable histocompatibility antigen. Proc. Soc. Exp. Biol. Med. 141:175-183, 1972. 5. Kerman. R.H., Harris, T.N. and Harris. S.: Preparation of a diaiyzable histocompati­ bility antigen from balb/c mice. Proc. Natl. Acad. Sci. 69:223-227, 1972. 6. Smith, R.A., Kerman, R., Ezdinii, E. and Stéfani. S.: A modified assay for the detection of human adult active rosette forming ceils. J. Immunol. Meth. 8:175-184. 1975. 7. Kerman. R. and Stefani. S.: Immunological evaluation of patients with solid tumors before ar.d after radiotherapy. In Crispen, R.G. (od.): Neoplasm Immunity. Mecha­ nisms, pp. 109-120. University of Illinois Press, 1976. 8. Stefani, S., Kerman, R. and Abbate, J.: Immune evaluation of lung cancer patients undergoing radiation therapy. Cancer 37:2792-2796, 1976. 9. Stefani. S., Kerman, R. and Abbate, J.: Serial studies of immunocompetence of patients undergoing radiotherapy for malignancies of the head and neck. Am. J. Roentgenol. 126:880-886, 1976. 10. Kerman, R.H. and Geis, W.P.: Total and active T-cell kinetics in renal allograft recipients. Surgery 79:398-407, 1976. 11. Kerman. R., Smith, R., Stefani, S. and Ezdinii. E.: Active T-rosette forming cells in the peripheral blood of cancer patients. Cancer Res. 3^:3274-3278, 1976. 12. Kerman, R., Smith, R., Ezdinii, E. and Stefani, S.: Unification and technical aspects of total T, active T and B lymphocyte rosette assays. Immunol. Comm. 5(7-8):685694,1976. 13. Dodson, M.G., Kerman, R.H., Lange, C.F., Stefani. S. and O’Leary, J..A.: T and B cells in pregnancy. Obstet. Gynecol. 49:299-302, 1977. Bibliogmony Ronald 11. Kerman. Ph.D. * 14. Korman. R.H. and Stefani. S.: PHA stimulation of lymphocytes from patients with lung cancer. Oncology 34:10-12, 1977. 15. Kerman. R.H. and Stefani, S.: Radio and immunotherapy of lung cancer: A preliminary rcoort. In Crispen, R.G. (ed.): Neoplasm Immunity-Solid Tumor Therapy, pp. 29-35. Franklin Institute Press, 1977. 16. Stefani, S. and Kerman, R.H.: Lymphocyte response to PHA before and after radiation therapy in patients with carcinomas of the head and neck. J. Laryngol. Otol. 91:605-6091 1977. 17. Kerman, R.H., Ing, T.S., Hano, J.E. and Geis, W.P.: Prognostic significance of the active T-RFC in renal allograft survival. Surgery 8_2:607—612, 1977. 18. Marshack, M., Toto, P. and Kerman, R.H.: Delayed hypersensitivity in the hamster cheek pouch. J. Immunol. Meth. _15:325-330. 1977. 19. Marshack. M., Toto. P. and Kerman. R.H.: Immunotherapy of chemically-induced tumors in the hamster cheek pouch with dinitrochlorobenezene. J. Dental Res. 57:625-630, 1973. 20. Stefani. S. and Kerman. R.: Prognostic significance of pre-therapy delayed hypersen­ sitivity and T-celi levels in patients with lung cancer. In Nieburgs, H.E. (cd.k Proceedings of the Third International Symposium on the Detection and Prevention of Cancer. Voi. 1, Part U, pp. 785-797. Marcei Dekker, inc., 1978. 21. Geis. W.P.. Iwatsuki. S., Molnar, Z., Giacchino, J.L., Kerman, R.H., Ing, T.S. ana Hano, J.E.: Immunoblastic pseudo-lymphoma in renal allogratt recipients. Arch. Surg. H3:461-466, 1978. 22. Dodson, M., Klegerman. M., Kerman, R.H.. Lange, C., Tessler. J. and O'Leary, J.: Bechet syndrome: With immunologic evaluation. Obstet. Gynecol. 5_l:621-625, 1978. 23. Dodson, M.G., Klegerman, M.E., Menon. M., Kerman. R.H., Lange, C.F. and O'Leary, J.A.: Establishment and characterization of a squamous ceil carcinoma of the vuiva in tissue culture and immunological evaluation of the host. Am. J. Obstet. Gvnecoi. 1_31_:606-519, 1978. 24. Kerman, R.H. and Geis, W.P.: T-RFC monitoring of CMI events in renal allograft recipients. Transpl. Proc. _H)(3):633-635, 197S. 25. Kerman, R.H., Ing, T.S., Hano. J.E. and Geis. W.P.: Predictive value of active T-RFC in renal allograft survival. Transpl. Proc. ]_0(3):637-638, 1978. 26. Kerman, R.H. and Stefani, S.S.: Effect of BCG immunotherapy on the active T and total T-RFC in patients with lung cancer. Cancer Immunol. Immunothcr. 4:41-47, 1978. 27. Kahan, B.D.. Kerman, R.H. and McConnell. R.: Combination of immunological and radionuclide techniques to diagnose allograft rejection. Surgical Forum. 29:364-366, 1973. ‘ ' _ 13429 Bibliography Ronald II. Kerman. Pli.D. 3 ‘23. Stefani. S. and Kerman. R.H.: Prognostic value of the immunologic profile in inoperable lung cancer patients treated by radiation. In Muggia. F. and Rozencweig, M. (eos.): Lung Cancer (Progess in Cancer Research and Therapy), Vol. 11, pp. 465470. Raven Press. Inc., New York. 1979. 29. Kerman. R.H.: Identification of human T and B lymphocytes. In Natelson, S., Pesce, A.J. and Dietz, A.A.: Clinical Immunochemistry: Chemical and Cellidar Bases and Applications in Disease, pp. 12-20. American Association for Clinical Chemistry, 1979. 30. Kahan, B.D., Floyd, M., Oka, T., Van Buren, C.T. and Kerman, R.H.: Immunological techniques in clinical renal transplantation. I. Cross-Match Methods, Jap. J. Trans­ plant. 14:1-13, 1979. 31. Kahan. B.D., Floyd, M., Oka. T., Van Buren, C.T. and Kerman. R.H.: bnmunological techniques in clinical renal transplantation. II. Immunological Monitoring Postallografting. Jap. J. Transplant. J_4:14-25, 1979. 32. Kerman, R.H.. Floyd, M., Conner, \V., McConnell, R., McConnell. B.J.. Van Buren. C.T. and Kahan. B.D.: Combined immunological and radionuclide techniques to monitor renal allograft rejection. Transpi. Proc. 1_1:1229-1231, 1979. 53. Geis. W.P., Giacchino, J.L., Buckingham, J.M., Bansal. V.K.. Iwatsuki.. S„ Kerman, R.H.. Ing, T.S. and Hano. J.E.: Does suppression of T-RFC determine in vivo immunosuppressive effe ct of ATG? Transpl. Proc. _U: 1433-1434, 1979. 34. Kerman. R.H.. Floyd, M., Van Buren. C.T. and Kahan, B.D.: Improved allograft survival of strong immune responder-high risk recipients with adjuvant ArG therapy. Transplantation 30:450-454, 1980. 35. Kerman, R. and Kahan, B.D.: Clinical histocompatibility testing in renal transplanta­ tion: Potential keys to alloimmune specificity and reactivity. In Reisàdd, R. and Ferrone, S. (eds.): Current Trends in Histocompatibility, Vol. 2, pp. 20I-Î26. Plenum Press, 1981. 36. Kerman, R.H. and Kahan, B.D.: Assessment of immune parameters « transplant recipients on immunosuppressive therapy. In Dean. J. and Padarathsingh, M. (eas.): Biological Relevance of Immune Suppression as Induced bv Genetic Theaneutic ann Envi mil in entai Factors, pp. 32-97. Van Nostrana Keinhold Co., New Yort, 19,31. 37 Kerman, R.H., Floyd, M., Van Buren, C.T. and Kahan, B.D.: Prolon^d allograft survival of strong pretransplant immune responders treated with ATG. Transpl. Proc. 13:332-335, 1981. 38. Kerman, R.II., Floyd, M., Van Buren, C.T. and Kahan, B.D.: Correlation of non­ specific immune monitoring with rejection or impaired function of renal allografts. Transplantation 32:16-23, 1981. 3 9 . Kerman, R.H., Floyd, M., Van Buren, C.T., and Kuhan. B.D.: Predictiona cadaveric allograft survival based on pretransplant nonspecific immunocompetents. Transpl. Proc. 13:1533-1535, 1981. Bibliograohy Ronald il. Kerman, Ph.D. 40. 4 Kerman. R.H.. Floyd, ?>!., Van Buren, C.T. and Kahnn, 3.D.: Serial measurement of nonsDecific immune parameters of chronically hemodialvzed renal failure patients. J. Clin. Immunol. 1:163-108, 1981. 41. Kerman, R.H.: New developments in transplantation immunology. Bulletin 33(6):231— 236, 1981. The Cancer 42. Kerman, R.H.: Effect of blood transfusion on renal allograft survival:Immunological considerations. Am. J. Kidney Diseases 2:125-127, 1981. 43. Kerman, R.H. and Kahan. B.D.: Immunological evaluation of transplant rejection: Pre and postoperative indices detecting immune responsiveness. In Hayry, P. (ed.): Present and Future Trends in Clinical Transplantation. Ann. Clin. Res. 13:244-263, 1981. 44. Kerman. R.H., Van Buren. C., Payne, W., Flechner, S.. Agostino, (L. Conley, S.. Brewer, E. and Kahan, B.D.: Influence of blood transfusions on immcsse resDonsiveness. Transpi. Proc. 14:335-337, 1982. 45. Kahan. B.D., Van Buren, C.T., Lin, S.N., Ono, Y., Agostino, G., LeGræ. S., Boileau, M., Payne. W. and Kerman, R.H.: Immunopharmacologic monitorng of Cyclo­ sporin A-treated recipients of cadaveric kidnev allografts. Transolantation 34:36-45. 1982. 46. Ono, Y., Kerman, R.H. and Kahan, B.D.: Natural cell-mediated cytotoxicity and suppressor activity for natural cell-mediated cytotoxicity in long-tens renal trans­ plant patients. Transplantation 34:103-107, 1982. 47. Van Buren. C.T., Kerman, R.H., Agostino, G., Payne, W., Flechner. S. and Kahan, B.D.: The cellular target of Cyclosporin A action in man. Surgery 92:lfT-174, 1982. 48. Kahan, B.D., Kerman, R.H., Agostino, G., Friedman. A. and LeGrue, SJ,; The action of Cyclosporin A on human lymphocytes. In White, D.J.G. (ed.): Cyclosporin A. pp. 281-293. Elsevier - Biomedical Press, Amsterdam, 1982. 49. Agostino, G.J., Kahan. B.D. and Kerman, R.H.: Suppression of rnised leucocyte culture using leucocytes from normal individuals, uremic individuals and allograft recipients. Transplantation 34:367-371, 1982. 50. Kerman, R.H., Conklin, R., Cahall, D., Van Buren, C.T. and Kahan, 3J3.: CMV and renal allograft survival. In Eisenstein, T. and Friedman, H. (eds.): Hog Defenses to Intracellular Pathogens, pp. 517-519. Plenum Press, Inc., New York, 12SI. 51. Ettenger, R.B., Kerman, R.. Jordan, S.C., Warshaw, B.L., Harris, R. and Fine, R.: Sensitization following donor-specific transfusions for living related raal transplan­ tation. Transpl. Proc. 15:943-945, 1983. 52. Van Buren, C.T., Kerman, R.H., Agostino, G., Flechner, S., Payne, W„ and Kahan, B.D.: Effect of cyclosporine on immunoregulatory cells of renal allograft recipients. Transpl. Proc. 15:527-530, 1983. 13431 Biblio.mony Ronaid '.I. Kerman, Ph.D. 53. Kerman. R.H., Van Buren, C.T., Payne, W„ Flechner, S. and Kahan, B.D.: Monitoring T eeii subsets and immune events in renal allograft recipients. Transpl. Proc. 15:1170-1172, 19S3. 54. Flechner, S., Kerman, R., Van 3uren, C.T., Payne, W., and Kahan, B.D.: The use of cyclosporine and prednisone for high MLC haploidentical living related renal trans­ plants. Transpl. Proc. 15:442-445, 1983. 55. Agostino. G., Kahan, B.D. and Kerman, R.: Detection of nonspecific suppressor cells from normal individuals, uremic patients and allograft recipients. Transpl. Proc. 15:72 4— 7 2S, 1983. 56. Kerman, R.H., Agostino, G., Van Buren, C.T., Payne, W., Flechner, S., Conley, S., Brewer, S. and Kahan, B.D.: E ffect of blood transfusions on graft survival and immune responsiveness. Transpl. Proc. 15:1022-1025, 1983. 57. Kerman, R.H., Van Buren, C.. Payne, W., Flechner, S., Agostino, G., Conley, S.. Brewer. ¿. and Kahan, B.D.: The influence of pretransplant blood transfusions from random donors on immune parameters affecting cadaveric allograft survival. Trans­ plantation 3(5:50-54, 1983. 58. Kerman, R.H.. Flechner, S., Van Buren, C.T., Payne, IV., and Kahan, 3.D.: Cyclo­ sporine improves allograft survival in immunologicaily high-risk renal allograft recipients. Transpl. Proc. 15:1909-1911, 1983. 59. Kerman, R.H., Van Buren. C.T., Payne, W., Flechner, S., and Kahan, 3.D.: Immune monitoring of renal allograft recipients treated with cyclosporine or azathioprine using donor-specific and nonspecific assays as well as monoclonal T cell reagents. Transpl. Proc. 15:1971-1973, 1983. 60. Kerman, R.H., Payne, W., Van Buren, C.T., Flechner, S., and Kahan, B.D.: Detection of host presensitization to donor alloantigens utilizing a. comprehensive immune crossmatch. Transpl. Proc. 15:1815-1816, 1983. 61. Flechner, S.M., Payne. W.D., Van Buren, C., Kerman. R., and Kahan. B.D.: The effect of cyclosporine on early graft function. Transplantation 36:268-272, 1983. 62. Verani, R.R.. Bergman, D., and Kerman, R.H.: Glomerulopathy in acute and chronic rejection: Ultrastructural characteristics and relationship to graft survival. Am. J. Nephrol. 3:253-256, 1983. 63. Kerman, R.H.: Editorial: Influence of IILA A. B and DR antigen matching in transfused cadaver renal transplant patients. Cleveland Clinic Quarterly 50:216-217, 1983. 64. Kerman, R.H., Flechner, S., Van Buren, C.T., Payne, '.V. and Kahan. B.D.: Immuno­ logical monitoring of renal allograft recipients treated with cyclosporine. Transpl. Proc. 16:2302-2305, 1983. B ibliograohy Ronald 'I. Kerman. Ph.D. 6 65. Van Buren. C., Kerman. R.. Agostino, G., Flechner, S., Payne, W.D., and Kahan, 3.: Effect of cvclosDorine on immunoregulatorv cells of renal allograft reciüients. Transpi. Proc. _Pît2293-2297. 1933. 65. Kahan, 3.D.. Van Buren, C., Flechner, S.. Payne, W.D., and Kerman, R.: Cyclosporine immunosuppression mitigates immunologic risk factors in renal allotransplantation. Transpi. Proc. T_5:2469-2478, 1983. 67. Flechner, S.M., Van Buren. C., Kerman, R.H., and Kahan, B.D.: The nephrotoxicity of cyclosporine in renal transplantation. Transpi. Proc. _16:2G89-2694, 1983. 68. Flechner, S.M., Van Buren, C.T., Kerman, R., and Kahan, B.D.: The effe ct of conversion from cyclosporine to azathioprine immunosuppression for intractable nephrotoxicity. Transpi. Proc., 1983 (In press). 69. Flechner. 3.M., Kerman, R.H.. Van Buren, C., and Kahan. B.D.: Successful trans­ plantation of cyclosporine treated haploidenticai living related renal recipients without blood transfusions. Transplantation, 1984 (In press). 70. Kerman. R.H.. Van Buren, C.T.. Flechner, S.M.. and Kahan, B.D.: Correlation of visual, 3 ^-Cr-release, and flow cytometry crossmatch results to graft survival. Trunspl. Proc., 1984 (In press). 71. Rogers, A.J., Kerman, R.H., and Kahan, B.D.: The pharmacokinetic and immunobiological activity of cyclosporine in man. Transpi. Proc., 1984 (In press). 72. Van Buren, C.T., Flechner, S.M., Kerman, R.H., Vaughn, W., and Kahan. 3.D.: Cyclosporine improves outcome in high risk cadaveric renal allograft reem ents. Transpi. Proc. 1984 (In press). 73. Kerman, R.H., Manner, C., Ford, K., and Hoots, K.: Comprehensive immune evaluation of 78 hemophiliacs. Ann. N. Y. Acad. Sc. 1984 (In press). 13433 Bibliography Ronald 11. Kerman. Ph.D. Abstracts and Presentations 1. Kerman, R.. Clark, J. and '.Vbeelock, E.F.: Mononuclear infiltrate into an air pouch: A new in vitro cell mediated immune assay. Fed. Proc, 32:973, Atlastic City, New Jersey, April 1973. 2. Wheelock, E.F., Kerman, R.H., Clark, J. and Toy, S.: Cell mediated immunity in dormant friend virus infections. Proc. Am. Assoc. Cancer Res. _H:68, Atlantic City, New Jersey, April 1973. 3. Stefani, S., Kerman, R. and Abbate, J.: Serial studies of immunocompetence in head and neck cancer patients undergoing radiotherapy. Abstract, American Radium Society Meeting, San Juan, Puerto Rico, May 1975. 4. Kerman. R., Stefani, S. and Geis, W.P.: Total and active T-cell dynamics in renal allograft recipients. Abstracts of the American Society Transplant Surgeons. Chicago. Illinois, May 1976. 5. Kerman, R., Stefani, S., Smith, R., Ezdinli, E. and Geis, W.P.: Immunological evaluation of patients with solid tumors and hematological malignancies. Presented at the 1975 Cancer Symposium, Neoplasm Immunity: Mechanism, Chicago, Illinois. September 1975. 6. Stefani, S., Kerman. R. and Abbate, J.: Immunological evaluation of patients with bronchogenic carcinoma. Presented at the American Society of Therapeutic Radi­ ology, San Francisco, California, October 1975. 7. Stefani, S. and Kerman, R.: Determination and prognostic value of aimunocompetence in patients with lung cancer treated by radiotherapy. Abstracts of the Third International Symposium on Detection and Prevention of Cancer, New York, April 1976. 8. Geis, W.P., Vaz, A.L. and Kerman, R.H.: Steroid sparing effe ct of ATG in high risk renal allograft survival. Presented at the American Society of Transplant Surgeons Meeting, Chicago, Illinois, May 1976. 9. Kerman, R.H., and Geis, W.P.: Prognostic significance of the active T-cell in renal allograft survival. Presented at the American Society Transplant Surpons Meeting, Chicago, Illinois, May 1976. 10. Stefani, S. and Kerman, R.: BCG and radiotherapy in bronchogesw carcinoma: Preliminary report. Presented at the American Society of Therapeu&k Radiology, Atlanta, Georgia, October 1976. 11. Kerman, R. and Geis, W.P.: T-RFC monitoring of CMI events in rsial allograft recipients. Presented at the Sixth International Congress of the Transplantation Society Special Session Immunological Monitoring of Transplant Recipia®, New York, August 1976. 12. Kerman, R. and Stefani. S.: Radio and immunotherapy of lung cancest A preliminary report. Presented at the 1977 Chicago Symposium: Immunotherapy ofSalid Tumors, Chicago Illinois, February 24-25, 1977. 13434' Bibliorrrnohy Roruild !I. Kerman, Ph.D. 8 13. Stefani. S. and Kerman, R.H.: Relevance of immunologic analysis for patients with inoperable lung cancer treated by radiotherapy. Presented at an NCI sponsored Symposium "The Second Conference on Lung Cancer Treatment," at Airlie House, Virginia. May 22-24, 1977. 14. Kerman. R.H., Ing, T.S., Hano, J.E. and Geis, W.P.: Prognostic significance of active T-RFC in renal allograft survival. Abstracts of First International Symposium on Immunological Monitoring of the Transplant Recipient. London, Ontario, June 8-10, 1977. 15. Kerman. R.H. and Geis, IV.P.: T-RFC monitoring of CMI events in renal allograft recipients. Abstracts of First International Symposium on Immunological Monitoring of the Transplant Recipient. London, Ontario, June 8-10, 1977. 16. Ezdinli, E.. Simonson, K.. Icli, F. and Kerman, R.: Effects of single vs. multiple agent therapy on cell-mediated immunity. Proc. Amer. Assoc. Clin. Oncol. J_3:355. Denver. Colorado. May 1977. 17. Geis. W.P., Iwntsuki. S.. Molnar. Z.. Giacchino. J.L., Kerman, R.H.. Ing. T.S. and Hano. J.E.: Immunoblastic pseudo-lymphoma in renal allograft recipients. Presented at the Western Surgical Association, Las Vegas, Nevada, November 15. 1977. 18. Kerman. R.H.. Roesler, H. and Kahan.B.D.: Specific stimulation of active T-Rosette forming cells by 3M KC1 solubilized antigen. Fed. Proc., 1978. Presented at the FASEB-AAI Meeting, Atlanta, Georgia, June 1978. 19. Kerman, R.H., Floyd, M., Conner. IV., McConnell, B.J.. McConnell, R. and Kahan. B . D.: Correlation of active T-RFC and spontaneous blastogenesis with decreased renal allograft function. Abstracts of the American Association for Clinical Histocompatibility Testing, Boston, Massachusetts, June 1978. 20. Kerman, R.II., Roesler, H. and Kahan, B.D.: Increased active T-RFC with in vitro stimulation by soluble donor antigen. Abstracts of the Amer. Assoc, of Clin. Histocomp. Testing, Boston, Massachusetts, June 1978. 21. Kerman, R.H., Floyd, M., Conner, IV., McConnell, R., McConnell, B.J., Van Buren, C. T. and Kahan, B.D.: Combined immunological and radionuclide techniques to monitor renal allograft rejection. Presented at the VII International Congress of The Transplantation Society, Rome, Italy, September 1978. 22. Kerman, R.H.: Invited speaker to a special workshop "Immunological Monitoring of the Transplant Patients", VII International Congress of The Transplantation Society, Rome, Italy, September 1978. 23. Kahan, B.D., Kerman, R. and McConnell, R.: Combination of immunological and radionuclide techniques diagnoses allograft rejection. Presented at the American College of Surgeons, San Francisco, California, October 1973. 24. Michelson, J., McConell, Kerman, R. and Kaaan, B.: Association of acute rejection episodes in renal transplant patients with scored results of computer anulyzed data. Presented at the Southwest Society of Nuclear Medicine Meeting, March 16, 1979, San Antonio, Texas. B ibliorrriJDliy Ronald H. Kerman, Ph.D. 9 25. Kerman. R.II., Macek. C. and Kahan, B.D.: Increase in 3 different E-wsette markers on human T cells following pHA activation. Fed. Proc. 38 (No. 3. Part II): 1282. Presented at the Annual Meeting of The American Association of Immunologists, Dallas, Texas. April 1979. 26. Kerman. R.H.: Immunological considerations in renal transplantation. Clinical Oncology Grand Rounds, M.D. Anderson Hospital and Tumor Institute, September 1979. 27. Kerman. R.H. and Kahan, B.D.: Assessment of immune parameters of transplant recipients on immunosuppressive therapy. Presented at an NIH Woctshop on "The Biological Relevance of Immune Suppression as Induced by Genetie Therapy and Environmental Factors," Williamsburg, Virginia, November 1979. 28. Invited participant in a working cadre for the NIH to develop a Consensus On Immunotoxicology" for the National Toxicology Program, November 1379, Research Triangle Park, N.C., NIEHS, NIH. 29. Kerman. R.H.: Histocompatibility testing in transplantation. Rounds, St. Luke's Hospital, January 1980. 30. Van 3uren, C.T., Kerman, R.H. VanBuren, D. and Kahan, B.D.: Correlation of immune resDonsiveness with nutritional indices in chronic renal faiiire patients. Presented at the American Society for Parenteral and Enteral Nutrition, Annual Meeting, Chicago, Illinois, January - February 1980. 31. Kerman. R.H.: Immune monitoring of renal allograft recipients. Rounds, University of Miami School of Medicine, March 1980. 32. Kerman, R.H.: Pre- and postoperative immune monitoring of allograft recipients. Medical Grand Rounds, Division of Dialysis and Transplantation, C’nilEen's Hospital of Los Angeles, April 1980. 33. Kerman, R.H. and Semchuk, R.: Delineation of a radioresistant T celltubpopulation. Fed. Proc. 39(3):945. Presented at the Annual Meeting of The Americsn Association of Immunologists, Anaheim, California, April 1980. 34. Kerman, R.H.: Effect of heat on the ability of human T cells to expres the active T and total T receptors. Fed. Proc. 39(3): 1137. Presented at the Anreal Meeting of The American Association of Immunologists, April 1980, Anaheim, California. 35. Kerman, R., Peddada. L. and Kahan, B.D.: Correlation of hyperacute rejection with LDA and CDA vs. ^ICr-labeled donor T and B cell targets. Presented at The American Association for Clinical Histocompatibility Testing, St. Lons, Missouri, April 1980. 36. Kerman, R., Floyd, M., Van Buren, C.T. and Kahan, B.D.: Improved afiagraft survival of strong responder-high risk cadaver recipients with adjuvant imrenaosuppressive therapy. Presented at the Annual Meeting of The American Associa&n for Clinical Histocompatibility Testing, April 1980. Pa&ology Grand Sjrgical Grand Bibliography Ronuld H. Kerman, Ph.D. 10 37. Kerman. R., Conklin, R.. Cahail, D. and Kahan, B.D.: Association of cytomegalovirus and renal allograft survival. Presented at the meeting of the American Association for Clinical Histocompatibility Testing, St. Louis, Missouri, April 1980. 3S. Kerman. R., Floyd, M., VanBuren, C.T. and Kahan. B.D.: Delineation of donor specific and nonspecific pretransplant immunocompétence as a predictor for LRD allograft survival. Presented at the Meeting of The American Association of Clinical Histocompatibility Testing, St. Louis, Missouri, April 1980. 39. Kerman, R.H., Floyd, M., VanBuren, C.T. and Kahan, B.D.: Improved allograft survival of strong immune responder-high risk recipients with adjuvant immuno­ suppressive therapy. Presented at the annual meeting of The American Society of Transplant Surgeons, Chicago, Illinois, May 1980. 40. Kerman, R.H., Floyd, M., VanBuren. C.T. and Kahan, B.D.: Correlation of nonsoecific immune monitoring of renal allograft recipients with rejection and impaired renal function. Presented at the Annual Meeting of The American Society of Transplant Surgeons, Chicago. Illinois, May 1980. 41. Kerman. R.. Floyd, M., VanBuren, C.T. and Kahan, B.D.: Prolonged allograft survival of strong pretransplant immune resDonders treated with ATG. Presented at the VIIIth International Congress of The Transplantation Society, Boston, Massacnusetts, June 1980. 42. Kerman, R., Floyd, M., Van Buren, C.T. and Kahan, B.D.: Prediction of renal allograft survival based on pretransplant non-specific immunocompétence. Presented at The Second International Symposium on Immunological Monitoring of the Trans­ plant Recipient, Leiden, The Netherlands, September 1980. 43. Kerman, R.H., Floyd, M., Van Buren, C.T,, McConnell, B.J., McConnell. R. and Kahan, B.D.: Delineation of renal allograft rejection and impaired renal function byserial measurement of non-specific immune parameters. Presented at The Second International Symposium on Immunological Monitoring of the Transplant Recipient, Leiden, The Netherlands, September 1980. 44. Kerman, R.H. and Kahan, B.D.: Increased expression of the active T-RFC receptor as a measure of allosensitization following in vitro stimulation of recipient lympho­ cytes by soluble donor HLA antigens. Presented at The Second International Symposium on Immunological Monitoring of the Transplant Recipient, Leiden, The Netherlands, September 1980. 45. Kerman, R.H., Floyd, M., Van Buren, C.T. and Kahan, 3.D.: Correlation of HLA A,B and DR typing to cadaveric and living related renal allograft survival. Presented at The Second International Symposium on Immunological Monitoring of the Transplant Recipient, Leiden, The Netherlands, September 1980. 46. Floyd, M., Kerman, R., Woo, J., Van Buren, C.T. and Kahan, B.D.: Relationships of beta-2-microglobulin metabolism, immune reactivity and renal allograft rejection. Presented at The Second International Symposium on Immunological Monitoring of the Transplant Recipient, Leiden, The Netherlands, September 1980. 13437 Bibliogrnohv Ronald II. Kerman. Ph.D. 11 47. Kerman. R.H.: Immune monitoring of renal allograft recipients. Rounds, University of Chicago, June L981. Surgical Grand 48. Kerman, R.H., Van Buren, C.T., LeGrue, S.J. and Kahan, B.D.: Immunopharmacological monitoring of cadaveric renal allograft recipients receiving Cyclosporin A. Presented at the Annual Meeting of the American Society of Transplant Surgeons, Chicago, Illinois. June 1981. 49. Kerman, R.H., Conklin, R., Cahall, D., Van Buren, C.T. and Kahan, B.D.: CMV and renal allograft rejection. Presented at a Symposium on Host Defenses to Intra­ cellular Pathogens, Franklin Plaza Hotel, Philadelphia, Pennsylvania, June 1981. 50. Schoenberg, L.P., Kahan, B.D. and Kerman, R.H.: The use of Cyclosporin A as immunosuppressive medication in renal transplantation. Presented at The National Kidney Foundation, Inc., Washington, D.C., November 1981. Amer. J. Kidney Diseases, Program for Clinical Dialysis and Transplantation Forum, p. 29. 51. Ettenger. R., Kerman, R., Arnett, J., Jordan, S., Warshavv, B., Harris, R., Wassner, S. and Fine. R.: Sensitization following donor-specific transfusions for live-related renal transolantation. American Society of Neohrology, Washington, D.C., November 1981. 52. Flechner, S.. Boileau, M., Payne, W., Van Buren, C., Kerman, R. and Kahan, B.: The use of Cyclosporin A in strong immune responder, high risk renal transplant reci­ pients. American Urological Association, Kansas City, Kansas, 1982. 53. Kerman, R.. Van Buren, C., Payne, W., Flechner, S., Agostino, G., Conley, S., Brewer, E. and Kahan. B.: Influence of blood transfusions on immune responsiveness. Presented at The Transfusion and Transplantation Conference, Los Angeles, Cali­ fornia, January - February 1982. 54. Agostino, G., Kahan, B.D. and Kerman, R.H.: Suppression of mixed leucocyte culture using mononuclear leukocytes from normals, uremics and allograft recipients. Pre­ sented at the Annual Meeting of The American Association of Immunologists, FASEB, New Orleans, Louisiana, April 1982. 55. Agostino, G.J., Kahan, B.D. and Kerman, R.H.: Measurement of suppressor cell status in potential allograft recipients. Presented at the Annual Meeting of The American Association of Clinical Histocompatibility Testing, San Francisco, Cali­ fornia, April 1982. 56. Kerman, R.H.: Invited presenter at two workshops on 1) Immune monitoring of allograft recipients and 2) The effect of transfused blood and blood products on uremic hosts. Presented at the Annual Meeting of The North American Transplant Coordinators Organization, San Antonio, Texas, May 1982. 57. Kerman, R.H., Van Buren. C., Flechner, S., Agostino, G., Conley, S., Brewer, E, and Kahan, B.D.: The influence of pretransplant blood transfusions from random donors on immune parameters affecting cadaveric allograft survival. Presented at The Annual Meeting of The American Society of Transplant Surgeons, Chicago, Illinois, June 1982. *2; O' B ibliography Ronuld IL Kerman, Ph.D. 12 58. Agostino. G., Kahan, B.D. and Kerman, R.H.: Suppression of mixed leucocyte culture using leucocytes from normal individuals, uremic individuals, and allograft recipients. Presented at The Annual Meeting of The American Society of Transplant Surgeons, Chicago. Illinois, June 1982. 59. Kerman. R.H.: Invited presenter at a workshop on "Human T lymphocyte subpopula­ tions: Their role in rejection and immunosuppression." Presented at the International Congress of The Transplantation Society, Brighton, England, August 1982. 60. Kerman. R.H.: Invited presenter at a workshop on "Mechanisms responsible for blood transfusion effects." Presented at The International Congress of The Transplantation Society, Brighton, England, August 1982. 61. Ettenger. R.B., Kerman. R., Jordan, S.C., Warshaw, B.L., Harris, R. and Fine. R.: Sensitization after donor-specific transfusions for live-related renal transplantation. Presented at The International Congress of The Transplantation Society, Brighton. England. August 1982. 62. Van Buren. C.T., Kerman. R.H.. Agostino, G.. Flechner. S. Payne. W. and Kahan. B.D.: Effect of cyclosporine on immunoregulatory cells of renal allograft recipients. Presented at The International Congress of The Transplantation Society, Brighton. England, August 1982. 63. Kerman, R.H., Van Buren, C.T., Payne, W., Flechner, S. and Kahan. B.D.: Monitoring T cell subsets and immune events in renal allograft recipients. Presented at The International Congress of The Transplantation Societv, Brighton, England. August 1982. 64. Flechner. S., Kerman, R., Van Buren, C.T., Payne. VV. and Kahan, B.D.: The use of cyclosporine and prednisone for high MLC haploidentical living related renal trans­ plants. Presented at The International Congress of The Transplantation Society, Brighton, England, August 1982. 65. Agostino, G., Kahan, B.D. and Kerman, R.: Detection of nonspecific suppressor cells from normal individuals, uremic patients and allograft recipients. Presented at The International Congress of The Transplantation Society, Brighton, England, August 1982. 66. Kerman, R.H., Agostino, G., Van Buren, C.T., Payne. IV., Flechner, S., Conley, S., Brewer, E. and Kahan, B.D.: E ffect of blood transfusions on graft survival and immune responsiveness. Presented at The International Congress of The Transplantation Society, Brighton, England, August 1982. 67. Kahan, B.D., Kerman, R., Payne, W.D., Flechner, S. and Van Buren, C.T.: Itnmunopharmacologic studies of cyclosporine-treated renal allograft recipients. Fifth Tripartite Meeting, Society of University Surgeons, Salzburg, Austria, September 1982. /a UibliograDnv Ronald !I. Kerman. Ph.D. r 13 63. Kerman, R.H., Flectiner, S.. Van Buren, C.T., Payne, W., and Kahan, B.D.: Cyclo­ sporine improves allograft survival in immunologicallv high-risk renal allograft recipients. Presented at the Third International Immunological Monitoring Sym­ posium, Key Biscayne, Florida, November 1982. 69. Kerman, R.H., Van Buren, C.T., Payne, W., Flechner, S., and Kahan, B.D.: Detection of host presensitization to donor alloantigens utilizing a comprehensive immune crossmatch. Presented at the Third International Immunological Monitoring Sym­ posium, Key Biscayne, Florida, November 1982. 70. Kerman, R.H., Payne, W., Van Buren, C.T., Flechner, S., and Kahan, B.D.: Immune monitoring of renal allograft recipients treated with cyclosporine or azathioprine using donor-specific and nonspecific assays as well as monoclonal T cell reagents. Presented at the Third International Immunological Monitoring Symposium, Key Biscayne, Florida, November 1982. 71. Kerman, R.H.: Invited plenary speaker at the First Annual Meeting of The American Society of Transplant Physicians, "Optimizing immunosuppression: Mode of action of cyclosporine." Chicago, December 1982. 72. Kerman, R.H., Van Buren, C.T., Payne, W., Flechner, S., and Kahan, B.D.: Cyclo­ sporine improves allograft survival in immunologicallv high-risk renal allograft recipients. Presented at The Annual Meeting, National Kidney Foundation, Clinical Dialysis and Transplant Forum, Chicago, December 1982. 73. Kerman, R.H.: Role of immune evaluation in clinical medicine. Clinical Immunology Grand Rounds, The Children's Memorial Hospital, Chicago, Illinois, December 1932. 74. Kerman, R.H.: Immunologic effects of toxic materials. Presented at Toxicology Clinical Update, University of Texas Medical Branch, Galveston, Texas, January 1983. 75. Kerman, R.H.: Cyclosporine improves allograft survival in immunologicallv high risk renal allograft recipients. Presented at Pathology Grand Rounds, University of Pittsburgh School of Medicine, February 1983. 76. Kerman, R.H.: Immune evaluation of renal failure patients and allograft recipients. Presented at Surgical Grand Rounds, St. Louis University Medical Center, St. Louis, Missouri, March 1983. 77. Kerman, R.H.: Immunological evaluation of hemophiliacs. Presented at a Symposium on Current Problems in the Management of Hemophiliac Complications, Houston, Texas, April 1983. 78. Flechner, S., Kerman, R.H., Van Buren, C.T., Payne, '»V., and Kahan, B.D.: Successful transplantation of high mixed lymphocyte culture haplo-identicul living related donors using cyclosporine and prednisone. Presented at the Annual American Urological Association, Las Vegas, Nevada, April 1983. 79. Kerman, R.H., Flechner, S., Van Buren, C.T., Payne, W., and Kahan, 3.D.: Immunolo­ gical monitoring of renal allograft recipients treated with cyclosporine. Presented at The First International Congress on Cyclosporine, Houston, Texas, May 1983. $ *lk Bibliography Ronaid IL Kerman. Ph.D. 14 80. Van Buren. C., Kerman. R., Agostino, G., Flechner, S., Payne, W.D.. and Kahan. B.: Effect of cyclosporine on immunorcgulatory cells of renal allograft recipients. Presented at The First International Congress on Cyclosporine, Houston, Texas, Mav 1983. 81. Kahan, 3.D.. Van Buren, C., Flechner, S., Payne, W.D., and Kerman, R.: Improved outcome of 150 renal allografts in immunologically high risk recipients treated with cyclosporine. Presented at The First International Congress on Cyclosporine, Houston, Texas, May 1983. 82. Flechner, S.M., Van Buren, C., Kerman, R.H., and Kahan, B.D.: The nephrotoxicity of cyclosporine in renal transplantation. Presented at The First International Congress on Cyclosporine, Houston, Texas, May 1983. 83. Flechner, S.M., Van Buren. C.T., Kerman, R., and Kahan, B.D.: The effect of conversion from cyclosporine to azathioprine immunosuppression for intractable nephrotoxicity. Presented at The First International Congress on Cyclosporine, Houston, Texas, May 1983. 84. Kerman, R.H., Flechner, S.. Van Buren, C.T., Payne, W., and Kahan, B.D.: Cyclo­ sporine immunosuDpression overcomes immunologic risk factors for recipients of cadaveric renal allografts. Presented at the Annual Meeting of The American Society of Transplant Physicians, Chicago, Illinois, June 1983. 35. Flechner. 5.M., Kerman, R.H., Van Buren, C.T., and Kahan, B.D.: The high risk hapioidenticai living related recipient: Transplantation without blood transfusions and steroid withdrawal using cyclosporine. Presented at the Annual "Meeting of The American Society of Transplant Physicians, Chicago, Illinois, June 1983. 86. Kerman, R.H.: Relationship of immunocompétence of hemophiliac patients and acquired immune deficiency syndrome (AIDS). Presented at the Gulf Coast Hemo­ philia Chapter Meeting, Houston, Texas, October 1983. 87. Kerman, R., Van Buren, C.T., Flechner, S., and Kahan, B.D.: Correlation of visual, 51-Cr-release and flow cytometry crossmatch results to graft survival. Presented at The Fourth International Symposium: Immune Monitoring of The Transplant Re­ cipient, Houston, Texas, November 1983. 88. Rogers, A.J., Kerman, R.H., and Kahan, B.D.: The pharmacokinetic and immunobiological activity of cyclosporine in man. Presented at The Fourth International Symposium: Immune Monitoring of The Transplant Recipient, Houston, Texas, November 1983. 89. Kerman, R.H., Manner, C., Ford, K., and Hoots. K.: Comprehensive immune evaluation of 78 hemophiliacs. Presented at the New York Academy of Sciences Symposium on Acquired Immune Deficiency Svndrome, New York, Now York, Novem­ ber 1983. 90. Kerman, R., Van Buren, C.T., Flechner, S.M., and Kahan, 3.D.: DRU’6 and DR3 phenotypes correlating with immune response. Presented at the Annual Meeting of The American Association for Clinical Histocompatibility Testing, Chicago, Illinois, November 1983. Bibliography Ronald H. Kerman. Ph.D. 01. 15 Van Buren. C.T., Flechner, S.M., Kerman, R.H.. Vaughn, W., and Kahan, B.D.: CyciosDorine improves outcome in high risk cadaveric renal allograft recipients. Presented at the First Meeting of The European Society for Organ Transplantation, Zurich, Switzerland, November 1983. 92. Kerman. R.H.: Cyclosporine immunosuppression for renal transplantation. Presented to Sandoz Pharmaceuticals, Inc., East Hanover, New Jersey, December 1983. 93. Kerman. R.H.: New horizons in transplantation: Influence of cyclosporine on renal transplantation. Invited presenter at the Western Dialysis and Transplantation Society, Park City, Utah, January 1984. 94. Sterling, R.P., Bradley, B.B., Khalil, K.G., Kerman, R.H., and Conklin, R.H.: Compari­ son of biopsy proven pneumocystis pneumonia in acquired immune deficiency syndrome (AIDS) patients versus renal allograft patients. Presented at The Society for Thoracic Surgeons, San Antonio, Texas. January 1984. 95. Rogers, A.J., Kerman, R.H., and Kahan, B.D.: Correlation of immunopharmacokinetic profiles of cyclosporine-treated allograft recipients and rejection. Presented at The Society for University Surgeons - Residents' Meeting, Chicago, Illinois, February 1984. M I. A R V I N S . L E G A T O R , P h . D . QUALIFICATIONS Dr. Legator is Professor of Environmental Toxicology, University of Texas Medical School at Galveston. His Curriculum Vitae is attached. Dr. Legator has been associated with many committes investigating various toxins, including TCDD, and most especially the recent EPA committee involved with dioxin exposure. II. SUBJECT MATTER The subject matter of Dr. Legator's testimony will include: the teratogenic and carcinogenic effects of TCDD, as well as its mutagenic potential; the multi-system effects of TCDD at extremely low concentrations the demonstrable effects, both gross and more subtle, of TCDD on animals; the extrapolation of the animal studies to humans, that is, the inherent, intended predictive aspects of the animal data to man. Dr. Legator will testify that the animal data are positive and consistent and provide a mechanistic linkage which confirms the Vietnamese epidemiological study of Hatch and others. Further he will testify to his work as a geneticist with respect to reproductive toxicology, i.e. male (Vietnam Veterans) mediated birth defects and certain untoward pregnancy outcomes. Further, insofar as the reproductive toxicological effects, i.e. birth defects and miscarriages, of Agent Orange and/or TCDD, et al. Dr. Legator will testify that such can occur through one or more of the following bio­ (1 )decreased quality of sperm resulting from gonadal logical mechanisms: lesion during spermatogenesis, altered hormonal regulation, or transmittable defects in heritable characteristics of sperm; (2 ) potentiation of xenobiotic metabolism in gonadal tissue; (3) secretion of chemicals in Agent Orange or their metabolites into seminal fluid and subsequent transfer to the womb. These mechanisms can result from either the long­ term effects of past exposure to Agent Orange or from the continuing presence of biologically active concentration of Agent Orange and metabolites of its constituent chemicals within the bodies of exposed persons. III. SCIENTIFIC PRINCIPLES See General Statement of Scientific Principles and Assumed Facts attached. Dr. Legator will describe the extraordinary precautions which are taken, and the fears of the researchers, in connection with the laboratory use of TCDD.I . V IV. SUBSTANCE OF OPINIONS A. That dioxins are extremely toxic, particularly 2,3,7,3-TCDD. B. That TCDD is exceptionally toxic at extremely low levels; C. That TCDD is a complete carcinogen; D. That, as a carcinogen, there is no safe level of exposure. E. That there is therefore no "no-effect" level of TCDD : F. That TCDD is the most toxic substance ever synthesized by man; G. That TCDD is acnegenic; H. That TCDD is immunosuppressive; I. That TCDD is teratogenic; J. That TCDD is fetotoxic; K. That TCDD is gonadotoxic; L. That TCDD is capable of transmitting genetic damage; M. That the miscarriage of Mrs. Dan G. Jordan and the congenital malformations of the children of Mr. and Mrs. Dan G. Jordan, as well as those congenital malformations and birth defects of Kerry Ryan, daughter of Mr. and Mrs. Michael F. Ryan, are consistent with the presumed exposure of representative plaintiffs Jordan and Ryan to phenoxy herbicides and dioxins - specifically 2,3,7,8-TCCD — while serving in Vietnam. GROUNDS FOR OPINIONS A. General The bases or grounds for such facts and opinions include Dr. Legator's: educational and professional experience; personal research; review of the appli­ cable medical and scientific literature; and a review of the medical record and/or data of the Jordan and Ryan familes. B. Specific The additional grounds can be found in:1 for Dr. Legator's opinions 1. Dioxins are extremely toxic: the EPA Criteria Documents, Publications and associated references. 2. TCDD toxic at low levels: the EPA Criteria Documents, Publications and associated references. 3. TCDD complete carcinogen: National Cancer Institute 1980a. Bio­ assay of 2 ,3,7,8 - tetrachloro-dibenzo-pdioxin for possible carcinogenicity (dermal study) U. S. Department of Health and Human Services Pub. No. 80-1757. National Cancer Institute 1980B. Bio­ assay of 2 ,3,7,8-tetrachloro-dibenzo-pdioxin for possible carcinogenicity (gavage study) U. S. Department of Health and Human Services Pub. No. 80-1765. 4. No safe level: IARC: Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. 5. No "no effect" level: IARC: Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. 6 . TCDD most toxic substance: EPA (cited above) IARC (cited above) 7. TCDD - acnegenic : Kearney, D.C., et al. 1973 Environmental Significance of chlorodioxins. Adv. Chem. Ser. 120:105 8 . TCDD - immunosuppressive: - Harris, M.W., J.A. Moore, J.G. Vos and B. N. Gupta. 1973. General biological effects of TCDD in laborator animals. Environ. Health Perspect. 5: 101. - Kearney, D.C. et al. 1973. Environmental significance of chlorodioxins. Adv. Chem. Ser. 120: 105. 9. TCDD - teratogenic: - Courney, K.D., D. W. Gaylor, M.D. Hogan and H. L. Falk. 1979. Teratogenic evaluation of 2,4,5-T. Science 1968: 864. - Kociba, R. J., P. A. Kesler, C. N. Park and P. J. Gehring. 1976. 2 ,3,7 ,8 -Tetrachlorodibenzop-dioxin results of a 13-week oral toxicity study in rats. Toxicol. Appl. Pharmacol. 35: 553. - Kociba, R. J., D. G. Keyes, J. E. Beyer, R. M. Carreon, C. E. Wade, D. A. Dittenberg, R. P. Kalnins, L. E. Frauson, C. N. Park, S. D. Barnard, R. A. Hummel and C. G. Humiston. 1978. Results of a two-year chronic toxicity and oncogenicity study of 2 ,3,7,8-tetrachlorodibenzo-p-dioxin in rats. Toxicol. Appl. Pharmacol. 46: 279. - Kociba, R. J., D. G. Keyes, J. E. Beyer, R. M. Carreon and P. J. Gehring. 1979. Long term toxicologic studies of 2 ,3,7,8-tetrachlorodibenzop-dioxin in laboratory animals. Ann. N.Y. Acad. Sci. 320: 397-404. 10. TCDD - fetotoxic: - McConnell, E.E., J. A. Moore and D. W. Dalgard. 1978a. Toxicity of TCDD in Rhesus monkeys (Macaca mulatta) following a single oral dose. Toxic. Appl. Pharmacol. 43: 175. '■ • TCDD - gonndotoxic: - Neuoert, D., P. Zens, A. Rothenwallner and H. J. Merker. 1,973. A survey of the embryotoxic effects of 1CDD in mammalian species. Environ. Health Perspect. 5: 67. i2. TCDD can cause genetic damages: - Murray, F. J., F. A. Smith, K. D. Nitschke, C. G. Humiston, R. J. Kocibe and B. A. Schwutz. 1979. Three-generation reproduction study .f rats given 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the diet. Toxicol. Appl. Pharmacol. 50: 241. - Seiler, J. P. 1977. Inhibition of testicular DNA synthesis by chemical mutagens and carcinogens. Preliminary results in the validation of a novel sh. rt-term test. Mutat. Res. 4t: 335. - Green, S. et al. 1977. Cytogenetic effect of 2 ,3,7,8-tetrachlorodibenzo-p-dioxin on rat bone marrow cells. U . S. Food and Drug Admin., Washington. D.C. FDA By-Lines 7: 292. Allen JR, Carstons LA. Lignt and electron microscopi. observations in Mncac ; mulatto monxeys ted toxic rat. Am J Vet Res 2o :1513-i_<20 , - Jons table J, Hatch M. Herbicide exposure and rcoroduc *v° outcome. In- Herbicides :n W ;r: The Lone-term Ef:rcts ni and ’of.ire, AW nesting, ec. New- iorx: tayior A rrancis, SJoi* yin press). _ Khera ”.S, Ruddick JA. Pciychlorodibenzoistar-p-dioxins: Perinatal effects and the dominant iotnal test in Wistar rata. In: Chiorcuioxms - Origin and Fate, l.:: Blairc, ed. Washington DC: American Chemical Society, 1973, pc 70-Sa . ~ Kociba F.J, Peeler PA< Pork CM, Gehr :ng PJ. 2,3,",Stctrachlorodibonao-p-aioxin (TCDD): Results of a 13-week oral toxicitv study m rats. Toxicol Appl Pharmacol 33:553-575, 1976. - McConnell PC'. Moore JA-.' Haseman JK, Harris MV?> The comparative toxicif of •.:.lormated ci ber.co-;>-d: oxins m mice and guinea pigs. Toxicol Appl Pharmacol -¿*:335-356, 1973. - Mattison DR, hvdroxvlase m Thorgeirsson SS. Gonadal arvl hvdrocarncn rats and mice. Cancer Res 33:1jo 8-i3~3, 1°7S. 13447 - N'orback DH, Allen JR. Biological responses of the nonhuman primate, chicken and rat to chlorinated dibenzo-p-dioxin ingestion. Environ Health Perspect 5:233-240, 1973. -Peterson, R. Hormonal changes and "wasting" observed in moderatelv-h:gh-u'se animal experiments. Presented at the Symposium or Putilic Health Risks of the Dioxins, The RocKeieller Lmversit y , October 19-20, 1933. (Proceedings in press, Alan R. Liss Inc.) -Poland A, Knutson JC. 2,3,7,S-tetrachlorodibenzo-p-dioxin and related aromatic hydrocarbons: Examination of the mechnanism of toxicity. Ann Rev Pharmacol Toxicol 22:517-554, 1982. -Tofilon PJ, Piper W’N. 2,3,7,8-tetrachlorodibenzo-p-dioxinmediated depression of rat testicular heme synthesis and microsomal cytochrome P-450. Biochem Pharmacol 31:3663-3666, 1982. In addition, Dr. Legator may rely on some of the following reference for his specific opinions REFERENCES A l l e n , J . R . , D.A. B a r s o t t i , J . P . Van M i l l e r , L . J . Abrahamson and J . J . Lauch. J 977 . Morphological cnanges in monkeys consuming a d ie t containing low l e v e l s of TCDD. Food Cosmet. To xic ol. 15: 401. B e r ry , D.L. et a l . 1976. Transplacental induction of carcinogen hy d rnx iy lc ti ng systems with 2 ,3 , 7 , 8 - tetrachlorodibenzo-p-dioxin. T o xic o l. Appl. Pharmacol. 36: 569. Be rry , D.L. et a l . 1972. Studies with chlor inated dibenzo-po io x in s , polybron.'inated biphenyls, and polychlorinated biphenyls in a two-stage system of mouse skin tumorinenes i s : potent an t ic arc in o qenic e f f e c t s . Am. N.Y. Acad. S c i . 320: 405. Chliabra, R .S. et a l . 1974. Selection of inducers as an importance f a ct o r in c h a r a c t e r iz in g genetic di ff er en ce s to induction or ary l hydrocarbon hydroxylase in s t r a i n s of mice. L i f e S c i . 15: 123. DiGiovanni, J . , A. V i a j e , D.L. Be rry , T . J . Slaga and M.R. Juchau. 1977. Tu m or- in it ia ti n g a b i l i t y of 2.3,7,8-Letrachlorodibenzo-pdioxin (TCDD) and Arochlor 1254 in the two-stage system of mouse skin carcinogenesis. B u l l . Environ. Contain. T o x ic o l. 18: 552. DiGiovanni, J . , D.L. B e r ry , M.R. Juchau and T . J . Slaga. 1979b. 2 ,3 .7, 8-T etr ach lor odi t; cr.zo -p- di ox in: po:.ent anticarcinogenic a c t i ­ v i t y in CD-I mice. Biomem. Biophys. Res. Comm. 86: 577. DiGiovanni. J . , D.L, Be rry , T . J . Slaga, A.H. Jones and M.R. Juchau. 1979a. E f f e c t s of pretreatment with 1CDD on the capacity of hepatic and ext raheoatic mouse t is s u e s to convert procarcinogens to mutagens f o r S t yphirn:;;-; cm auxotrophs. To x ic o l. Apr'. Pharmacol. 50: 229. (i re c r, 5. arid F . S . Moreland. 29 75. Cytogenetic evaluation of several dioxins in the r a t . To x ic o l. A r p l . Pharmacol. 32: 161. Grieg, J . B . a no F. DoMatteis. 1973. E f f e c t s of 2 , 3 , 7 ,8 -t e tr a ch lo r o dahc-n:::j- p-oioxir. on dre'" metabolism and heoatic microsomes of ra t s and mice. Environ. Health Aersoect. 5: 211. Guenther, T.M ., J.M. Fysh and G.W. Nebert. 1979. 2 ,3 , 7 , 8 - Te t r a ch 1orodibenzo-p-ciioxin: covalent binding of r e a c t iv e metalib o lic intermediates p r i n c i p a l l y to protein in v i t r o . Pharmacology (19) 1; 12- 22 . Hussain. S. , L. Ehrenberg, G. Lofroth and T. G e j v a l l . 3972 . genic e f f e c t s of TCDD on b a c te r ia l systems. Ambio. 1: 32. Muta­ Jones, G. and J . E . G; iec*. 1575. Pathological changes in the l i v e r of mice given ? , 3 , 7 , 8 - Letrachlorodibenzo-p-dioxin. Exp erien tia 31(12) : 1315-1317. Khera, K.S. and J . A . Roddick. 1973. Pcl.ychlorodibenzo-p-dioxins: prenatal e f f e c t s and inn dominant let hal test in Wistar r a t s . In: E.D. B l a i r ( e d . ) , Chi orodi oxi ns - o r i g i n s end f a t e . Adv. Clism. S e r . , No. 120. Am. Chem. Soc. , Washington, D.C. o. 70. K o u r i , R. 1976. . .ationship between le v e ls of aryi hydrocarbon hydroxylase a c t i v i t y and s u s c e p t i b i l i t y to 3-methyicholanthrene and benzo(a)-pyrene-induced cancers in inbred s t r a i n s of mice. j_n: R . J . Freudr-’ thal and P.W. Jones ( e d s . ) , Polynuclear aromatic hydrocarbons: chemistry, metabolism and carcinogenesis. V o l. 1. Raven Pr es s, N.Y. p. 139. K o u r i , R .E . and [).W. Nebert. 1977. Genetic regulation of suscep­ t i b i l i t y to p o l y c y c l i c hydrocarbon-induced tumors in the mouse. I n : Proc. Symp. Origins of human Cancer. Cold Spring Harbor, N.Y. L u c i e r , G.W. et a l . microsomal enzymes. 1973. TCDD-induced changes in r a t l i v e r Environ. Health Perspect. 5: 199. Matsumura, F. and H . J . Benezet. 1973. Studies on the bioaccumula­ tion and microbial degeneration of 2,3 ,7 ,8 -t et ra c hl oro di be nz o-p d i o x i n . Environ. Health Perspect. 5: 253. McConnell, E . E . , J . A . Moore, J . K . Haseman and M.W. H a r r i s . _ 1978b. The comparative t o x i c i t y of chlor inated dibenzo-p-dioxins in mice and ouinea pigs. To x ic o l. Appl. Pharmacol. 44: 335. Moore, J . A . , B.fl. Gupta, J . G . Z i n k l , J . G . Vos. 1973. Postnatal e f f e c t s of maternal •.-oosure to 2 ,3 , 7 , 8- te tra ch lo ro di benzo-p-di ox in (TCDD). Environ, lie ■ch Perspect. 5: 81. Neal, R . A . , P.W. Beatty and T.A. Gasiewicz. 1979. Studies of the mechanisms of t o x i c i t y of 2 ,3 ,7 ,8 -te tra c hl oro di be nz o-p- d io xin (TC;'T). Ann. N.Y. Acad. S c i . 320: 204. P i t o t , H. C. , T. Goldsworthy, H.A. Campoell and A.‘ Poland. 1980. Quan titative evaluation of the promotion by 2 , 3 , 7 , 8 - t e t r a c h l o r o dibenz -p-dioxin o? hepatocarcinoaenesis from d i e t 1, initrosamine. Can. Res. 40: 3516-3620. Poland, A.P. and E. Glover. 1973a. Chlorinated dibenzo-p-dioxins: potent inducers of u-Aminoievulinic acid synthetase and aryl hvdrocarbon hyoroxylase. II. A study of the structure- a c t i v i t y r e l a t i o n s h i p . Molecular Pharmacol. 9: 736. Poland, A.P. and E. Glover. 1973b. 2,3 ,7, 8-T etrachlorodibenzo-pd i o x i n : a potent inducer of u-Aminolevulinic acid synthetase. Science 179: 476. Poland, A.P. and E. Glover. 1974. Comparison of 2 , 3 , 7 , 8 - t e t r a chlorodibenzo-p-dioxin a potent inducer of a r y l hydrocarbon hydroxylase with 3-methylcholanthrene. Mol. Pharmacol. 10: 349. Poland, A.P. and E. Glover. 1979. An estimate of the maximum in vivo covalent binding of 2 ,3 ,7 ,8 -t e t ra c h lo r o d ib e n z o -p -d io xin to ra t l i v e r p r o t e i n , ribosomal RNA, and DNA. Cancer Res. 39: 3341. Poland, A.P. and A. Kende. 1976. 2 ,3 ,7 ,8 -te tra c hl oro di be nz o-pd i o x i n : environmental contaminant and molecular probe. Fed. Proc 35: 2 m Poland, A . P . , D. Smith, G. Metier and P. P o ' s i c k . 1971. A health survey of workers in a 2,4-D and 2 , 4 , 5 - T p i j t. Arch. Environ. Health 22: 316. 13450 Poland', A.P. et a l . 1974. Genetic expression of aryl hydrocarbon hydroxvlase a c t i v i t y induction of mono-oxygenase a c t i v i t i e s and cvtochrome P-1-450 formation by 2,3,7,8-TCDD in mice g e n e t i c a l l y . Jour. B i o l . Chem. 249: 5599. Seiler, J.P . 1973. A survey on the mutagenicity of various p e s t i ­ c id e s. Experientia 20: 622. Smith, F . A . , B.A. Schwetz and K.D. Nitschke. 1976. Te ra tog eni cit y of TCDD in CF-1 mice. T o x i c o l . Appl. Pharmacol. 38: 517. Sparschu, G . L . , F . L . Dunn and V. K. Rowe. 1971. Study of the t e r a ­ to g e n ic i ty of TCDD in the r a t . Food Cosmet. T o xic o l. 9: 405. Toth, K. , S. Somfai-Relle, J . Sugar and J . Bence. 1979. Carcino­ g e n i c i t y of herbicide 2,4,5-trich loro-ph en oxy etha nol -con tainin g dioxin and of pure dioxin in Swiss mice. Nature 278: 548. CURRICULUM VITAR NATE: Marvin Seymour Legator, Ph.D. DATS: November, 1983 PRESENT POSITION AND ADDRESS: Professor and Director Division of Environmental Toxicology Department of Preventive Medicine and Community Health University of Texas Medical Branch Galveston, Texas 7755*0 Office phone: 409/761-1803 BIOGRAPHICAL: Date of Birth: June 27, 1926 Place of birth: Chicago, Illinois Marital Status: Married Children: Three Home Address: 70 Colony Park Galveston, Texas 77951 Socia.1 Security Number: 348-16-3682 EDUCATION : 1948 Microbiology-Biochemistry 3.A. University of Illinois Urbuna, Illinois 1948 Biochemistry M.S. University of Illinois Urbana, Illinois 1981 Microbial Genetics-Biochemistry Ph.D. University of Illinois Urbana, Illinois PROFESSIONAL AND TEACHING EXPERIENCE: 1976-present Professor aid Director Division of Environmental Toxicology Depiirtment of Preventive Medicine and Community Health University of Texas Medical Branch Paye 2 Curriculum Vi rae - Ilarviti oeymour Legator Galveston, Texas 1972-1976 Professor of Genetics Brown University Providence, Rhode island 1965-1972 Professor (part-time) General and Medical Genetics George Washington University Washington, D.C. 1962 - 1972 Chief, Branch Genetic Toxicity Branch Food and Drug Administration Washington, D.C. 1952-Ì952 Head, Animal Healtli Program Shell Development Company Modesto, California 1951-1952 Senior Microbiologist Julius Hyman Company Denver, Colorado 19^-1550 instructor University of Illinois Urbana, Illinois COMMITTEE RESPONSIBILITIES: UT!3 Committees : University Cancer Center Committee (through 1952) University Appointment, Promotion and Tenure Committee (through I960) University Fellows Grants Committee Department of Preventive Medicine and Community Health Executive Committee Department of Preventive Medicine and Community Health Steering Committee Department of Preventive Medicine and Community Health Application, Promotion and Tenure Corsmittee Outside Committees: 1953 Environmental Protection Agency Research 1953 Subject Selection Assistance Program 195U March of Dimes Committee on Reproductive Hazards (Chiirrnan) 1950 Environmental Protection Agency Research Grant Review Panel 19oU Environmental Protection Agency Criteria Document Panel Committee of Science the Review Texas Panel, for Health Veterans Agent Orange 13153 Curriculum Vitae - Marvin Seymour1 Legator Page 3 19Ö0 Environmental Protection Agency Committee Chairman, Gene-Tox Program (HHA) 19Ö0 Science Committee of Food Safety Council 1975 Oversight Committee for Proctor and Gamble to determine adequacies of toxicological procedures 1975 Committee 17, Analysis of Methodology of Mutagenicity Testing 1973 National Academy of Science Cocmittee on Biological Hazards Levels of Radiation 1972 Member of Testing 1971 Japanese and United States Government Committee on Toxicology 1971 Member of World Health Organization Committee on Use of Hycanthone 1971 Chairman of Preparations 1970 Member Steering Toxicology 1970 National Institute of Mental Health - Committee on Genetics of Drug Abuse Swedish Government Government Low Sponsored Corrmittee on Mutagenicity Hearing Committee of on on Safety of Lmmunological Industry-Academic, Committee on Effects MEMBERSHIP IN SCIENTIFIC SOCIETIES: American College of Toxicology Environmental Mutagen Society New York Academy of Sciences Society of Occupational and Environmental Health HONORS: Honorary Health Advocate Award - "... awarded in recognition of outstanding contributions in health advocacy and promotion of the public's health to Marvin S. Legator." Health Policy Advisory Center, New York, New York, November lb, 19Ö3- Food Safety Council 1976-1932 - "With deep appreciation for the tireless effort that Marvin Legator devoted to help the Food Safety Council achieve its goals. Ibis experiment in concensus building ins s h o w that representatives from industry and non-industry with different viewpoints can work together toward a better way for mailing food safety decisions." 45 ■ Curriculum Vi cue - Marvin eymour Legator Page 4 U.S. Environmental Protection Agency Certificate of Award - Presented to Marvin S. Legator in recognition of noteworthy contribution and special achievement for the U.S. Environmental Protection Agency, Cincinnati, Ohio Visiting Scholar Award at Western Michigan University 1980 Nominated for I98O Distinguished Faculty Research Award F.D.A. Award of Merit - Presented to the Genetic Toxicology Branch (M. Chief), 1971 Legator, Key Lecture Award by the American Genetics Association for Outstanding Contributions on the Implementation of Genetics for Hunan Welfare and Improvement, 1970 U.S. Government Award - Technique Advance in Cell Culture, 1985 ADDITIONAL INFORMATION: Areas of Teaching and Research Competency: Mutagenicity Cytogenetics Reproductive Studies Biochemistry Molecular Biology Tissue Culture (Post Doctorate Course, University of Wisconsin, Madison, Wisconsin) Consulting Activities: Panel Member, Toxicology Panel on Psychochemicals, Commission on Life Sciences, National Research Council, National Academy of Sciences, 1983 Expert Witness, Texas Senate Subcommittee on Consumer Affairs, 1982 Expert Witness, U.S. House Subcommittee on Oversight and Investigations of the Committee on Energy and Commerce, 1982 Consultant, Hooker Chemical Company, 198U Consultant, JRB Associates, 198U Consultant, Toxi-Genics (Fabrizio), 1980 Consultant for Environmental Protection Agency, 197b-l980 Consultant for Lady Clairol, 1978-1978 Expert Witness, Committee on Science and Teclinology, 1979 Dow Chemical Company, 197^—1979 National Institute of Drug Abuse, 1973-1980 Consultant, Senate Committee on Public works, 1970 Other Activities: Elected Member, Collegium Ramazzimi, 1983 Member of the Board of Directors, Committee for Responsible Genetics, 1983. 13455 Curriculum Vitae - Marvin „¿ymour Legator Page 5 Member, Critical Issues Committee on Accreditation, Certification and Standardization, Environmental Mutagen Society, 1983-84. Co-chairperson, Workshops and Training Committee, Environmental Mutagen Society, 1983-84. Member of the Board, Texas Center for Rural Studies, Inc. The corporation is organized to provide research and educational services rcgaruing the quality of life in Texas, including, but not limited to, the health, economic and environmental effects of pesticides and other chemicals; public policies effecting the rural economy; and the enhancement of the role of family farmers, farm laborers and rural residents in Texas agriculture, 1983, Austin, Texas. Co-Director of Workshop, Environmental Influences on Fertility, Pregnancy, and Development: Directions for Future Research, May 24-25, 1982, Cincinnati, Oiiio Director of CME Workshop for Practicing Physicians, Recognizing, Diagnosing, and Treating Chronic Toxic Chemical Effects, July 16-18, 1981, Galveston, Texas Director of Annual Genetic Toxicology Course, Galveston Director of Annual Genetic Toxicology Course, Hunt Valley Co-Director of Annual Toxicology and Law Course, Houston Director of Annual Workshop on Carcinogenicity, Mutagenicity and Teratogenesis sponsored by the March of Dimes Birth Defects Foundation Faculty member of short course on Toxicology at Wayne State University, 1976-1979 Coordinator of Workshop on Occupational Monitoring for Genetic Hazards, March 27-29, 1975 Visiting lecturer to Heidleburg University, Germany, 1971 ies¡sensibilities: Editor, Journal of Teratogenesis, Carcinogenesis, and Mutagenesis Editorial Board of Environmental Mutagenesis Journal (through 1981) BIBLIOGRAPHY: Journal Articles: Legator, M.S., and Gottlied, D. 1954. The Biosynthesis of Chloramphenicol 1 Precursors Stimulating the Synthesis. J. Bacteriol. 2. Legator, M.S., and Racussen, D. Bacteriol. 2. 1959- Mechanism of Ally Alcohol Toxicity. J. Legator, M.S., and Withrow, A. 1964. Aflatoxin: Effects on Mitotic Division in Cultured Embryonic Lung Cells. J. Assn. Official Agricultural Chemists 47:1007-1009. Cliilds, V.A. , and Legator, M.S. 1965- Lactic Detiydrogenase. Isozymes in Diploid and Heterploid Cells. Life Sciences 4: 1p 43-1650. Legator, M.S., Zuffante, S.M., Harp, A.R. 1965- .Aflatoxin: Effect on Cultured Heteroploid Human Embryonic Lung Cells. Mature (London) 208:345-347- Curriculum Vitae - Marvin Seymour Legator P a g e 6 Childs, V.A., and Legator, M.S. 1966. Induction of Thymidine Kinase by Aflatoxin. Life Sciences 5:1053-lU56. Legator, M.S., Jacobson, C.B., Perry, M., and DolLmpio, D. 1966. Tlie l/ooly Opossum — A New Research Tool for Cytogenetic Studies. Life Sciences 9:397-402. Legator, M.S. 1966. Biological Effects of Aflatoxin in Cell Culture. Bacteriological Reviews 30:471-477Wragg, J., Ross, V.C., and Legator, M.S. 1967* Effect of Aflatoxin B1 on Deoxyribonucleic Acid Polymerase of Escherichia Coli. Proceedings of the Society for Experimental Biology and Medicine 125:1052-1055Kolbye, S., and Legator, M.S. 1966. Mutation Research 6:367-369- Mutagenic Activity of Streptozotocin. DolLmpio, D., Jacobson, C., and Legator, M.S. 1966. Effect of Aflatoxin on Human Leukocytes. Proceedings of the Society for Experimental Biology and Medicine 127:559-562. Legator, M.S., and Jacobson, C.B. 1966. Clinical Proceedings 24:164-169- Chemical Mutagens as a Genetic Hazard. Gubridge, M.D., DeNunzlo, A., and Legator, M.S. 1969- Cycasin: In Vivo Detection of Associated Mutagenic Activity. Science 163:669-691Gabridge, M.G., DeNunzio, A., and Legator, il.S. 1969- Microbial Mutagenicity of Streptozotocin in Animal-Mediated Assays. Nature 221:66-70. Gabridge, M.G., Oswald, E.J., and Legator, M.S. the Host-Mediated Assay for Mutagenicity. 1969- The Role of Selection in Mutation Research 7-117—119- Gabridge, M.G., and Legator, M.S. 1969- A Host-Mediated Microbial Assay for the Detection of Mutagenic Compounds. Proceedings of the Society for Experimental Biology and Medicine 130:631-634. Mayer, V.U. and Legator, M.S. 1969- Production of Petite Mutants of Saccharomyces Cerevisiae by Putulin. J Agric Food Chern 17:454-456. Legator, M.S. and Mailing, H.V. 1969. Concepts in Mammalian Testing for Chemical Mutagens. EMS Newsletter 1:12-15Legator, M.S., Palmer, K.A., Green, S., and Petersen, K.W. 1969- Cytogenetic Studies in Rats of Cyclohexylanine, a Metabolite of Cyclamate. Science 165:1139-1140. Legator, M.S., Kelly, F.J., Green, S., and Oswald, E.J. 1969of Captan. New York Academy of Sciences 160: 344-351- Mutagenic Effects Mayer, V.W., and Legator, M. 1970. induction of N-Metiiyl-N'-Nitrosoguanidine and IT/ Light of Petite Mutants in Aerobically and Anaerobically Cultivated Saccharomyces Cerevisiae. Mutation Research 9:193-196. IM S Page 7 Curriculum Vitae - Marvin ..--yrnour Le¿a cot’ Green, 3., Palmer, K.A., and Legator, M.S. 1970. In Vitro Cytogenetic Investigation of Calcium Cyclamate, Cyciohexylamine and Trifluoropromazlne. Food and Cosmetics Toxicology 6:617-623. legator, M.S. 1970. Chemical Mutagenesis Comes of Age: Environmental Implications. Journal of Heredity 61: 269-292. Legator, M.S. 1970. Mutagenic Effects of Aflatoxin. Veterinary Medical Association 159:2060-2(163. Legator, M.S. 1970. Host-Mediated Assay. Journal of the American E1S Newsletter 3:39. Legator, M.S. 1970. Chemical Mutagens in Man's Environment— Book Review. Newsletter 3'-33-39. H-1S Palmer, K.A., Green, S., and Legator, M.S. 1970. Cytogentic Effects of DDT and Derivatives of DDT in a Cultured Mammalian Cell Line. Toxicology and Applied Pharmacology 17:276. Kelly, F., and Legator, M.S. 1970. Effect of N-Methyl-N'-Nitro-NNitrosoguanidine on Cell Cycle and Chromosomes of Human Embryonic Lung Cells. Mutation Research 10:237-296. Zeiger, E., and Legator, M.S. 1971- Mutagenicity of N-Nitroso-Morpholine in the Host-Mediated Assay. Mutation Researcli 12:969-971« Kelly, F., ana Legator, M.S. 1971. Tne Effects of N-Methyl-N'-Nitro-NNitrosoguanidine and Strepzotocin on Mammalian Cell Cultures. Mutation Research 12:163-190. Legator, M.S. 1971« Method for Detecting Chemically-Induced Mutations in Food Additives. Journal American Oil and Chemical Society 96:333A. Brusick, D., and Legator, M.S. the Host-Mediated Assay. 1971« Utilization of Saccharomyces Cerevisiae in EMS Newsletter 9:31-32. Legator, M.S. 1971. Deficiencies in our Present Protocol for Chemical Evaluation and Possible Remedies. Annals of the New York Academy of Sciences 179: 508-513« Zeiger, E., Legator, M.S., and Lljinsky, W. 1972. The Mutagenicity of N-Nltroso-Piperazines for Salmonella typhimurium in the Host-Mediated Assay. Cancer Research 32:1598-1599Legator, M.S. 1972. Genetic Effects of Environmental Contaminants. Population and Pollution. Proceedings of the Annual Symposium of the Mutagen Society, 6 th (1971), pages 95-99« Legator, M.S. 1972. Chemical Mutagens. Annual Review of Medicine 23:913-926. Legator, M.S. 1972. Hie Need to Detect Chemically Induced Mutations in Experimental Animals. Mutagenic Effects of Environmental Contaminants, pp. 67-79« 13458 Curriculum Vitae - Marvin Seymour Legator Page 8 Legator, M.3. 1972. Indirect Indicators for Mutagenicity Testing— An Overview. ElIS Newsletter b:10. Green, S., Palmer, K.A., and Legator, M-S. 1972. Effects of Cyclohexylamine on the Fertility of Male Rats. Food and Cosmetic Toxicology 10:29-34. Peterson, K., Legator, M.S., and Figge, F.H. 1972. Dominant Lethal Effects of Cyclohexylamine in C57 B1 Fe Mice. Mutation Research 14:126-129. Palmer, K.A., Green, S., and Legator, M.S. 1972. Cytogenetic Effects of DDT in a Cultured Mammalian Cell Line. Toxicology and Applied Pharmacology 22:355-364. Palmer, K. A., Kelly-Gavert, F., and Legator, M.S. 1972. Methods for Preparing Anaphase Figures from Rat Bone Marrow. Mutation Research 16:111-112. Kelly, F., and Legator, M.S. 1970. Effects of Cyclohexylamine on the Fertility of Male Rats. Food and Cosmetics Toxicology 10:29-34. Petersen, K., and Legator, M.S. 1973- The Dominant Lethal Results of Trlfluoropromazine in Hybrid C3D2F1/J Mice. Mutation Research 17'-87-92. PaLmer, K.A., Green, S., and Legator, M.S. 1973- Dominant Lethal Study of p,p'-DDT in fiats. Food and Cosmetics Toxicology 11:53-62. Kelly-Gavert, F., and Legator, M.S. 1973* Photoactivation of Ciilorpromazine: Cytogenetic and Mutagenic Effects. Mutation Research 21:101-105Kelly-Gavert, F., DDT and DDE and Legator, M.S. 1973- Cytogenetic and Mutagenic Effects of in a Chinese Hamster CellLine. Mutation Research 17:223-229* Green, S., Carr, J.V., Sauro, F., and Legator, M.S. 1973* Effects of Hycanthone on Spermatogonial Cells (Cytogenetics) DNA Synthesis and Dominant Lethality in Rats. Journal of Pharmacology and Experimental Therapeutics 187:437-443. Green, S., Sauro, F.M., and Legator, M.S. 1973* Cytogenetic Effects of Hycanthone in the Rat. Mutation Research 17:239-244. Carr, J.V., and Legator, M.S. 1973* Hexachlorophene-Induced Alterations in a Metabolism of Cultured Human Lung Cells. Proceedings of the Society for Experimental Biology and Medicine 142:564-566. Kelly-Gavert, F., and Legator, M.S. 1973* Cytogenetic and Mutagenic Effects of DDT and DDE in a Chinese Hamster CellLine. Mutation Research 17:223-229Legator, M.S., PaLmer, K.A., and Adler, I.D. 1973- In Vivo Cytogenetic Analysis - A Collaborative Study. Toxicology and Applied Pharmacology 24:337-350. Legator, M.S., and Flamm, W.G. 1973- Environmental Mutagenesis and Repair. Annual Review of Biochemistry 42: 683-7U8. Legator, M.S. 1973. Procedure for Conducting the Host-Mediated Assay Utilizing Bacteria (Salmonella typhimurium). Agents and Actions - Svriss Journal of Pharmacology, 3irkiiauser Verlag, Switzerland 3:111-115. Curriculum Vitae - Marvin Seymour Legator Page 9 Connor, T., Stoeckel, M., and Legator, M.S. 1974. Niridazole, A Direct Acting Frameshift Mutagen, Not Affected by Microcoral Enzyme Preparation Wliich can be Detected in the Host-Mediated Assay. Mutation Research 26:456-457Legator, M.S. 1974. Mutagenesis and Its Environmental Implications. Occupational Medicine 16(10):672-675- Journal of Legator, M.S. 1974. Relevance of Mutagenesis to Carcinogenesis. Proceedings of the Annual Conference on Environmental Toxicology 5th, pp. 293-306. Legator, M.S., and Williams, R. 1974. The Inadequacies of Submammalian Tests for Mutagenicity. Molecular and Environmental Aspects of Mutagenesis, Proceedings Publ Rochester International Conference on Environmental Toxicology 6 th (1973), pp. 266-262. Legator, M.S., Stoeckel, M., and Connor, T. 1974. Techniques for Isolating Mutagenic Substances from Urine and Blood of Treated Mammals Using Histidine Auxotropns of S. typhimurium as the Indicator Organism. Mutation Research 26:456. Michel, T.M., and Legator, M.S. 1974. Chromosomal Aberrations Induced In Vivo by DNA Repair Synthesis and Triethyieneneiamlne. Mutation Research 24:41-45Weber, E., Bidwell, K., and Legator, M.S. 1974. An Evaluation of the Micronuclei Test for Routine Cytogenetic Analysis. Mutation Research 26(5):461. Michel, T.M., and Legator, M.S. Research 26(5):460. 1974. Comparative Study of Mutagens. Mutation Legator, M.S., Connor, T., and Stoeckel, M. 1975- Detection of Mutagenic Activity of Metronidazole and Niridazole in Body Fluids of Humans and Mice With Salmonella typhimurium. Science 166:1116-1119Legator, M.S., and Ziirmering, S. Fnarmacoiogy 15:367-406. 1975. Genetic Toxicology. Committee 17 of the Environmental Mutagen Society. Hazards. Science 167:503-514. 1975- Annual Review of Environmental Mutagenic Legator, M.S., and Zimmering, S. 1975- Integration of Marrmaiian, Microbial and Drosophila Procedures for Evaluating Chemical Mutagens. Mutation Research 31. Legator, M.S., Connor, T.H., and Stoeckel, M. 1975- The Detection of Mutagenic Substances in the Urine and Blood of Man. Annals of the New York Academy of Sciences. M.S. Legator and A. Hollaenaer, ed., 269:16-20. Bidwell, K., Weber, E., Nienhold, I., Connor, T., and Legator, M.S. 1975Comprehensive Evaluation for Mutagenic Activity of Dieldrin. Mutation Research 31:314. Gupta, A.K., and Legator1, M.S. 1975. Chromosome Aberrations in Cultured Human Leucocytes After Treatment with the Fungicide Benlate. Proceedings of . Symposium on Mutagenicity, Carcinogenicity and Teratogenicity. Chemistry, Curriculum Vitae - Marvin Seymour Legator PP- Page 10 95-103* Stoeckel, M., Weber, E., Connor, T., and Legator, M.S. 1975- Failure to Detect Mutagenic Effects of Delta-9-Tetrahydrocannabinol in In Vitro and In Vivo Studies with Mice. Mutation Research 31:313-314. Weber, E., Bidwell, K., and Legator, M.S. 1975* Evaluation of the Micronuclei Test using Triethyleneanine, Trimethylphoshate, Hycanthone and Niridazole. Mutation Research 28:101-106. Zimmering, P.K., Legator, M.S., and Weber, E. 1975- Effect of Pyrogen Treatment on Cytogenetic ResDonse with Chemical Mutagens in Mice. Mutation Research 31:339-340. Green, S., Zeiger, E., Palmer, K.A., Springer, J.A., and Legator, M.S. 1976. Protocols for the Dominant Lethal Test, Host-Mediated Assay and In Vivo Cytogenetic Test Used in the Food and Drug Administration's Review of Substances in the GRAS (Generally Recognized As Safe) List. Journal of Toxicology and Environmental Health 1:921-928. Nienhold, I., Kaplan, S., and Legator, M.S. 1976. Decrease in 3H-Tiiymidine Incorporation in Cells Derived from Systemic Lupus Erythematosus Patients Following Exposure to 4-Nitroquinoline 1-oxide. Mammalian Chromosomes Newsletter 217(1/2):¿3. Connor, T.H., Stoeckel, M., Evrard, J., and Legator, M.S. 19*77. The Contribution of Metrinidazole and Two Metabolites to trie Mutagenic Activity Detected in Urine of Treated Humans and Mice. Cancer Research 37:629-633Kilian, D.J., Moreland, F.M., Benge, M.C., Legator, M.S., and Whorton, E.B., Jr. 1977. Collaborative Cytogenetics Study to Measure and Minimize Interlaboratory Variation. Mutation Research 44:97-104. Connor, T., and Legator, M.S. 1978- Method for Separation and Analysis of Body Fluids in Rodents and Humans for Mutagenic Components Using Salmonella typhimurium as the Indicator of Mutagenicity. Mutation Research 33:71-72. Coutino, R., Meyne, J., and Legator, M.S. 1978. Cytogenetic Studies in Chinese Hamster Ovary Cells With the Narcotic Antagonistic Naltrexone. Mutation Research 53:80. Kilian, D.J., Pullin, T.G., Connor, T., Legator, M.S., and Edwards, H.N. 1978. Mutagenicity of Epichlorohydrin in the Bacterial Assay System: Evaluation by Direct In Vitro Activity and In Vivo Activity of Urine from Exposed Humans and Mice. Mutation Research 53:72. Kilian, D.J., Whorton, E.B., Jr., and Legator, M.S. 1978. Response to Critique of Paper 'A Collaborative Study to Measure and Minimize Interlaboratory Variation'. Mutation Research 50:293-294. Meyne, J., Rinkus, S., and Legator, M.S. Breaks Induced by Three Chemicals. 1978. Distribution of Chromosomal Mutation Research 53:80. Molina, L., Rinkus, S., and Legator, M.S. 1978. Evaluation of the Micronucleus Curriculum Vitae - Marvin Seymour Legator Procedure Over a 2-Year Period. Page 11 Mutation Research 53:125- Rinkus, S., and Legator, M.S. 1978. Deficiencies in the Microbial Activation System for l'lutagenic-Oarcinogenic Screening. Clinical Genetics 13:133-134. Troung, L., and Legator, M.S. 1978. In Vivo Determination of Alkylation of Amino Acids in Hemoglobin and Urine to Detect Potential Mutagenic-Carcinogenic Effects. Mutation Research 33:121. Nienhold, 1. and Legator, H.S. 1978. Assessment of Unscheduled DNA-Syntnesis in Lupus-Erythematosus (SLE) Patients. Clinical Genetics 13(1):130. Biles, R.W., Connor, T.H., Trieff, N.M., and Legator, M.S. 1978. The Influence of Contaminants on the Mutagenic Activity of Dibromochloropropane (DBCP). Journal of Environmental Pathology and Toxicology 2:301-312. Truong, L., Ward, J.B., Jr., and Legator, M.S. 1978. Detection of Alkylating Agents by the Analysis of Amino Acid Residues in Hemoglobin and Urine. 1. Tne In Vivo and In Vitro Effects of Etnyl Methanesulfonate, Methyl Methanesulfonate, Hycanthcne Methanesulfonate, and Naltrexone. Mutation Research 54:271-281. Rinkus, S.J., and Legator, M.S. 1979* Chemical Characterization of 465 Known or Suspected Carcinogens and Their Correlation with Mutagenic Activity in the Salmonella typhimurium System. Cancer Research 39:3289-3318. Legator, M.S., Kouri, R.E., Parmar, A.S., Zimmering, S., Putman, C., Latt, R., Heicklen, J., Meagher, J.F., weaver, J., and Kelly, N. 1979* Mutagenic Testing of Diethylhydroxylamine, Nitroethane and Diethyfamine Hydrogen Sulfite. Environmental Research 20:99-124. Connor, T.H., Meyne, J., Molina, L., and Legator, M.S. 1979* A Combined Testing Protocol Approach for Mutagenicity Testing. Mutation Research 64:19-26. Legator, M.S. and Zimmering, S. 1979* Review of the Genetic Effects of Caffeine. Journal of Environmental Science and Health, Part C-Environmental Health Sciences 13(2):135-188. Moreland, F.M., Kiiian, D.J., Palmer, K.A., Springer, J.A., Green, S. and Legator, M.S. 1979- A Collaborative Dominant Lethal Study of Triethylenemelamine in the Rat. Toxicology and Applied Pharmacology 49(1):161—170Trieff. N.M., Walker, R.D., Connor, T.H., Mackenzie, K. and Legator, M.S. 1979Mutagenic Assessment of Air Particulate Samples of Houston, Texas USA. Fed. Proc. 38(Vol. 3, part 1):535Infante , P.F. and Legator, M.S. 1979* Workshop on Methodology for Assessing Reproductive Hazards in the Workplace - Recommendations for Future Research - April 19-22. Environmental Research 20(1):217-223Connor, T.H., Cantelli-Forti, G., Sitra, P. and Legator, M.S. 1979* Bile As a Source of Mutagenic Metabolites Produced in vivo and Detected By Salmonella typhimurium. Environmental Mutagenesis 1(2):269-276. Page 12 Curriculum Vitae - Marvin Seymour Legator Legator, M.S. iy79- Chronology of Studies Regarding Toxicity of 1-2-Dibromo- j-CliloroproDane. Annals of the New York Academy of Sciences 329:331-338. Connor, T.H., Pullin, T.G., Meyne, J., Frost, A.F. and Legator, M.S. 1980. Evaluation of the Mutagenicity of Normal-BGE in a Battery of Short-Term Assays. Environmental Mutagenesis 2(2):284. Connor, T.H., Meyne, J. and Legator, M.S. 1980. Hie Mutagenic Evaluation of Tetraids (Hydroxymethyl) Phosphonium Sulfate Using a Combined Testing Protocol Approach. Journal of Environmental Pathology and Toxicology 4(1):145-158. Meyne, J. and Legator, M.S. 1980. Sex-Related Differences in Cytogenetic Effects of Benzene in the Bone Marrow of Swiss Mice. Environmental Mutagenesis 2:43-50. Connor, T.H., Ward, J.B. Jr., Meyne, J., Pullin, T.C-. and Legator, M.S. 1980. The Evaluation of the Epoxide Diluent, n-Butylglycidyl Ether, in a Series of Mutagenicity Assays. Environmental Mutagenesis 2:521-530. Kapp, R.W., Jr., Benge, M.C., Picclano, D.J., Kilian, D.J., Legator, M.S., and Jacobson, C.B. I98 O. Monitoring Y Chromosomal Nondisjunction in Humans with the YFF Sperm Test. In: Proceedings of a Workshop on Methodology for Assessing Reproductive Hazards in the Workplace. DHHS (NI0SH) Publication No. 81-100. U.S. Government Printing Office, Washington, D.C. Legator, M.S. 1980. Human Exposure to Formaldeliyde Monitored by Several Assays for Mutagenesis in Man. Toxicology Research Projects Directory 5(H)Made Gowda, N.M., Sadagopa Ramanujam, V.M., Trieff, N. M., and Legator, M.S. 1980. Assay of Thioacetamlde and Thiobenzanide 'with Chlorumine-T. Analytical Chemistry 52:209-211. Rinkus, S.J. and Legator, M.S., 1980. An Evaluation of In Vitro Testing for Mutagens. DHHS (NIOSH) Publ. (U.S.):81-100, Proc. Workshop Methoaol Assessing Reprod. Hazards Workplace, pp. 117-33* Albrecht, T., Speelman D.J., Sadagopa Ramanujam, V.M., Lund, H.W., Legator, M.S. and Trieff, N.M. 1980. Correlation of the Chemical Structure of 4-Nitroquinolines Inactivating Human Cytomegalovirus and established In Vivo Carcinogenicity Tests. Teratogenesis, Carcinogenesis, and Mutagenesis 1(2):161-169Legator, M.S. I960. Radiation Equivalents for Chemical Mutagens: A Critique. International Atomic Energy Agency, Vienna, pp. 87-90. Adams, P.M., Fabricant, J.D., and Legator, M.S. 1981. Cyclophosphamide Induced Sperrnatogenic Effects as Detected in the FI Generation by Bellavioral Testing. Science 211:80-82. Ramanujam, V.M.S., Connor, T.H. and Legator, M.S. 1981. High Performance Liquid-Chromatographic Determination of Normal 3utylgiycidyl Ether. Microchemical Journal 26(2):217-220. 13463 Page 13 Curriculum Vicue - Marvin Seymour Legator Trieff, N.M., Ramanujam, V.M.S., Connor, T.K., ilade Gowda, N.I1. and Legator, M.S. 1981- Mutagenicity Studies of Aromatic Amines. Environmental Mutagenesis 3(3):322-j2o. Legator, M.S. 1981. Mutagenicity of Captan. Mutation Research 85(4):220. Speelman, D., Li, J.L.H., Ramanujam, V.M.S., Legator, M.S. and Albrecht, T. 1981. Herpes-Viruses Inactivation by Chemical Carcinogens - Differential Inactivation of Herpes-Simplex Viruses By 4-Nitroquinoline 1-Oxide and Related Compounds. Environmental Mutagenesis 3(4):467-476. Rinkus, S.J. and Legator, M.S. 1931. Salmonella Revisited: A Reply to Ames and McCann. Cancer Research 41:4196-4203Fabricant, J.D. and Legator, M.S. 1981. The Mutagenicity of Vinyl Cliloride. Environmental Health Perspectives 41:189Legator, M.S. 1931. Mutagenesis Test Systems - Development. Projects Directory 6(10). Toxicology Research Fabricant, J.D. and Legator, M.S. 1931. Etiology, Role and Detection of Chromosome Aberrations. Journal of Occupational Medicine 23(9):617-625Frost, A.F. and Legator, M.S. 1932. Unscneduled DMA synthesis induced In Human Lymphocytes Ey Butyl Glycdyl Ethers. Mutation Research 102:193-200. Legator, M.S., Bueding, E., Batzinger, R., Connor, T.H., Eisenstadt, E., Farrow, M. G., Fiscor, G., Ksle, A., Seed, J., and Stafford, R.S. 1982. An Evaluation of the Host-Mediated Assay and Body Fluid Analysis. A Report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation Research 93(3):319-374. Walker, R.D., Connor, T.H., MacDonald, E.J., Trieff, N.M., Legator, M.S., Mackenzie, K.W., Jr., and Dobbins, J.G. 1982. Correlation of Mutagenic Assessment of Houston Air Particulate Extracts in Relation to Lung Cancer Mortality Rates. Env. Research 28:303-312. Adams, P.M., Fabricant, J.D., and Legator, M.S. 1982. Active-Avoidance Behavior in the FI Progeny of Male Rats Exposed to Cyclophosphamide Prior to Fertilization. N'eurob. Tox. 4(5):53I-534. Fabricant, J.D., Legator, M.S., and Adams, P.M. 1983- Post-Meiotic Cell Mediation of Beriavlor in Progeny of Male Rats Treated with Cyclophospliamide. Mutation Research 119(2):185-190. Meyne, J., and Legator, M.S. 1983- Clastogenic Effects of Transplacental Exposure of Mouse Embryos to Nitrogen Mustard or Cyclophospnomide. Teratog. Carcinog. Mutagen 3(3):281-287. Connor, T.H., V.M. Sadagopa Ramanujam, Rinkus, S.J., Legator, M.S., and Trieff, N. M. 1983- The evaluation of mutagenicities of 19 structurally related aromatic amines and acetamides in Salmonella typhimurium TA98 and TA100. Mutation Research 118:49-59. Curriculum Vi cae - Marvin Seymour Legator used for immunotherapy desensitization. Lancet ii, p. Page 14 915- Books/Book Chapters: Ledley, R.S., Legator, M.S., and Wilson, J.B. I96 B- Automatic Determination of Mitotic Index. Pictorial Pattern Recognition. B.C. Cheng, R.S. Ledley, D.K. Pollock, and A. Roseru'eld, eas. , Thompson Book Company, Wasiilngton, D.C. Legator, M.S. 1969- Biological Assay for Aflatoxin. Aflatoxin - Scientific Background, Control, and Implications. I. Goldblatt, ed., pp. 107-149, Academic Press. Legator, M.S., and Sperling, D. 1970. Selective Toxicity: Genetic Implications. Laboratory Diagnosis of Diseases Caused by Toxic Agents. F.W. Sunderman ana F.W. Burroeman, Jr., eas., pp. ±7-22, Warren~H. Green, Inc., St. Louis, Missouri. Legator, M.S., and Jacobson, C.V. 1970. Detection of Cytogenetic Effects of Toxic Agents in Mammalian Systems. Laboratory Diagnosis of Diseases Caused By Toxic Agents. F.W. Sunderman and F.W. Sunderman, Jr., eds., pp. ¿b-c-L, Warren h. Green, Lnc., St. Louis, Missouri. Legator, M.S. 1970. The Host-Mediuated Assay: A Practical Procedure for Evaluating Potential Mutagenic Agents. Chemical Mutagenesis In Animals and Man. F. Vogel and G. Rohrborn, eds., pp. 260-270, Springer-Verlag, New York and Germany. Legator, M.S. and Mailing, H.V. 1971- The Host-Mediated Assay: A Practical Procedure for Evaluating Potential Mutagenic Agents in Mammals. Chemical Mutagens. A. Hollaender, ed., Vol. 2, pp. 569-909, Plenum Press, New York and London. Epstein, S.S., and Legator, M.S. 1971. The Mutagenicity of Pesticides. Massachusetts institute of Technology Press, Camcriage, Massachusetts. Legator, M.S. 1972. The Use of Indirect Indicators for Mutagenicity Testing.. Non-Psychiatric Effect of Drugs of Abuse. S.S. Epstein, ed., pp. 171-176, Government Printing Office, Washington, D.C. Legator, M.S. 1972- Drugs as Potential Mutagens. Mutagenic Effects of Environmental Contaminants. E. Sutton and II.I. Harris, eas., Academic Press, New York. Legator, M.S., and Epstein, S. 1974. Environmental Mutations in Man. Environmental Problems in Medicine. M.S. Legator and S.S. Epstein, eas., Criarles C. Thomas, Springfield. Legator, M.S., and Simmering, S. 1975- Genetic Toxicology. Annual Review of Pharmacology. .Annual Reviews Inc., Palo Alto, California. Curriculum Vitae - Marvin Seymour’ Legator Legator, M.S., and Nichols, W. Plenum Press. 1975- Page 15 Mutagenicity Testing. Laboratory Manual, Legator, M.S. 1975* Environmental Problems in Medicine, Mutagenic rffects of Environmental Agents, diaries C. Thomas Publishing Company, Springfield, Ohio. Legator, M.S., Zinmering, S., and Connor, T. 1976. Use of Indirect Indicator Systems to Detect Mutagenic Activity in Human Subjects and Experimental Animals. Chemical Mutagens and Principal Methods for Their Detection. A. Hollaender, ed., Vol. A, pp. 171-191', Plenum Press, New York and London. Kilbey, B.J., Legator, M.S., Nichols, W. and Ramel, C. 1977- Handbook of Mutagenicity Test Procedures. Elsevier/North Holland Biomedical rress, Amsterdam. Legator, M.S., Rinlcus, S.J. 1977. Tlie Chemical Environment and Mutagenesis. Women and the Workplace. J. Wagoner and E. Bingham, eds., Government Printing Office, Washington, D.C. Legator, M.S., Pullin, T.G., and Connor, T.H. 1977. The Isolation of liutagenic Substances in Body Fluid and Tissues of Animals and Body Fluid of Human Subjects. Handbook of Mutagenicity Test Procedures. B.J. Kilbey, M.S. Legator, W. Nichols, and 0. Hamel, eds., pp. 149-159, Elsevier/Iiorth Holland Biomedical Press, Amsterdam. Lilian, D.J., Moreland, F.M., Benge, M.S., Legator, M.S., and Whorton,E-B., Jr. 1977- Collaborative Study to Measure Interlaboratory Variation Widi the In Vivo Bone Marrow Metaphase Procedure. Handbook of Mutagenicity Test Procedures. B.J. Kilbey, M.S. Legator, W. Nichols, and C. Hasel, eds., pp. 2AP-LÖU, Elsevier/North Holland Biomedical Press, Amsterdam. Butterworth, B.E., Longstaff, E., Clive, D., Plenta, R.J., Kuna, R., Legator, M.S., Tliilly, U.G., Ray, V.A., Sheridan, W., Williams, G.M., and Efenkel, V. 1979* II. Practical Guidelines for the Use and Interpretation of Short-Term Testing for Hutagens/Carcinogens. Strategies for Short-Term Testing for Mutagens/Carcinogens. B.E. Butterworth, ed., CRC Press, Inc., West Palm Beacn, Florida. Rinlcus, S.J., and Legator, M.S. 1979- An Evaluation of In Vitro Testing for Mutagens. Genetic Damage in Man Caused by Environmental Agents. L Berg, ed., pp. 34p-po2, Academic Press, New York. Legator, M.S. 19Ö1. A Holistic Approach to Monitoring High-Risk Populations by Short-Term Procedures. Banbury Report 9: Chantifleafion of Occupational Cancer, pp"! 3j5-3^5, Cold Spring harbor Laboratory. Legator, M.S., and Rinlcus, S.J. 19Ö1. Mutagenicity Testing: Problems 22 Application. Short-Term Tests for Chemical Carcinogens. H.F. Stich and R-H.C. San, eds., pp. 4Öj>-5ü4, Springer-Verlag, New York. Ward, J.B., Jr., Rinlcus, S.J., and Legator, M.S. 19ol. Strategies for r 3rerooming the Deficiencies of Microbial Activation Systems for Detecting Cheical Mutagens. Microbial Testors for Chemical Carcinogens. I. Cecil iellcner, Curriculum Vitae - Marvin Seymour Legator ed., pp. Page 16 107-166, Marcel Dekker Inc., New York. Legator, M.S. and Harper, B.L. 1962. Animal-Human Studies: An Integrated Approach to Identifying Hazardous Chemicals in the Workplace. Mutagens In üur Environment. M. Sorsa and H. Vainio, eds., pp. 161-2U2, Alan R. Liss, Inc., New York. Harper, B.L., Rinlcus, S.J., Scott, M.J., Anmenheuser, M., Bang, K.M., Lowery, M., and Legator, M.S. 1962. Correlation of NCI and IARC carcinogens with their mutagenicity in Salmonella, in: Use of Human Cells for the Evaluation of Risk from Physical arid Chemical Agents. a NAIL) Publication. Plenum Press pp. 656-424. Legator, M.S. and Harper, B.L. 1962. Prom Bacteria to Man, The Evolution of Mutagenicity Testing, in: Use of Human Cells for Evaluation of Risk From Physical and Chemical Agents. A NATO Publication. Plenum Press pp. 467-496-' SUBMITTED: Legator, M.S. and Ward, J.B., Jr. Genetic Toxicology - Relevant Studies with Animal and Humans. Anglo-American Conference on Pregnant Women at Work, The Royal Society of Medicine, June 16-15, 1966Ward, J.3., Jr., Hokanson, J.A., Smith, E.R., Chang, L.W., Pereira, M.A., Whorton, E.B., Jr., and Legator, M.S. Sperm Count, Morphology and Fluorescent Body Frequency (YFF) In Autopsy Service Workers Exposed to Formaldehyde. Mutation Research. IN PRESS: Sadagopa Ramanujam, V.M., Made Gowda, N.M., Trieff, N.H., and Legator, M.S. Ultraviolet Spectrophotometric Assay of p-Aminobenzenesulfonamides. Microchemical Journal (in press). Legator, M.S. The Successful Experiment That Failed. Institute. Hastings, New York (in press). Bulletin of Hastings Adams, P.M., Siiabrawy, 0. and Legator, M.S. Male-Transmitted Developmental and Neurobehaviorul Deficits. Environmental Influences on Fertility, Pregnancy, and Development: Directions for Future Research. May 24-26, 1962, Vernon Manor Hotel, Cincinnati, Ohio (Meeting Proceedings in press). Legator, M.S. and Ward, J.B., Jr. Personnel Monitoring with Cytogenetic and Other Short Term Bioassays. Ann Arbor Science Publishers (in press). OTHER: Oswald, E.J., Harp, A.R., and Legator, M.S. 1966. in Antibiotics. Bacterial Proceedings _lb- Survival of PPLO ¿aid "L" Forms 13467 Page 17 Curriculum Vitae - Marvin Seymour Legator Childs, V.A., and Legator, M.S. 1966. Lactic Deliydrogenase Activity and Isozyme Pattern as a Function of Age in Diploid Cultures. Proceedings of the 16th Annual Meeting of Tissue Culture Association 77. Legator, M.S., and Reedy, R.J. 1966. The Use of Semisynthetic Pennicillians in Tissue Culture. Conference on Antibiotics and Chemotherapy. Legator, M.S. 1970. Drug Risks. Symposium, National Academy of Science National Academy of Engineering. Legator, M.S. 1970. Mutagenic Effects of Environmental Intrusions. of Food and Drug Officials of the U.S. 34 (1). Brusick, D., and Legator, M.S. the Host-Mediated Assay. Association 1971. Utilization of Saccharomyces Cerevisiae in EEM3 NEWSL; 4:31-32. Legator, M.S. and Hollaender, A. 1975* Occupational Monitoring for Genetic Hazards. Annals of the New York Academy of Sciences. 269:1-45. PATENTS: Legator, M.S. 1961. Initibiting Growth of Bacteria in Water Flooding Process. U.S. Pat. 2,967,475Legator, M.S. 1961. Rader, Legator. Slimicide. 1962. Racusen, Legator. U.S. Pat. 3,006,607. Preservation of Foods. 1962. Soil Fumigant. Legator, Kreutzer, Soloway. 1963- U.S. Pat. 3,044,864. U.S. Pat. 3,052,596. Soil Fungicide. U.S. Pat. 3,060,274. Legator, M.S. 1964. Synergistic Antibiotic Compositions and Preparation. U.S. Pat. 3,126,316. Legator, M.S. 1964. Tieman, Legator. Growth Promotant Substances. 1965- Trihalo-substituted Esters. Fan, Rader, Legator, Dowding. U.S. Pat. 3,215,708. 1965- U.S. Pat. U.S. 3,146,968. Pat. 3,169,969* Polyhydronaphtiialene Biepoxides. Haynes, Legator. 1966. Coccidiosis Control Compositions and Methods of Using Same. U.S. Pat. 3,234,087. Legator, M.S. 1966 . Growth Promotant Substances. U.S. Pat. 3,240,605. Legator, M.S. 1966 . Control of Microorganisms with Acrolein. U.S. Pat. 3,250,667« Legator, Page. 1971. Use of Certain Polyamines as Antimicrobial Agents. U.S. Pat. 3,567,420. 13468 J ALAN SCOTT LEVIN, M.D. I. QUALIFICATIONS Dr. Levin is engaged in Che practice of medicine in San Franciso. His Curriculum Vitae and Addendum, listing Professional Societies and Awards, are attached. II. SUBJECT MATTER Dr. Levin will discuss the following in his testimony: the immune system, with its organic, cellular, and humoral components - most especially with regard to the latter, T-helper cells, B-cells, plasma cells and immuno­ globulin production; immune response, both beneficial and harmful; the various experimental studies, particularly those demonstrating atrophy of the thymus, weight loss, depletion of lymphoid organs, lymphopenia, cutaneous type delayed hypersensitivity (skin thickness) and altered bacterial immunity. In addition, Dr. Levin will discuss the following and their significance: immunology as molecular biology; chemical-induced immune dis- regulation; T-cells (lymphocytes from thymus) acting as immune modulators (for which there is "no effect" level); immune surveillance; the similarity of the immune, neurologic, and endocrine systems and their significance in the area of immuno-toxicity; the relationship of immune disregulation caused by chemicals and carcinogenicity, including cancer and the oncogene theory. Also, Dr. Levin will discuss clinical uses of the epidemologic approach, i.e., clinical epidemiology. A n d , D r . L e v i n w i l l d i s c u s s t h e p r o b l e m s o f d i a g n o s i n g " p s y c h i a t r i c disease" and the misdiagnosis which frequently occurs. III. SCIENTIFIC PRINCIPLES See General Statement of Scientific Principles and Assumed Facts attached. IV. SUBSTANCE OF OPINIONS A. That phenoxy herbicides and their contaminants, specifically dioxin, most especially 2,3,7,8-TCDD, cause, an assortment of immunological responses, i.e. immuno-toxicity, which predispose persons exposed, by absorption and/or ingestion and/or inhalation, to such chemicals to a whole host of adverse health effects, such as: chloracne or other skin rashes; liver and other organ damage; various neuro-toxic effects; reproductive effects; and neoplasm. B. That, in connection with the carcinogenic effect, there is no safe level for TCDD or any other carcinogen, and that a single exposure several years earlier can result in human cancer many years later. C. Dr. Levin will then testify to the causal relationship of the various Agent Orange/dioxin related adverse health effects of the representative plaintiffs, including: chloracne; liver damage; neuro-toxic effects, both neurologi­ cal and psychological; reproductive toxic effects, both miscarriages and birth defects; and such neoplastic processes as soft tissue sarcoma, as here a 13470 A L A N S C O T T L E V I N , M . D . ADDENDUM Professional Societies1 1. Alpha Omega Alpha Honor Medical Society 2. Certified Diplomate-American Board of Allergy and Immunology 3. Certified Diplomate-American Board of Pathology-Clinical Pathology 4. Member-Medical Quality Review Committee if 4, Board of Medical Quality Assurance, State of California 5. Fellow-American College of Emergency Physicians 6. Fellow-College of American Pathologists 7. Fellow-American Society 8. Member-American Academy of Allergy 9. Member-American Association of Clinical Chemists 10. Member-Americal Medical Association 11. Member-California Medical Association 12. Member-San Francisco Medical Society L3. Member-Society for Clinical Ecology of Clinical Pathologists Awards 1. American Cancer Society Faculty Research Award D r . L e v i n w Gallo, R.C. June 1983. i l l a l s o r e l y o n t h e f o l l o The Virus-Cancer Story: w i n g a r t i c l e s : Hospital Practice pp. 79-89, Leder, P. Genetic Control of Immunoglobulin Production: Practice pp 73-82, February 1983. Bishop, J.M. Oncogenes and Proto-Oncogenes: pp. 67-74, August 1983. Hospital Hospital Practice Biological Relevance of Immune Suppression as Induced by Genetic, Therapeutic and Environmental Factors: J. H. Dean and M. L. Padarathsingh Editors, Litton Bionetics, Van Nostrand Reinhold Co. New York, Cincinanti, London, 1981. Inadvertent Modification of the Immune Response: The Effects of Foods, Drugs and Environmental Contaminantsl Proceedings of the 4th FDA Science Symposium August 28-30, 1978. Immunologic Considerations in Toxicology Vol 1 & 2, Raghubir P. Sharma, CRC Press, Inc. Boca Raton, Fla. 1981. Pathology of Drug-Induced and Toxic Diseases: R.H. Riddell editor. Churchill Livingstone, New York and London, 1983. Goldberg, R.J. Clinical Uses of the Epidemiologic Approach: Hospital Practice pp. 177-188, August 1983. C. With respect to Opinion IV B, note the following IARC. EPA Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Criteria Documents, Publications and Assorted References Re: TCDD 13472 A PLEA FOR THOUGHTFUL CONSIDERATION Submitted to THE BOARD OF MEDICAL QUALITY ASSURANCE By THE SOCIETY FOR CLINICAL ECOLOGY (Northern California Chapter) Alan S. Levin. M.D. 450 Sutter Street. Suite 1138 San Francisco. California 94108 Richard B. Spohn. Esq. NOS SAMAN, GUTHNER. KNOX & ELLIOTT 100 The Embarcadero. Third Floor San Francisco. California 94105 TABLE OF CONTENTS I. Introduction II. Clinical and Scientific Demonstration of the Efficacy and Safety of Provocation Testing and Neutralization Therapy. III. Flaws In The Opponents' Case Against Provocation/Neutralization V. References I. The members of the INTRODUCTION Society for Clinical Ecology. Northern California Chapter ("Petitioners") are most anxious that this presentation be given the closest, most thoughtful attention by the Board of Medical Quality Assurance. of' the attacks on their certain quarters for techniques some time. They are acutely aware that have emanated The Petitioners from understand that medical break-throughs and innovations are often resisted by those who techniques. have The become Petitioners comfortable have each with made accustomed the extremely modest intellectual and clinical journey represented in testing and treating their allergy patients with the subject techniques, which are but precise refinements, albeit important refinements, of the more traditional techniques. The Petitioners have been dismayed by the virulence of the attacks on their techniques and upon themselves. They have been dismayed at the refusal of their antagonists to engage in a good faith, collaborative scientific dialogue in which an exchange could take place. amazed as much at the Indeed. Petitioners have been refusal of their antagonists to observe patients or to examine carefully the statistical and - 1 - t “ -? r' immunological research their antagonists as they have been embarrassed for over the seriously flawed analyses upon which they have been forced to rely in rejecting the provocation/neutralization modalities. The Board of Medical Quality Assurance should at once acknowledge this internecine conflict and yet avoid getting drawn into it. It should acknowledge it. for what it is — the manifestation of pains of scientific growth and advance­ ment. New clinical and research findings, which are explained by corroborative evidence in basic immunology, have led a large number of allergy practitioners to techniques of testing and treatment. dramatic. modify the The results have been Many individual allergy sufferers who have each typically been treated by several classical practitioners without success have had their symptoms relieved. techniques classical of testing are quicker, The newer and the treatment far less burdensome to the patient. The newer techniques rely far newer less on drug therapy. The techniques in the entirety of their application are demonstrably less costly. -2 i f ?5 I »3 Si t OO .<•’ These various indices of effectiveness can be threatening to those who do not use the techniques and who are not knowl­ edgeable about the literature or the immunological bases of the techniques. In the end. however, the controversy is a classic of innovation and change. viewed also as a clinical vs. immunological discourse In the past it has been academic conflict, presented below should but the erase that false dichotomy. The Petitioners officers of months ago. appreciated the Board the opportunity to meet with of Medical Petitioners in Quality Assurance this Presentation some bring to BMQA's attention a number of rigorously scientific studies that document and explain the safety and efficacy of the sublingual, intracutaneous and subcutaneous provocative and neutralization testing and neutralization therapy tech­ niques. detail the immunological framework and They mechanisms which explain not only why these techniques are sound, medical but also why they are more knowledge than parallel consonant with modern testing and therapeutic techniques of certain other allergists. An extensive methodological and statistical critique is also -313477 made of the reports critical of the provocative neutraliza­ tion techniques. alternative Finally, allergy the scientific soundness of the testing and treatment are placed in perspective'. Petitioners request the Board to review these comments care­ fully, and stand ready to assist the Board and its staff in securing further clarification. (These Comments were originally prepared for submission to the Health Care Financing Administration of the U. S. Department of Health and Human Services for its enlighten­ ment and assistance niques as eligible in evaluating the Petitioners' for Medicare coverage. section numbering and pagination.) -4- tech­ Hence the odd I I . CLINICAL AND SC IEN TIFIC DEMONSTRATION OF THE EFFICACY AND SAFETY OF PROVOCATION TESTING AND NEUTRALIZATION THERAPY L ■h (Prepared by Alan S. Levin, M.D. with the assistance of Joseph D. Miller, M.D. and Sidney Weinstein, B.A.) INTRODUCTION Opponents brand the provocation and neutralization techniques of allergy testing unreliable. in treatment as "experimental" and Yet. this technique has proven safe and effective thousands afforded and of relief clinical to trials. patients whose Furthermore, allergies have it has proven unresponsive to less precise methods of allergy testing and treatment, either because of the type of sensitivity example, poison sensitivities oak-ivy)^" ("chemical or because the extent of or "immune their immune system’s ability to respond appropriately to antigens. It is dysrégulation" ) have hypersensitivity" (for seriously compromised a method whereby permanent relief from food, inhalant, and chemical allergies and other antigen-related illnesses can be obtained without the use of harmful psychotropic drugs, artificial alternatives such as prostaglandin inhibitors, or r -2 1 - 13479 synthetic adrenal Provocation corticosteroids. neutralization also obviate the need bronchodilator, or steroid therapy, for the and antihistamine, long-term side effects of which have never been tested. The efficacy of this approach is well-supported by well-known immunological mechanisms. Three recent rigidly controlled, placebo-controlled studies 3 ’-4.’ 5 have double-blind demonstrated the scientific validity of this approach and have substantiated the immunological mechanisms of action as well. A number of earlier studies also statistically validate the efficacy of provocation/neutralization'. In support scientific of the soundness safety, of reliability, provocation and efficacy, and neutralization techniques, this section will describe: II. CLINICAL AND SCIENTIFIC DEMONSTRATION OF EFFICACY AND SAFETY OF PROVOCATION TESTING NEUTRALIZATION THERAPY THE AND A. What is provocation testing and neutralization treatment? 3. The clinical observations which initiated the development of the provocation/neutralization techniques C. How does provocation/neutralization differ from conventional allergy techniques? D. Which kinds of medical illnesses treated with provocation/neutralization? E. The controlled double-blind which establish the provocation/neutralization are clinical efficacy best trials of F. Modern concepts of the immune response and how they relate to provocation/neutralization 1. The highly regulated and controlled immune system 2. The phasic phenomenon of immune response 3. How provocation/neutralization works k. The immune -response is often mediated by factors other than IgE 5. Two interacting immune mechanisms explain non-IgE mediated allergic reactions 6. Cellular and humoral phasic immune response effectors of the role of a- Role of macrophages b. Basophils histamine and mast c. Role of lymphocytes -23- cells: d. Role of neutrophils G. Why do intradermal and sublingual administration of antigen provoke and neutralize symptoms? -24- A. WHAT IS PROVOCATION TESTING AND NEUTRALIZATION THERAPY? The provocation and neutralization method of testing and treating allergies is a technique by which the clinician can quickly ascertain the doses of allergen that will induce ("provoke") symptoms of allergy, then relieve ("neutralize") the induced symptoms.® To determine the precise beneficial.concentration of each antigen to be tested, a concentration of an inhalant extract designed to induce ("provoke") mild symptoms wheal is measured initially 10 intradermally. The minutes Wheal later. considered "positive". in wheal size is size is growth of greater than injected 2x2 mm is Less than 2x2 mm growth or reduction considered "negative". Consecutively stronger or weaker concentrations, depending on whether the initial wheal is negative or positive, are then.injected at 10 -minute intervals until the strongest concentration is found which relieves ("neutralizes") the induced symptoms in 10 minutes and produces a negative wheal. This is the therapeutic or neutralizing dose. To use this technique correctly, the practitioner must systematically evaluate the effects of a series of different dose levels in each individual. Provoked signs and symptoms are sometimes strikingly intensified rather than relieved by -25- vO f subsequent administration of a much less concentrated dilution of extract than the provoking dose. Therapy is begun with intradermal injections of a solution containing the full individually determined neutralizing dose of each antigen. In some cases, relief can be achieved during the first testing session. __ Most patients beginning immunotherapy with this technique note marked improvement or complete clearing of symptoms within two to three weeks. Thereafter, marked relief usually begins within 30 minutes after each injection and lasts a week. Scientific evidence has shown that sublingual drops are generally as effective as intradermal injections and provide relief in less than 10 minutes. When indicated, inhalation challenges with practitioners conduct oral and allergens or placebo in a single-blind manner to verify the validity of their patients' responses. As will be seen later in this section, provocation and neutralization techniques initiate a biochemical process that alters the ratio of suppressor to helper|inducer T-cell subsets, thereby changing the phase of immune response and resulting in immune unresponsiveness to challenge with additional specific antigen. 13 -26 - B.THE CLINICAL OBSERVATIONS WHICH INITIATED THE ' DEVELOPMENT OF PROVOCATION/NEUTRALIZATION TECHNIQUES Virtually every practicing allergist has noted a strange phenomenon in some patients receiving build-up immunotherapy. When these patients reach a particular dosage level, they report relief which begins in minutes or hours and lasts 'about a week. Some that each injection provides marked return once a week requesting another "relieving injection". This immediate response is unanticipated. the doctors' It does not fit accepted concepts of immunotherapy, yet many allergists have wished they could duplicate this phenomenon in all of their patients. This relieving phenomena is duplicatable in most cases. most patients, a specific For symptom-relieving therapeutic concentration for each antigen extract exists and can be determined by individually skin testing. This clinical principle behind provocation/neutralization. is the In "the case of multiple allergies, the relieving concentration•for each antigen may differ considerably. However, all of the relieving doses can be combined into a single vial to provide response to all the allergens at once. -27- 134-85 C. HOW DOES PROVOCATION/NEUTRALIZATION DIFFER FROM TRADITIONAL ALLERGY TECHNIQUES? Provocation/neutralization has been in use for close to 40 years, and represents a refinement of older techniques. Both use the same allergy extracts supplied by the same supply houses. Both skin test intradermally with stock solutions of extracts. Practitioners of the newer techniques, however, use certain crucial refinements of the traditional methods. (1) They test one item at a time., in 1:5 concentrations, rather than 20-40 allergens at one time in 1:10 dilutions. (2) They carefully observe the patients during the 10 minutes between tests. The wheal size is always monitored, but they also observe every nuance of the patient's affect behavior. indicated, they measure: nasal passageway patency; When pulse; blood pressure; pulmonary function (using a peak flow meter); handwriting changes; and picture-drawing abilities. On the basis of the above monitored criteria, a decision is made concerning the correct treatment dose for therapy for the individual item which is being tested on that particular patient. The most radical difference techniques Traditional is between traditional and newer the determination of the therapeutic dose. allergists start therapy with a dose that 13486 p r o d u c e s a "safe" wheal, t hat is, w h e r e the increase in wheal size is not excessive within 10 minutes. In contrast, the refined approach determines the correct dilution that will neutralize symptoms for that particular patient for the items tested. The traditional therapy requires injections by the physician 1-3 times a week for up to 30 weeks, and then once a month for many years. With the refined approach, once the correct therapeutic dilution is determined, it is combined with the correct dilutions of the other tested items. The patient can then self-treat safely, using sublingual therapy 3 times a week to once every two weeks, or injection therapy once daily and in time once every week or two, as indicated. \ D. WHAT KINDS OF MEDICAL ILLNESSES ARE BEST TREATED WITH PROVOCATION/NEUTRALIZATION ? Provocation and neutralization techniques can be used to test and treat a wider variety of allergic disorders than can those employed by conventional allergists. response is often most gratifying. provocation/neutralization report The patient's Most physicians using that use of specific neutralizing doses of specific stock allergy extracts results in improved "tolerance" to offending antigens when compared to conventional hyposensitization techniques. Traditional allergists are often perplexed by patients who have classical year-round or seasonal asthma or hayfever without having positive skin reactions. of provocation testing The newer techniques and neutralization therapy enable these patients to be effectively treated with stock allergy extracts once it is realized that their illnesses are not caused by an IgE mechanism. Conventional allergists are somewhat successful in treating traditional allergic reactions to pollen, dust, and mold for traditional nasal symptoms, asthma, post-nasal drip, conjunctivitis, urticaria, and at times atopic dermatitis. Most are mediated by IgE mechanisms. of these Practitioners reactions using provocation/neutralization modalities have successfully treated these and other symptoms that have 13488 -30- Finally, these techniques have proven useful for treating , as various syndromes and infectious diseases 10,167-171 such resistant vaginal candidiasis 12 , dysmenorrhea 12 , and active viral infections1 0 as well as certain autoimmune disaeses such as lupus erythematosus.12 ’13 -3 2 - 13489 been linked for the past environmental factors, years ¿0 to a wide variety of including foods, chemicals, and infectious diseases. pets, toxic These immune reactions are mediated by factors other than IgE (including IgG, IgA, 7 etc.) and frequently involve diverse parts of the body. A surprising number of patient complaints include both the typical and allergy. less well-recognized signs and symptoms of Both types of illnesses respond equally well to neutralizing antigenic immunotherapy material appropriate has once been include: aphthous chronic ulcerative colitis; urticaria; hyperkinesis; appropriate determined symptom-relieving illnesses the and specific injected in doses. Examples of stomatitis; chronic diarrhea; dermatitis; chronic atopic migraine; and some such resistant respiratory inhalant syndromes including perennial allergic g g g rhinitis, asthma, and recurrent laryngeal edema. ’ ’ Some patients sensitive to foods, inhalants, and|or chemicals have multi-system disease with symptoms referable to many organs. In these patients, immune complexes affect almost or other the entire #» vascular perturbation vasculature. factors Formerly, these patients were often considered neurotic because of- the multiplicity of their complaints and intractable because no adequate therapy was available. Many of are these patients have multiple sensitivities that readily relieved by neutralization therapy. -3 1 - 1348 o E. THE CONTROLLED DOUBLE-BLIND CLINICAL TRIALS WHICH ESTABLISH THE EFFICACY OF PROVOCATION/NEUTRALIZATION Three rigidly controlled, allergy testing and efficacy of addition, several double-blind placebo treatment clearly provocation/neutralization earlier studies also studies demonstrate on the techniques. In illustrate their efficacy. Boris et al (1983) . These researchers have recently reported a double-blind controlled study on the effect of neutralization therapy on asthma. They evaluated 19 subjects with a history of wheezing to animal dander. The subjects were challenged with inhaled animal antigen to determine the dose causing a 20% decrease of FEV^. The neutralizing dose was serial determined technique. by the On two five-fold subsequent days, dilution skin one week apart, the specific antigen neutralizing dose of placebo was injected and bronchoprovocation was performed with the dose previously ascertained by the provocation test. FEV'1 decreased 31.8% from baseline in the controls, 27.4.% post-placebo, and 10.7% post-neutralization injection (p less than 0.01). FVC and FEF 25-75, and PEF had similar responses. These results demonstrate that when performed, in neutralisation therapy. properly produces a statistically significant improvement bronchospasm in asthma patients sensitive to animal dander. 13491 -3 3 - Rea et al (1983)^. This group performed a similar study using food-sensitive patients. were selected certain foods. intradermally foods. who had A In this study, 22 subjects a documented adverse neutralizing titrating the dose subjects was to the reaction to obtained by sensitizing The patients were then given oral food challenge and injected with neutralizing dose or placebo in a double-blind controlled experiment. Discomfort Rating, Signs and symptoms, Visual Analogue heart rate, Aaron Smith Symbol Digit Modalities Test, Symbol Digit Modalities Subtest, and patient signature were evaluated. The neutralizing dose, compared to placebo, produced a 'protective measured. Statistical analysis showed the difference between neutralizing dose and placebo effect on all parameters to be highly significant (p less than 0.001-0.05) in all parameters with the exception of the Symbol demonstrate Digit Modalities that neutralization Subtest. therapy, These results when properly performed, produces a statistically significant improvement in the symptoms of food intolerance. McGovern et al (1983)5. McGovern et al studied the reliability of the provocative challenge test in six patients and controls. This study used a double-blind, randomized, placebo-controlled protocol. In addition to clinical parameters, it measurea cellular and humoral immune factors in the blood of these subjects. The investigators measured IgG, IgA, IgM, IgD, Co, C^, IgE, immune complexes (by the -3 4 - 13492 polyethylene glycol technique complement-associated and complexes), total white lymphocytes, total T which detects both non-complement-associated immune blood cells, cell T-helper count, cells, absolute T-suppressor cells, and helper/suppressor ratios. The injection of specific doses of allergenic extracts and haptens ’ induced statistically objective significant physical frequency compared with placebo injections. abnormalities with in when patients, In ten additional patients and controls, the authors showed that the neutralization, but not the placebo injection, brought about a reversal of the patients1 induced clinical significant frequency. provocation and reaction with .statistically Blood samples taken before and after neutralization injections in allergic subjects showed' markedly fluctuating levels of parameters of inflammation directly when compared correlated after provocative with- controls. These with the onset of systemic levels reactions injection and with the disappearence of systemic reaction after neutralization. This study is unique. Not only does it demonstrate that provocation/neutralization testing techniques, when performed correctly, produce statistically significant clinical responses when compared to placebo, but it also objectively demonstrates the marked instability immune systems. -3 5 - of allergy patients' In addition to these controlled studies, 3 most recent double-blind placebo there are 9 other controlled studies- which establish the efficacy of provocation/neutralization testing and treatment techniques. Of these nine studies, three 8 ’17 ’X 8 stand out as well-controlled scientific studies which when considered alone, clearly demonstrate the efficacy of the provocation/neutralization technique. Two 19 ’20 of the remaining reports are studies performed in well-controlled, very convincing double-blind . crossover-controlled fashion on single patients. The remaining four 2 1 ’6 ’2 2 ’2 3 studies, when viewed with-the others, further corroborate the efficacy of provocation/neutralization. Q Miller, J. (1977) . This is a well-designed, double-blind, crossover-controlled study which was the first in a series .of confirmatory studies on the provocation/neutralization technique. The major attribute of this study was that it was carefully performed in a double-blind fashion by the recognized leader in the development and clinical use of the technique. symptoms caused Patients found from frequently double-blind phase, were selected extensive by food who clinical experience sensitivities. subjects underwent presented Prior with to be to the a trial treatment J period with neutralization therapy. phase, 2 0 -day or eight subjects were For the double-blind treated during four separate periods either with the putative neutralizing antigens phenolated saline colored with mushroom extract to t O / ’O -36- simulate the neutralizing vaccine. A careful symptom survey was made during the first office visit and symptom changes were recorded during and at the end of each of the four 20-day courses of therapy. Each subject received two courses of antigen and two of placebo in a crossover fashion. During neutralization dose therapy the average improvement score was 3.68 while that for the placebo was 2.25. The difference is stasitically significant (p less than .0 0 2 ). This study clearly provocation/neutralization demonstrates therapy produces that statistically significant improvement when compared to controls. King, D. (1982)17. This is one of the most definitive studies ever performed to test the efficacy of sublingual provocation/neutralization testing. The author evaluated allergy patients who had also had at least one psychological symptoms such as anxiety, difficulty concentrating. depression, confusion, or The major question was whether sublingual provocation with antigen or placebo would induce psychological symptoms more frequently. Selection of the antigens for challenge was based on the patient’s individual history. Thirty patients were challenged with four selected foods and with triple distilled water as placebo. four kinds of trials: given three times), three times), 3) 1 ) allergen 2 ) There were trials (four antigens, each placebo trials (two tests, each give base-rate trials -37 in which the subjects received nothing sublingually but for which the dependent end points were measured (three trials), and 4) open placebo trials to assess the biological reactivity to the placebo (three trials). symptoms. Two blinded judges independently assessed Symptom severity was reported quantitatively. The integrity of the double-blind was evaluated, and data points in which the double blind might have been jeopardized were excluded. Average symptom scores for psychological symptoms were times higher four after antigen than after placebo provocation. This difference was statistically significant (p=0.001). Severe, reactions were also more frequent after antigen challenge (p=0.'006). symptoms were (p=0.02). Somatic symptoms were significantly more.frequent after antigen analysis, more Mixed psychological-somatic frequent provocation but this after according difference was antigen to provocation one method of not statistically that psychological significant using a different analysis. This comprehensive symptoms can be study demonstrates provoked with statistically significant frequency using active antigen administered sublingually when compared to placebo controls. Lee, L.K. (1982) 1a This controlled study measured the relative efficacy of skin endpoint therapy as compared to conventional treatment and finds the titration technique superior. -3 8 - Q 1 O1 ■Q Rapp,___ D_.____(1978) placebo-controlled 9-year-old boy. 19 This study of is milk a double-blind, sensitivity in one The patient was treated with neutralization therapy after the study and improved dramatically. A study of one patient does not prove the case when considered alone, However, when confirmatory considered studies, in this conjunction with well-designed other double-blind, placebo-controlled study further corroborates the efficacy of provocation/neutralization therapy. Rapp, D. (1982) 20 placebo-controlled This study documented wheat allergy. is performed another double-blind, on patient one with This patient was diagnosed by two opthalmologists as having moderately severe chronic allergic blepharo-conjunctivitis. These symptoms improved markedly on a wheat-elimination diet. The patient was then tested intradermally with wheat antigen and opthalmologic symptoms returned. A neutralizing dose of wheat antigen was then determined. The patient was then asked to avoid wheat•in all forms and to ingest 24. capsules (six teaspoons) each day for a period of 12 days. The capsules for each three-day period contained either wheat germ or similarly colored group peanut which had been coded in a double-blind manner. remained asymptomatic throughout the entire The patient 1 2 -day period. She was then told to eat large quantities of wheat. Shortly after reintroducing wheat into her diet, her opthalmologic -3 9 t-Q X *$ t::O' t symptoms recurred. wheat During the next 12 weeks, she limited her ingestion to 1 slice of bread per day while she was treated sublingually with the neutralizing dose of wheat antigen. Her eyes returned to the asymptomatic condition and remained in period. Three bottles, that condition throughout identical then prepared and double-blinded. saline while the 12-week test in color and taste were Two contained phenolated the third contained phenolated saline and her neutralizing dose of wheat antigen. While ingesting large quantities of wheat each day, the patient found that 'her eyes began to tear for the first time in three months after she had used a placebo solution for five' days. Her eyes continued to tear for the next three days while she tried the second‘placebo solution. 1/2 days of using the Her symptoms cleared within 1 bottle containing the active neutralizing dose. This study constitutes a brilliant investigative effort for a busy practicing clinican and a cooperative patient. Although this study involved only one patient, every busy practitioner will appreciate that this patient was definitely responding favorably to the active treatment dose and was not benefitting from a placebo response. Mandell, M. and Conte, A. (1982)21. In the Mandell study, the investigators studied 30 volunteers with documented arthritic pain. Each received a sublingual -4 0 - challenge of 19 food 4S 8 antigens, 9 inhalants, and 4 placebos of distilled water. The positive symptomatic response was 61% for the foods, 38% for the inhalants, and 6.6% for placebos. Each■difference is highly significant statistically. The data and structure of this study are somewhat difficult to assess and the method of assuring the double-blind are not clearly outlined. Despite these flaws, this report adds further corroborative evidence to the efficacy of sublingual provocation/neutralization in conjunction with techniques the when it is considered other positive double-blind controlled studies. Miller, J .(1972)^ . This book represents a comprehensive text on the "how to" of provocation/neutralization techniques. O'Shea, J., and Porter, S. (1981) children who met were chosen hyperkinetic syndrome. teachers was adaptation of 20 on 22 . In this study, fifteen the clinical criteria of The mean score by both parents and the Conner’s Abbott's Hyperkinetic hyperkinesis scale). Index A (an detailed history and physical examination confirmed the diagnosis of hyperkinetic syndrome. and multiples of inhalant five extracts for were serially diluted testing. .The food dyes were commercial food colors sold in most food stores. in Food intradermal Placebo was preservative-free chlorophyll. The study lasted for seven weeks and consisted of two 3-week -4 1 - 13499 periods 3-week separated period, by every one weeks's child was allergy extract or the placebo. vacation. randomly each given either the The same Hyperkinetic Index was used as in the Connor study. that study, During However, in contrast to the children were monitored daily. The allergy extract could be differentiated from the placebo solution by 11 of 14. (78%) of the parents and 7 of "13 (54%) of the teachers because of improved activity and behavior patterns in the children studied. This study indicates that allergy extract therapy can produce significant symptomatic hyperkinetic children, dangerous practice improvement often of obviating treating in the these documented need for the children with amphetamine-like drugs. Rapp, D. (1979) 23 treated with testing. In a food study, extract ‘ Extract subcutaneously. this was These after eleven sublingually remained sensitive. Five of eight foods patients or improved, measured by the Abbot Hyperkinesis Index Scale, three months while ingesting the were titration food allergy administered patients children as for one to to which they were then completed a double-blind evaluation of the food extract and successfully differentiated the latter All were dispensed solutions solution from two placebo patient recognition of color. in opaque bottles to ones. avoid Two of the three children who -42- 13500 failed to correctly identify the food extract relapsed when food therapy was discontinued. They responded favorably when the therapy was reinstituted. This study, like the O'Shea one, further corroborates the efficacy of sublingual provocation/neutralization therapy for food allergy treatment. -4 3 - 13501 F. MODERN CONCEPTS OF THE IMMUNE RESPONSE AND HOW IT RELATES TO PROVOCATIVE/NEUTRALIZATION Although the efficacy of provocation/neutralization has been firmly established clinically and double-blind studies, controversy techniques. This based, assumptions is that mediated by IgE, the in treatable by placebo-controlled still part, surrounds on allergic the the critics’ reactions are and that no immunologic mechanisms exist which can explain the provocation/neutralization phenomenon. The past decade has brought major changes in the concepts underlying the mechanisms of allergy. We originally thought that the immune response was a specific reaction to challenge from a specific antigen, mediated was seen as ever-increasing doses of ever-increasing amounts immune response by a IgE linear specific of antibody. function antigen antibodies, The of producing until the immunologically reactive cells were exhausted and immunologic unresponsiveness ("tolerance") resulted. 24- Although immunologic tolerance is the'goal of build-up immunotherapy modalities, these conventional allergy methods have been unsuccessful in treating non-IgE-mediated allergies (Type 1, immediate response) as well as some classical IgE-mediated illnesses. We now know that many types of allergies, e.g., those cue to -44- 13502 foods and environmental chemicals, cause other-than-IgE mediated reactions. The immune response is a complex series of interactions well-programmed and counteractions between various cellular and humoral components of the immune system. These interactions follow a biphasic or multiphasic curve if plotted out. Because the immune system is part of a larger interactive network the lymphoreticular, nervous, 2 5 ’2 5 and endocrine systems, 2 5 ’2 5 an immune response may involve multiple diverse clinical addiction, 7 hyperkinesis, involving systems and organs and result in such signs and behavior symptoms or as mood migraine, changes, 27 food 23 ’29 ’30 22 ’23 heart problems, 31 or joint diseases. 21 Provocation/neutralization is the clinical correlate of the phasic immune response, where one dose of antigen provokes an immune response, a lower dose cancels ("neutralizes") it, and a still lower dose again provokes it. This pattern occurs because the various components of the immune system involved in an immune reaction are dynamically interacting to return the organism using these to homeostasis modalities antigen-related administration can allergies of a or nonreactivity. safely in neutralizing and most dose Physicians effectively treat cases because of specific antigen alters the body's phase of immune response, thereby enabling it to return to homeostasis. 1. THE HIGHLY REGULATED AND CONTROLLED IMMUNE SYSTEM The immune system is a highly regulated system which monitors and responds to changes in the chemical composition of the body. These molecular changes elements trigger of signals the immune from cellular system which distinguish between harmless and harmful agents. The signals various cellular and humoral effectors "on" control and modulate growth and organism. They interact not and or development only with switch "off" within elements of to the the lyimphoreticular system but with those of the neuroendocrine system as well. Immunologic regulation is effected _bj£ a tightly controlled interactive balance between inducer and suppressor T-cell subsets, antibodies, and a idiotypic multitude of and other anti-idiotypic immunomodulatory molecules and cells Once the immune system has distinguished between harmful and harmless agents, it must induce the appropriate molecular and cellular reactors to ignore reactions) or challenge (suppress active inflammatory (induce active inflammation). Many of the factors secreted by immune-reactive cells are soluble peptides and lipids which circulate to remote sites of the 135 ’4.1-4.4. body and cause effector functions. Objective changes in brain chemistry, 25 joint metabolism, and endocrine glands result from remote immunologic The immune system's tightly reactions. controlled interaction of 13504 antibodies and cells are directed against specific antigens and are called idiotypes. modulated by the specific antigen-combining Production of these idiotypes is antibodies . (anti-idiotypes) site of these antibodies against and cells. The production of these anti-idiotypes are in turn controlled by anti-anti-idiotypes and these by anti-anti-anti-idiotypes. The presence of the family of anti-idiotypic antibodies lends smoothness to the immune response, much like extra cylinders provide smooth function to a gasoline engine. -4 7 - 13505 2. THE PHASIC PHENOMENON OF IMMUNE RESPONSE Specific immunologic unresponsiveness when responsive cell clones ("tolerance”) occurs have been eliminated by prior contact with antigen, with the result that no immune response against that antigen occurs on re-administration. One of the original workers immunological to note the phasic nature of responsiveness Mitchison.51 and unresponsiveness was In his study, newborn rats were injected daily for 2 weeks with a wide range of doses of bacterial flagellin antigen. Control rats including controls, received no antigen. All animals, were then given a stimulatory dose (10 meg) of flagellin twice a week for 4 more weeks, and their antibody responses measured. The results are shown in figure 1 at the end of this subsection. As can be seen in the figure, the response to varying doses of antigen in distribution. than 10 the tolerized animals produced a biphasic At very low tolerizing doses of antigen (less pg of flagellin antigen/gr body weight) the animals responded to the immunizing dose with near-normal (control) levels. As the tolerizing doses animals developed specific (low-dose tolerance). around 10-1 ("overshoot") pg, the immune approached immunologic 10-3 pg, the unresponsiveness As the tolerizing dose increased to animals responded response. -48- with a supernormal When the tolerizing dose IS approached 100 pg and above, the animals again exhibited specific unresponsiveness. This phenomenon has been shown to be due to the modulatory effects of suppressor concentrations of T cells antigen. which These respond suppressor to various cells can be categorized as non-antigen-specific and specific. through body. soluble factors which Most react can circulate throughout the "Tolerance" occurs when the specific suppressor T-cell factors are dominant over specific helper/inducer T-cell - , 60-74. factors. Biphasic and mediators of multiphasic the responses inflamatory to antigen process are and other not' unusual. Although not specifically discussed, they have been found by a number of investigators in their studies. For example, in experiments using spin label probes to detect the release of myelin-basic membrane, biphasic protein from lipid vesicles in an artificial Boggs et a l .52 showed a reciprocal and essentially response between antibody-independent specific release as a antibody-dependent function of and increased antigen concentration. Eichmann^ found that bacterial carbohydrate 50% of cross-reacting idiotypes. with anti-idiotypic the produced antibodies to a specific by a strain of mice had When these animals were pretreated antibody, their -4 9 - idiotype response was s 3 suppressed. The amount of suppression followed a biphasic y curve. Small amounts idiotypic suppression, of anti-idiotype intermediate produced little doses produced maximum suppression, and larger doses produced less suppression. I A similar phenomenon was demonstrated by Szewczk et al5'14’ ci when they measured the affinity distribution of the IgG cells the of animals ri anti-TNP 1 plaque-forming in spleen treated with various doses of histamine which is a suppressor cell inducer. Sullivan et al^5 found that modulation of cyclic AMP in ri purified rat mast cells by pharmacologic stimuli follows a biphasic mode. purified rat They mast demonstrated cell cAMP to vj a biphasic response of carbamycholine, exogenous adenine, and diazoxide. J :1 A biphasic response develped in rats1 capacity to respond to sensitization with a supraoptimal dose of oxazolone when they were pre-treated with various doses of oral concentrations weeks cyclophosphamide.5 S Serial assessment of These biphasic and antibody after 57 immunization with antigen often shows a multiphasic curve. multiphasic responses to varying concentrations of antigen are due to the phasic nature of the immune network which is a complex interaction of idiotypes 1350 - 5 0 - and . . 58 anti -idiotypes. When the helper/inducer cells are dominant in function, idiotypes are synthesized. This provokes a reciprocal synthesis of anti-idiotypes which enhance the activity of the suppressor cells. The suppressor cells then suppress the action of the idiotype-producing B cells. This cycle continues with ever-decreasing intensity until the base line is re-established. 75-77 figure 1: 51 The Phasic Nature of the Immune Response -5 1 - 3 . HOW PROVOCATION/NEUTRALIZATION WORKS Many types of allergic formation of immune reactions are mediated through the complexes. Provocation/neutralization works because it alters the ratio of antibody to antigen by addition of a small amount of antigen. The combination fundamental of antibody life-preserving with antigen processes of is one of immunology. the Yet these complexes,once formed, must be completely removed from the circulation quickly, for their persistence is itself a threat to survival of the organism. persistence leucocytes can call complement This is because such and polymorphonuclear into action to destroy the remaining complexes. Since these destructive effects are nonspecific, cells in the vicinity of the complexes may be damaged or destroyed, possibly resulting in lethal immune-complex-mediated disease. The existence and potential pathogenicity of immune complexes 78 were first suggested in 1905 by von Pirquet and Schick. Immune complexes are formed daily in everyone from foods, 7 9 -8 1 inhalants, micro-organisms, and many other antigens, but their size, are such level, that and rate of removal from- the circulation clinical immune complex disease does not normally occur. Very small complexes which are formed in antigen excess are less likely to be pathogenic than somewhat -52- 82 larger ones. 13510 This is because they may contain only one IgG antibody which is incapable of activating complement. They are small enough to circulation pass completely out of the through inter-endothelial cell pores in vascular basement membranes. These very small complexes do very little harm since they activate complement and do not deposit in vessels. Very large'complexes (over 19S) formed in antibody excess are efficiently cleared from the circulation by macrophages of go the reticulo-endothelial system. They are also relatively harmless. Intermediate-sized complexes formed at approximate - equivalence (ag:ab ratio of approximately 3:2) with a molecular weight of about one million, are the potentially toxic ones. to be They are too small efficiently phagocytosed by macrophages, and are too large to completely traverse the pores of vascular basement membranes. They tend to persist become lodged in these pores. the complement and cascade tissue the circulation and This automatically activates which polymorphonuclear leukocytes. endothelial in in turn . attracts The destruction of neighboring cells flows from two mechanisms, destruction by complement cascade proceeding to C8 and C9, and neutrophil enzymatic digestion. 82 -5 3 - JLO jl. A If complement activation proceeds only to the point of liberating anaphylatoxins, particularly if only to C3a, there is much less likelihood of inducing irreversible cell injury by either mechanism. Anaphylatoxins can cause release of histamine and other mediators from mast cells and basophils, inducing reversible enlargement of inter-endothelial cell pores resulting in increased capillary permeability and local edema. It is chiefly by way of such edema that allergic symptoms can be initiated without the involvement of IgE'and without the cellular destruction associated with full complement activation and neutrophil participation. Antigen-antibody interaction in immune complex formation is a highly dynamic process. can quickly Antigens and antibodies in complexes dissociate Complement and activation recombine and in other ratios. inactivation and anaphylatoxin-induced mediator release can occur in seconds or minutes. 83 Adding a small amount of antigen or antibody can reaction rapidly and markedly. shift the This shift results in smaller or larger- complexes, thereby altering the potential for complement activation.. If the right amount of antigen is added to shift the curve from pathogenic nonpathogenic mode, rapid symptom-relief occurs. what happens in neutralization. of antigen keeps controlled. to a This is Repeatedly adding this dose equilibrium reactions stable and symptoms If the amount of antigen added is too small or too large, symptoms are induced. The induction and relief of symptoms in this manner are consistent with the "turn-on"/"turn-off" phenomena noted during provocation and neutralization testing and with the long-term relief provided by regularly figure 2 administered (next two neutralization pages) for provocation/neutralization works, a injections. See diagram how of and an explanation of the diagram. 13513 -55- FROM SKI M G I TRACT -56TòX IU S EDEMA) AWRPHVLA- 1/A5CUL AR --------------- » PERMEABILITY FROM AWT I GEN AMTIGEN figure X: How Provocation/Neutralization Works 1- Legend to figure 1 How Provocation/Neutralization Works 1. Antigen from G-I tract (A) enters circulation, is bound byantibody to from ag-ab complexes. 2. If complexes persist in circulation, activated, anaphylatoxin released. complement is 3. Anaphylatoxin triggers mast cells and basophils to release mediators, resulting in vascular permeability, edema, and allergic symptoms. 4. Antigen injected into skin (B) in appropriate doses takes three pathways a. Enters circulation to alter circulating antigen-antibody ration and affect immune complex formation. b. Combines with IgE antibody on surfaces of mast cells in skin, and also possibly with basophils in circulation, or arriving in tissue at site of antigen injection. This stimulates local release of mast cell mediators, including histamine. Histamine stimulates mast cells and basophils to stop mediator release, and stimulates T-suppressor cells to secrete HSF. HSF suppresses T-helper cells, which turns of B-cell release of IgE, reducing vascular permeability, edema, and allergic symptoms. c. Stimulates skin macrophages to transmit signals to T. cells to turn on increased B-cell formation of fgG, which enter circulation and favorably affect' antigen-IgG ration, reducing formation of toxic complexes. -57- 4. THE IMMUNE RESPONSE IS OFTEN MEDIATED BY FACTORS OTHER THAN IgE The past allergy 10 years and have immune changed many response. of For our example, concepts the of common consideration of IgG only as a blocking ("good") antibody in allergy, and IgE only as a symptoms-inducing ("bad") antibody is obsolete. explain Such a simplistic scenario is too incomplete to recently accumulated data concerning complicated interactions among humoral and cellular reactants and the two cell types (helpers and suppressors) that can effect opposite reactions. 46 ’84 For example, IgG can form immune complexes to. produce harmful allergic .syndromes as well as lethal 80 _. diseases. . Conversely, IgE can induce local histamine release which itself can quickly turn off allergic symptoms and stimulate expansion of clones of protective suppressor i u *. 85-99 lymphocytes. Allergy symptoms are mediated by the formation of specific antigen-induced immune antibodies. mediated complexes rather than by specific As demonstration of this, symptoms of non-IgE allergy antigen-induced may immune be produced in complexes, and some relieved patients by by antigen injection which induces rapid clearing of these complexes. It is well-recognized that immune complex-mediated disease can be associated with symptoms in virtually any organ. classic example is systemic lupus -58- erythematosus. A Lupus 13516 patients with experience central headache, disorientation, symptoms nervous have system hyperactivity, involvement visual changes, aggressiveness, -and frank psychosis. been shown may These to be related to the presence of immune complexes in the peripheral circulation and to changes in complement components fluid.30 ’ They histamine release increased capillary structures. are in the caused by cerebrospinal anaphylatoxin-induced from mast cells and basophils leading to permeability in the brain or adjacent Similar symptoms occur after the ingestion of ,, . 102-104 allergenic foods. In lupus, the immune double-stranded anti-DNA complexes DNA . antigen are and generally a antibody. made up of complement-fixing In allergic IgG patients, antigens complexed with circulating and cell-fixed antibodies activate complement histamine release to produce resulting in the anaphylatoxin-mediated increased capillary permeability which causes the observed allergic symptoms. A 80 81 recent series of -papers by Brostoff et al ’ and Paganelli 7g et al confirm the existence in food allergic patients of circulating immune complexes composed of food antigen and a variety of immunoglobulins including IgG, IgA, and IgE. Matthews and demonstrated Soothill^09 complement and Atherton activation et secondary al^° have to immune complex mediation in food allergic patients undergoing food 5. -5 9 - challenges with their allergenic foods. Frick^^ also found that delayed food allergy. chronic high background immune May 112 blood Minor, Tolber, and complexes has participate similarly levels of in demonstrated histamine in food-allergic patients. 135 5. TWO INTERACTING IMMUNE MECHANISMS EXPLAIN NON-IgE MEDIATED ALLERGIC RESPONSES Two interacting immune allergic reactions. symptoms caused by mechanisms The explain non-IgE mediated first mechanism concerns allergic increased capillary permeability due to antigen-induced, immune complex-mediated relief of such symptoms by doses of antigen to beneficially .alter ratios and allow for more This is complexes. immune injecting precisely efficient accomplished complex-clearing antigen-stimulated macrophages, determined clearing through and antigen-antibody of these interactions systemic skin macrophages, various humoral products. phenomena, of macrophages, T cells, B cells, and Injected antigen interacting with T cells, and B cells also stimulates B cells to produce specific IgG, thus increasing specific IgG levels to favorably alter the ratio of antigen to antibody in immune complex formation. Secondly, injected antigens interacting with mast cell-bound IgE in the skin cause the release of histamine which can produce, two opposing effects. Histamine causes symptoms by stimulating "turn on" allergic effector cells However, at known "turns off" further basophils, "turns to concentrations, histamine off" histamine release by symptoms. also mast quickly cells and IgE-forming B cells by stimulating T-cell secretion of histamine-induced suppressor factor, stimulates and expands T suppressor populations. -61- 35 36 ’ fi and Injected antigen interacting with macrophages, T cells, and B cells also stimulates B cells to produce specific IgG, thus increasing specific IgG levels to favorably alter the ratio of antigen and antibody in immune complex formation. These two mechanisms are interdependent facets of a single system. Their operation is reflected in experimental evid­ ence and clinical experiences from many laboratories and clinics. Resulting predictions can be tested by available laboratory and clinical techniques, and correlations can be made that place hitherto puzzling observations of responses to allergy and immunotherapy in the mainstream of current immunological understanding. 13 on -61a- 6. CELLULAR AND HUMORAL EFFECTORS OF THE PHASIC IMMUNE RESPONSE The cellular neutrophils, interwoven systems platelets, with responses. VN> • r~. the The endocrine (macrophages, and and humoral humoral kinins and coagulation humoral participants, cell-basophils, lymphocytes) are system produce elements, non-endocrine mast hormones, cascades as to inextricably including allergic antibodies, eicosanoids, plasma well as many including neurotransmitters, other are also integral parts of the same system. The sequence of biochemical allergy, for example combine with which trigger food antigens complexes, which release histamine increased symptoms. immune food to from allergic form 1) activation other in to is: complement 3) result allergy, antibodies anaphylatoxins, mediators food events that produce symptoms of mast induce cells capillary and of produce basophils, permeability, 2) and 4.) which edema, and It is chiefly by way of such edema that allergic symptoms can be initiated without the involvement of IgE and without the cellular destruction associated with full complement activation and"neutrophil-participation. a . R o le o f M a c ro p h a g e s Macrophages serve two functions in this process: clearing of r-: L immune complexes, and secretion of suppressor and -helper factors. 13521 -62- It is well-known complexes the that the rapidity with which immune can be cleared from the circulation depends upon integrity of the phagocytic cells of the blood and tissues. The macrophages of intact animals clear complexes rapidly. Animals with reticulo-endothelial blockade, caused by injection of bentonite or carbon particles are unable to clear their circulation of immune complexes. The same is true of animals whose reticulo-endothelial cells are engorged with viruses or bacteria from overwhelming infection. Chronic or repeated circulation of humans reticulo-endothelial clearing of showers of also immune produce blockade. The seen some symptoms in complexes varying in the degrees of slower or more limited patients multiple with sensitivities indicates a temporary or prolonged overload on the phagogytic system. Macrophages also participate in the initiation and regulation of immune responses4’^ by secreting humoral factors, including some with These helper and substances restricted. 4.7—49 are Thus, some with suppressor antigen-specific functions.^6 ’4-7 and genetically for example, macrophages can secrete specific suppressor and helper factors for ovalbumin just as can ovalbumin-sensitive suppressor and helper The symptoms allergy are seen in some caused by: patients 1) -63- T cells. with non-IgE transient mediated showers of 13522 r antigen-antibody activation, leads complexes initiating partial complement 2) which induce anaphylatoxin formation, to release 3) which of histamine and other mediators from mast cells and basophils, and ¿) which results in allergic edema. The presence, severity, and duration of symptoms is, in part, a function of the level, size, and persistence of such result from 82 complexes. Provocation and neutralization alterations in blood complexes. 2 5 ’ and Circulating of tissue monocytes symptoms levels of pathogenic and _fixed macrophages are important participants in these reactions through removal of immune complexes. When antigen is introduced into the skin, antigen-stimulated l skin 0 macrophages are the cells most intimately secretion of antigen-specific helper which formation can affect ... circulating antibody .. . .. . antigen-antibody involved and suppressor and in factors turn .. 115-119 ratios. in alter When T suppressor lymphocyte function becomes inadequate to control ills IgE-forming B cells, allergy results. Injecting precisely chosen doses of specific antigens into the skin cam Ë stimulate and "train" skin macrophages to assume a greater portion of the needed suppressor function.^20 13523 r. b. Basophils and Mast Cells: Role of Histamine released from mast cells and basophils by IgE and non-IgE mechanisms can turn on immediate allergic symptoms by binding to HI receptors smooth muscle (a on target cells proflammatory such as bronchial effect). At higher concentrations, histamine can also quickly turn off symptoms through a feedback loop to the H2 receptors on mast cells and basophils, stopping further histamine release (an anti-inflammatory effect).86,86 In addition, histamine has a delayed and prolonged effect on other cellular interactions. By binding to H2 receptors on T lymphocytes, and neutrophils, eosinophils, histamine modulates the function of these cells involved in delayed as well as immediate into the skin, stimulate reactions. 87—92 After antigen injection mast cell-released histamine in the skin can local T supresssor cells Histamine-induced Suppressor Factor to release (HSF). HSF their traverses the circulation and suppresses distant helper T cells, thus turning off antibody synthesis cell-fixed by B cells, altering ratios. 91 94. 95 ’ ’ circulating and Histamine levels released from complement-stimulated . neutrophils,96 histamine levels are are antigen-antibody and themselves regulated modulated by a product by histamine and of histamine degradation, imidazole acetic acid. 13k Specific local concentrations of histamine are critical determining which mode is operative. mast cells and from basophils in Histamine release from recruited to the skin in 13524 -65- cutaneous basophil hypersensitivity is inhibited in vivo by locally released histamine in the concentration range of lo-6 _4 , 1. to 10 M. blood 92 of persons elevations T: High in levels with of histamine are found food blood allergies. histamine 97 in the Significant levels occur with subcutaneous injection of an allergenic food extract. These patterns reflect the high local histamine occuring transiently in the micro-environment degranulating mast cells and basophils. concentrations around 92 12 In neutralization therapy, a dual therapeutic response occurs consisting of subcutaneous r* ( l; rapid relief treatment tolerate exposures in minutes injection, o r •hours after each" and increasing ("hyposensitization") weeks, months, and years. Rocklin et al ability to to the antigen over 99 and Evans et al 131 have demonstrated that antigen-specific suppressor cells are induced < . by suppressor repeated activity injections leads Stimulation of increased suppressor T cell of antigen. to clinical suppressor populations Decreased allergic sensitivity. activity account for and much increased of the n long-term improvement in allergic patients on immunotherapy. 0 Thus, it is well established that symptoms of allergy can be caused by histamine released from mast cells and basophils by both IgE and non-IgE mediated mechanisms. These symptoms can be quickly relieved by injecting a quantity of antigen which r\ induces the release of the precise amount of histamine 13525 -66-- required to turn off further histamine release. Maintenance treatment with repeatedly stimulates suppressor T further suppressing these cells extracts to release HSF, specific IgE antibody production. This effect of antigen on suppressor T cells can be direct or mediated by histamine or by stimulated macrophages. As discussed earlier, suppressor T increased cell populations injections. through are Finally, macrophages, repeated T cells, increased specific altering antigen-antibody interactions and IgG by antigen and injections acting also production, ratios the antigen B .cells antibody diminishing repeated stimulate favorably in immune complex potential for complement reported that leucocyte activation and symptom induction. c. Role of Lymphocytes Minor, Tolber, and Frick 109 have migration inhibition factor (LIF) was frequently elevated, in patients this with delayed type lymphocyte-secreted lymphocytes postulate take that food allergy. product The presence of supports the fact that part in delayed allergic reactions. They LIF release is a result of antigen-antibody complexes on the surface of lytmphocytes or neutrophils (Type III response). May 97 reported histamine release that these a high nonspecific background in food-sensitive patients. chronically high histamine blood leucocyte He suggested levels can be 13526 -67- explained by Circulating immune food attached to histamine from complexes antigen basophils the on the complexed induce basophils. observations that complex-mediated phenomena surface a with antibodies and discharge of constant It food of basophils. is evident from antigen-induced, cause commonly such immune encountered food allergy symptoms by several pathways, and that further study of these interacting pathways might well illuminate puzzling clinical observations. L_, The phenomena is thus intradermal tied- into injected skin, of antigen, the interactions antigen-stimulated cell responses. 132 of or transmissions, suppressing or 1)intradermally macrophages, which come macrophages in signal action of: 2)antigen-processing 3)T and B lymphocytes participate provocation and neutralization in the in contact with the soluble factors to and k)the subsequent T stimulating B cell Langerhans cells themselves can be damaged by immune complex-activated complement and destroyed by killer T lymphocytes. 61 33 ’ Thus, the regulators are themselves regulated. Mast cell histamine release can participate in this series of n * L, interactions by increasing local capillary permeability to facilitate the movement of antibodies and cells into the site of can the reaction. then As local histamine levels rise, terminate increased - ...... capillary histamine permeability by 68 - _ 13527 turning off further histamine release through H2 receptors on mast cells • and basophils. stimulting local T IgE-forming B cells. cells Histamine can also release HSF and to Injected act by turn off antigen can also act by increasing specific IgG levels to favorably alter the ratio of antigen and antibody in immune complex formation, and by stimulating and expanding T cell populations. If additional histamine release is required by the mast cells to accomplish ■i .their ends, these cells can recruit basophils to enter the reacting site and provide the additional histamine. All the individual facets of these multiple interactions are well documented and conform to the clinical phenomena observed in intradermal provocation and neutralization. c. Role of Neutrophils A major factor in food allergy disease process is the generation of an immune complex complement-consuming process j .. which precipitates intravascular inflammatory events. These > inflammatory events produce endothelial damage in various target organs. Inflammatory events can be the result of the action of one or a few cells. immune I complexes Complement activation by can cause the aggregation of leukocytes through the action of the chemotactic factors of C3a and C5a.^3® Granulocytes are capable of causing both endothelial and interstitial radicals injury. Neutrophils liberate superoxide and other highly reactive oxidant byproducts of phagocytosis. The superoxide radical has- been shown in -69- 13528 - tissue culture to injure endothelial cells. neutrophils produce neutral and ' acid 137 In addition, proteases 138 that destroy structural proteins such as collagen elastin and the adhesive glycoprotein fibronectin, 139 a necessity for ordering the interstitial topography of cells and connective 14,0 tissue. These proteases also cleave fibrinogen, the Hageman factor, complement, and other plasma proteins. Thus, neutrophil proteases can both destroy intersitial t;V architecture and permit local amplification of tissue injury K. U by activating further plasma precursors leukocyte that ultimately aggregation and result in intravascular coagulation. E Using the lung as a model target organ for immune tissue P3 damage, it has been demonstrated that the tissues' natural defense against damage induced by alpha 1 antitrypsin from plasma, n i'-.l superoxide radical or by superoxide radicals, can be inactivated by the oxygen leaking into damaged tissue. The sequence of events is as follows: complexes lodge in a target organ, fi Id 1)circulating immune 2) which results in local activation of complement, 3) which generates C5a and C3a, and 4.) which cause leukocyte aggregation in the target organ. As B L in the case of the heart or brain, very small numbers of leukocytes could produce wide-ranging symptoms. r u Aggregated 13529 -70- neutrophils injure endothelial cells by the generation of toxic oxygen radicals. The neutrophil liberates proteases that destroy structural proteins such as collagen, elastin, i bl 3 1.1 and fibronectin as well as promote further local inflammatory changes by proteolysis of circulating plasma proteins such as the Hageman factor, fibrinogen, and complement. i'i time, protective antiproteases are At the same inactivated by oxygen radicals released from immune effector cells. •J Endothelial damage caused by' small numbers of inflammation cells can cause wide-ranging symptoms with little or no histologically definable target organ damage. For example, microscopic inflammatory events in the heart can cause fatal arrythmias with little or no detectable histologic changes. Microscopic inflammatory events in the brain can cause wide-spread symptoms of behavioral changes and epilepsy with little or no detectable histologic changes. 144 Thus, reversible microvascular inflamatory events caused by small numbers of neutrophils are most probably the basis of many antigen-associated allergies, for example to foods. -71- (no page 72) 13531 G. WHY DO INTRADERMAL AND SUBLINGUAL ADMINISTRATION OF ANTIGEN PROVOKE AND NEUTRALIZE SYMPTOMS? The epidermis (and sublingual tissue) is one of the most immunologically active organs in the body. It contains most if not all of the cells known to be functional in immune response. ' The epidermis is the first line of defense bacterial, and parasitic fungal, in infestation. Complement-consuming dermatopathologic processes induced by immune complex formation have been documented as being caused by the inhalation of aerosolized petrochemicals from copying machines, 145 foods. various petrochemicals used in plastics, and Mediators originating from immunologic reactions in the skin can quickly become systemic due to the skin’s vascular structure, making the skin testing overall immune reactivity. the ideal organ for The epidermis (and sublingual tissue) contains a meshwork of fixed macrophages, the Langerhans contracting cytoplasmic extensions. cells, with long These cells contain la antigens and are very active antigen-processing cells. Just below basement the capillary network. this network' and membrane of Materials injected intradermally reach absorb very the epidermis rapidly by is a comparison rich with materials injected into subcutaneous fat or muscle tissue^0 where macrophages and capillaries are less concentrated. -73- Fixed macrophages in the skin are therefore well-equipped and well-situated to quickly detect and process specific antigens injected intradermally and to humoral factors can quickly systemic circulation. which Once secrete in specific find the their modulating way circulation, to the they can traverse the entire body in approximately 15 seconds. factors thus can quickly antibody secreting B suppress cells in the or stimulate These specific gastrointestinal tract, central nervous system, and other distant regions. Langerhans cells in the epidermis can migrate to the dermis and also through lymphatic channels to regional n o d e s .^'4'8 ’ In nodes they are capable of transmitting signals to many T and B cells. dermatitis 117 They are known to function in contact as well as in herpes simplex virus infections, responses to intradermally injected P P D , ^ 8 D N F B , ^ 3 various haptens, and other allergens. 119 While macrophages in the subcutaneous tissues perform similar functions, those vigorously. more in and neutralization with vigorous do so neutralization peak symptom intradermal administration. characteristically reaching epidermis more rapidly This fits observed clinical- phenomena, rapid antigen the induces beginning effect marked within in ten -74- injection symptom three including provocation as compared to Intradermal and to and subcutaneous of antigen provocation four minutes. minutes or and Sublingual 13533 administration works as fast as and by the same mechanisms as intradermal induces injections. Subcutaneous administration usually such changes more gradually over a period of thirty minutes. O o -75- III. FLAWS IN THE OPPONENTS' CASE AGAINST PROVOCATION/NEUTRALIZATION The opponents' techniques is case flawed against and provocation/neutralization scientifically unsound. In addition, the studies supporting the efficacy of traditional techniques are also efficacy as an flawed and fail to demonstrate their alternative to provocation/neutralization. This section will contain: A. Critique of the opponents' provocation/neutralization case against B. Representative flaws in the science supporting the clinical techniques of conventional allergists 1353 A. CRITIQUE OF THE OPPONENTS’ CASE AGAINST PROVOCATION/NEUTRALIZATION The careful reviewer of these comments may note information gap between the NCHCT 1981 Evaluations, an upon ' which the proposed HCFA action is based, and the empirical and scientific justification for the. efficacy and safety of provocation/neutralization outlined sections of these Comments. only one the preceeding The gap is real. The NCHCT of the in Evaluations cite 12 supporting provocation/neutralization. laboratory studies They do not even attempt to examine the immunological mechanisms behind these techniques. The latest critical bibliographic entry for the intradermal/subcutaneous NCHCT report is dated 1976, and the latest citation in support of provocation/neutralization is dated 1978. For the sublingual report, the latest critical citation is 1980, and the latest supportive one is 1980. Finally, both NCHCT reports were issued in 1981, before 3 of 3 4. 5 the strongest double-blind studies ’ ’ in support of provocation/neutralization had been published. Yet no attempt has been made to incorporate the new data into HCFA's rule-making. NCHTC references criticizing provocation/neutralization techniques lack scientific credibility. In support of its 13536 -77- criticisms of the intradermal/subcutaneous modalities, NCHTC offers: 2 abstracted reports (one 7 years old, the other 12 years old, and neither have been followed up by full-length scientific articles); one letter to the editor (12 years old and never followed up by a full-length scientific article); and one uncontrolled study which appeared as a 1 -page article in the Archives . cited are report of Otolaryngology. favorable. cites: the For the same The other references sublingual modalities, 1 2 -year-old abstract; the a seriously flawed 9-year-old committee report; and a more recent study c whose author has study". acknowledged " many inadequacies in the The other references cited were favorable. u. Kailen and Collier (1971) r cJ B 3-paragraph letter alive the yet to letter . This study is a 12-year-old, the editor. has never The authors are still been full-length article in a refereed journal. reason for this is that the followed up by a The only possible study was not good enough. Nothing more need be said about it. ' ' * i G Hirsch et criticized al(198l) by otolaryngologic This pediatric, allergists study internal. as well as has been medicine, by roundly and immunologists familiar with provocation/neutralization techniques. Among the more obvious errors in this study is its poor structure. The individuals administering the test had less than 4. hours i .■ i_j of didactic training in the technique (physicians practicing r. ■ i "■ -78- this method are usually trained continuing education courses). objectivity has been through graduate or In addition, the observers' questioned by a variety of investigators. The only parameter identified by critics as significant is the so-called "Symptoms Medication Index". subjective and difficult to assess. provocation/neutralization Symptoms are very Most practitioners using techniques use far fewer prescription medications than practitioners of conventional build-up immunotherapy. Therefore, the information derived through this index must be considered unreliable. The worst aspect of this study is that although the investigators measured certain biochemical parameters in an attempt to correlate them with the clinical findings, never measured any of the immunological effect neutralization in immunotherapy. they factors known to Any allergist who is current with the immunology literature Of the last decade knows that effective generation of investigators immunotherapy is characterized by the antigen-specific in this study suppressor never cells. bothered to The examine suppressor cell activity. In summary, unfamiliar this study was with the technique provocation/neutralization conducted by people being techniques who evaluated. were performed were The in a 13538 -79- manner inconsistent with current cliriical practice. statistically unreliable significant subjective finding is based observations. The only solely on Finally, the investigators never attempted to measure obvious objective immunological parameters which would have truly established the efficacy or inefficacy of the techniques. The remaining studies attempt to assess provocation testing. The critiques of these critiques are expanded in Appendix A, excerpted from a paper prepared by Dr. David S. King, M.D. of the Department of Psychiatry, University of California, San Fransico Medical Center. Dr. King examines the concepts of reliability and validity as well as the proper statistical techniques by which to assess them. He then reviews the research purporting to evaluate provocation testing methods. In reviewing this critical literature, Dr. King includes the A studies upon which the American Academy of Allergy based its position statement (issued May 1981) branding subcutaneous and sublingual testing as ineffective. same studies Academy of provocation also Allergy form the basis communication techniques to be for the to These 1980 American the NCHCT declaring unproven and therefore •"experimental". Since NCHCT and HCFA, by adoption of NCHCT's positions, rely so Allergy's heavily conclusions, on reviewers the American should give Academy of their very deliberate and detailed attention to these critiques. 1315S9' -80- Dr. King's review finds that serious flaws in study design and analysis are common in the critical literature. These shortcomings include: 1) comparison of subjects' responses to antigen and placebo without verification of their having specific sensitivities to the antigens administered, 2) failure to incorporate double-blind procedures with placebo controls in the study design or execution, 3) failure to analyze study results statistically, k) improper statistical analysis, and 5) in some cases, re-analysis of the original dataseriously affecting the conclusions of the study. Bronsky et al(1971)153. authors of which This is a 12-year-old abstract, the are still alive. .The data was never presented in a full-length report which could be ahalyzed by unbiased observers. Since blinding seems unlikely. no placebo was given, double The design of the study does not rule out the possibility that the children were not sensitive to some or all of the foods tested. It is also not known whether the children were medicated. Caplin, I.(1973) 15k subjects were This report describes a study in which challenged foods and also placebo. separate occasions. statistically sublingually with five standard Each antigen was challenged on two Although the results are reported as insignificant, the committee's statistical consultant stated, "because of the design of this study one ■81 must be careful of drawing any conclusions". Despite this warning, the committee reached the conclusion that the "test doesn't discriminate between control and food extracts". The protocol called for substantially more patients than were actually tested and Additionally, even fewer received feeding tests. the data on 17 of the patients was rejected without explanation. It is not stated whether this attrition occurred before or after the double-blind code was broken. Fifty percent of the remaining data was rejected for analysis because of "faulty protocol". factor in data of the investigators were unfamiliar with the techniques used. Of the analysis 10 physicians is An additional confounding the participating, fact only that most 3 had had previous experience with sublingual provocation. In stammary, this study is seriously flawed by its poor design and irregular handling of the data. The investigators were inexperienced, and the data was manipulated in an unexplained fashion. Despite the- warning by its statistician, the committee chose to form a conclusion based on this study. (Surprisingly, • this data report discussed below.) was used in the 1974. follow-up The numerous methodological and analytical flaws in this study have been extensively noted and critiqued. Crawford et al(1976)^55. This is a 7-year-old abstract which was never followed up by a full-length article. -32- Since this ■£ O P / ^ study has only been published evaluate the in abstract materials, form, methods, it or is impossible to data analysis. It is curious that the scientists who were charged with assessing a technique which has been in continuous use for close to 40 years chose to cite studies whose data is unavailable for critical analysis by unbiased observers. I ■i Draper, L.W. (1972) . This is a 1-page article which reports the findings of a study for which lack of proper controls renders clear interpretation of the data impossible. 4 No statistical tests were reported. The absence of blinding and the failure to incorporate placebos in the design both seriously detract from the study. Since the intradermal tests were given only once, nothing can be said regarding their reliability. i Breneman et al(1974)158. mentioned above, patients. The placebo response rate as calculated from the data was 50%. as This report contains the 1973 data, This well as information the 1973 additional is inordinately high and leaves the objectivity of this study in serious doubt. in on report, there is In addition, as unexplained attrition of patients in this study. The protocol called for 30 patients, but 20 the data on analysis. only patients are included in this No mention is made of precautions taken to insure blind conditions. The data are presented in summary form in tables, with no statistical analysis provided. -83- CO' ■7* In summary, this report relies on seriously questionable data to form the conclusion that the technique evaluated was not effective. It is curious that the investigators were \ apparently oblivious to the obvious flaws in their to assess the experimental design and data analysis. V ' u Lehman, 0 efficacy C.(1980) of 157 This sublingual study food claims allergy provocation. The investigator attempts to quantitate changes in the edema and L; r- swelling of the nasal antigens and placebo. is cited by the mucosa induced by specific food The major design error in this study author constantly changing as himself, from one "the nasalmucosal 10-minute edema is interval to another, independently of placing food antigens under the tongue” . n U i This choice of an inherently non-stable endpoint compromises any assessment based on that endpoint. Another design error V ; LJ is that patients were to' be P specific antigens to be S e L'< have a food allergy". clinical "history of not tested. food However, sensitivity was required allergy to Subjects were supposed to or other demonstration of according to the reported suspected for only li antigens which were challenged. to provoke sensitive of data, the 6C There is no reason to expect symptoms with an antigen to which the subject is not sensitive. No statistical analysis was reported. i. In summary, this study used an unreliable L i -84- endpoint to test the reaction of poorly selected patients against antigens to which they were not sensitive. In fairness to the author, it should be noted that he acknowledged "many inadequacies in the study". 13544 -85- B. REPRESENTATIVE FLAWS IN THE SCIENCE SUPPORTING THE CLINICAL TECHNIQUES OF CONVENTIONAL ALLERGISTS Although some immunologists good science associated with is being classical performed allergists, by- most of the double-blind, placebo-controlled clinical trials by which they attempt to establish the efficacy modalities are seriously flawed. of their treatment The data from these studies is questionable, and the conclusions drawn by the authors are consequently unsound. An analysis of some representative studies follows. Conners et al studies frequently support (1976)^^. of cited their Foundation-supported double-blind This article is one of the major by- the conventional methods. study experiment This purports although The allergists its to be Nutrition a controlled conclusions "control" in have conditions of been severely criticized. the challenge diet and "placebo-controlled" challenge trials are invalid and misleading. In this study of allergic children, milk, eggs, corn, wheat, allergy-producing addition, foods) were chocolate used as (all inert common placebo. In the challenge dose of food coloring constituted as little as 1/12 of the real-world exposure of children to food coloring additives. The children were evaluated weekly for evidence responses, a schedule of ignored the allergic wide that completely diversity of reaction times among allergic children. It is doubtful that the aberrant behavior of even a single child would become apparent on such an observation schedule. This study training clearly and bias demonstrates of the the lack of investigators. scientific That it was published as the lead article in Pediatrics is a telling commentary on the peer reviewers. Norman and Lichtenstein (1978)^63. This study purported to show clinical and immunological specificity of therapy in..a group of patients with rhinitis caused by ragweed and grass pollen. The investigators used ragweed antigen only. They showed an and increase significantly in reduced IgG symptom "blocking response antibodies" scores to ragweed without a corresponding reduction in the symptom response to grass pollen or production of IgG paper is widely cited as in these patients. establishing the This efficacy of conventional build-up immunotherapy for pollen sensitivity. The major flaw is that the investigators were measuring parameters which had nothing to do with clinical efficacy. The concept that IgG "blocking antibodies" effect clinical responses in patients treated with specific antigen immunotherapy had been obsolete for at least 3 years at the time of publication. Worse yet, this concept is still cited in text books used by conventional allergist today as the 13546 reason for symptomatic improv e m e n t , e v e n though it has been proven unsound for more than a decade. In addition to this parameter, Medication which is the authors to Conventional scientific been to investigator is the investigators' foods were a major the main, lack sufficient basic immunological principles credible clinical safety In No in of perform of conventional one report,^55 5 of nodosa received polyarteritis immunotherapy. too, to Index", factor in symptoms. questioned. developed and vulnerable whether understanding the "Symptom interest, allergists, practices addition, Of consider their subjects' and a highly subjective and patient bias. failure used such finding has trials. In allergy treatment has 19 ever been patients who conventional reported in patients receiving provocation/neutralization therapy. Thus, based on the design and performance of the "classical studies" cited by conventional allergists as proof, it is far from clear that conventional allergy testing and treatment is either safe or effective. 88 3 V. REFERENCES 1. Miller JB, Personal Communication. 2. McGovern JJ Jr., Lazaroni JL, Saifer P, Levin AS, Rapp DJ, Gardner RW: Clinical evaluation of the major plasma and cellular measures of immunity. Journal of Orthomolecular Psychiatry; 1983; 12(1): 12. 3. Boris M, Schiff M, Weindorf S, and Inselman L: Bronchoprovocation blocked by neutralization therapy. Journal of Allergy and Clinical Immunology 1983; 71:92. 4. Rea WJ, Podell RN, Williams ML, Fenyves E, Sprague DE, and Johnson AR: Intracutaneous neutralization of food sensitivity: a double-blind evaluation. Archives of Otolaryngology 1983 (in press). 5. 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CODEN: TXAPA 3 HUMAN HEALTH EFFECTS FROM ACCIDENTAL RELEASE OF TETRA CHLORO BENZO-P-DIOXIN AT SEVESO ITALY POCCHIARI F; SILANO V; ZAMPIERI A IST. SUPER. SANIT., ROME, ITALY. NICHOLSON, W. J. AND J. A. MOORE (ED.). ANNALS OF THE NEW YORK ACADEMY SCIENCES, VOL. 320. HEALTH EFFECTS OF HALOGENATED AROMATIC HYDROCARBC INTERNATIONAL SYMPOSIUM, NEW YORK, N.Y., USA, JUNE 24-27, 1978. X+730P. YORK ACADEMY OF SCIENCES: NEW YORK, N.Y., USA. ILLUS. MAPS. PAPER. I 0-89766-008-0. 0 (0). 1979 (R E C D . 1980). P311-320. CODEN: ANYAA INDUCTION OF CYTOCHROME P-450 FORM 6 IN RABBIT KIDNEY AND LUNG BY 2 3 TETRA CHLORO DI BENZO-P-DIOXIN LIEM H; MULLER-EBERHARD U; JOHNSON E F DEP. BIOCHEM., SCRIPPS CLIN. RES. FOUND., 10666 N. TORREY PINES RD., JOLLA, CALIF. 92037, USA. 64TH ANNUAL MEETING OF THE FED. AM. SO C . EXP. BIOL., ANAHEIM, CALI USA, APR. 13-18, 1980. FED PROC 39 (3). 1980. ABSTRACT 3931. COD FEPRA INDUCTION OF ALDEHYDE DEHYDROGENASES EC-1.2.1.3 DEITRICH R A; BLUDEAU P; ROPER M; SCHMUCK J DEP. PHARMACOL., UNIV. COLO. SCH. MED., DENVER, COLO. 80262, USA. BIOCHEM PHARMACOL 27 (19). 1978. 2343-2348. CODEN: BCPCA RAT LIVER ALDEHYDE DEHYDROGENASE EC-1.2.1.3 EC-1.2.1.4 EC-1.2. IMMUNOCHEMICAL IDENTITY OF 2 3 7 8 TETRA CHLORO DI BENZO-P-DIOXIN INDUCÏ NORMAL LIVER AND 2 ACETYLAMINO FLUORENE INDUCIBLE HEPATOMA ISOZYMES LINDAHL R; ROPER M; DEITRICH R A DEV. BIOL. SECT., DEP. BIOL., UNIV. ALA., UNIVERSITY, ALA. 35486, USA. BIOCHEM PHARMACOL 27 (20). 1978. 2463-2465. CODEN: BCPCA IDENTIFICATION OF THE MAJOR CYTOCHROME P-450 FORM TRANS PLACENTA INDUCED IN NEO NATAL RABBITS BY 2 3 7 8 TETRA CHLORO DI BENZO-P-DIOXIN NORMAN R L; JOHNSON E F; MULLER-EBERHARD U DEP. BIOCHEM., SCRIPPS CLIN. RES. FOUND., LA JOLLA, CALIF. 92037, USA. J BIOL CHEM 253 (23). 1978. 8640-8647. CODEN: JBCHA CHEMICAL SEPARATION OF HELPER CELL FUNCTION AND DELAYED HYPER SENSITIV RESPONSES FAITH R E; LUSTER M I ; MOORE J A BIOMED. RES. CENT., ORAL ROBERTS UNIV., 7777 S. LEWIS, TULSA, OK 74171 USA. CELL IMMUNOL 40 (2). 1978 275-284. CODEN: CLIMB ANALYSIS OF 2 3 7 8 TETRA CHLORO DI BENZO-P-DIOXIN IN ENVIRONMEN SAMPLES MCKINNEY J D RAMEL, C. (ED.). ECOLOGICAL BULLETINS NRF (NATURVETENSKAPL FORSKNINGSRADET), NO. 27. CHLORINATED PHENOXY ACIDS AND THEIR DIOXINS. M OF ACTION HEALTH RISKS AND ENVIRONMENTAL EFFECTS. CONFERENCE. STOCKHO SWEDEN, FEB. 7-9, 1977. 302P. ILLUS. SWEDISH NATURAL SCIENCE RESEA COUNCIL: STOCKHOLM, SWEDEN. ISBN 91-546-0234-3. 1978 53-66 CODEN: 06 4 •1 Q K € K Ju IMMUNO TOXICOLOGIC EFFECTS OF 2 3 7 8 TETRA CHLORO DI BENZO-P-DIOXIN LABORATORY ANIMALS SHARMA R P; KOCIBA R J; GEHRING P J TOXICOL APPL PHARMACOL 45 (1). 1978 333 CODEN: TXAPA STUDIES ON 2 3 7 8 TETRA CHLORO DI BENZO-P-DIOXIN INDUCED IMMU) SUPPRESSION AND DECREASED RESISTANCE TO INFECTION ENDO TOXIN HYP' SENSITIVITY SERUM ZINC CONCENTRATIONS AND EFFECT OF THYMOSIN TREATMENT VOS J G; KREEFTENBERG J G; ENGEL H W B; MINDERHOUD A; VAN NORRLE JANSEN M NATL. INST. PUBLIC HEALTH, P.O. BOX 1, BILTHOVEN, N E T H . TOXICOLOGY 9 (1-2). 1978 75-86. CODEN: TXCYA SYNTHESIS OF 1 AMINO-3 7 8-TRICHLORO DI BENZO-P-DIOXIN AND 1 AMINO-2 3 8-TETRACHLORO DI BENZO-P-DIOXIN AS HAPTENIC COMPOUNDS CHAE K; CHO L K; MCKINNEY J D AGENCY DEF. DEV., SEOUL, S. KOREA. J AGRIC FOOD CHEM 25 (5). 1977 1207-1209CODEN: JAFCA RADIO IMMUNOASSAY FOR 2 3 7 8 TETRA CHLORO DI BENZO-P-DIOXIN ALBRO P W; CHAE K; LUSTER M; MCKINNEY J D; CHAUDHARY S; CLARK G; FAWKES ; CORBETT J ENVIRON HEALTH PERSPECT 20. 1977 (RECD 1978) 247 CODEN: EVHPA IMMUNOLOGIC RESPONSE AND FACTORS AFFECTING ITS ASSESSMENT MOORE J A; FAITH R E ENVIRON HEALTH PERSPECT 18. 1976 (RECD 1977) 125-131 CODEN: EVHPA MULTIPLE FORMS OF CYTOCHROME P-450 FROM LIVER MICROSOMES OF RABBI TREATED WITH 2 3 7 8 TETRA CHLORO DI BENZO-P-DIOXIN JOHNSON E F; MULLER-EBERHARD U FED PROC 36 (3). 1977 833 CODEN: FEPRA Immunosuppressive effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin strains of mice with different susceptibility to induction of ar hydrocarbon hydroxylase Vecchi A.; Sironi M.; Canegrati M.A.; et a l . 1st. R i c . Farmacol. 'Mario Negri', 20157 Milan ITALY TOXICOL. APPL. PHARMACOL. (U.S.A.) ,1983, 68/3 (434-441), Code TXAPA Lectin-mediated attachment assay for teratogens: Results pesticides Braun A.G.; Horowicz P.B. D e p . Radiat. Ther., Harvard Med. S c h ., Boston, MA 02115 U.S.A. J. TOXICOL. ENVIRON. HEALTH (U.S.A.) ,1983, 11/2 (275-286), JTEHD with Code 5 135613 Biochemical aspects of action mechanisms of 2,3,7,8-tetrachlorodibenzo-dioxin (TCDD) and related chemicals in animals Matsumura F. Pestic. Res. Cent., Michigan State Univ., East Lansing, MI 48824 U.S.A. PHARMACOL. THER. (ENGLAND) ,1982, 19/2 (195-209), Coden: PHTHD Immunochemical comparison and quantitation of microsom flavin-containing monooxygenases in various hog, mouse, rat, rabbit, do and human tissues Dannan G.A.; Guengerich F.P. Dep. Biochem., Vanderbilt Univ. Sc h . Med., Nashville, TN 37232 U.S.A. MOL. PHARMACOL. (U.S.A.) ,1982, 22/3 (787-794), Coden: MOPMA Quantitation of hepatic cytochrome Psub 1-450 mRNA with the use of cloned DNA probe. Effects of various P-450 inducers in C57BL/6N and DBA/ mice Tukey R.H.; Negishi M.; Nebert D.W. Dev. Pharmacol. Branch, Natl. Inst. Child Health Hum. Dev., Natl. Ins Health, Bethesda, MD 20205 U.S.A. MOL. PHARMACOL. (U.S.A.) ,1982, 22/3 (779-786), Coden: MOPMA Functional and quantitative effects of 2,3,7,8-tetrachlorodibenzo-p-dic in (TCDD) exposure on the cell-mediated immune system in mice Jackson J.D.; Sharp J.G. Dep. Anat., Univ. Nebraska Med. Cent., Omaha, NE 68105 U.S.A. INT. J. IMMUNOPHARM. (ENGLAND) ,1982, 4/4 (323), Coden: IJIMD Epidemiological problems with TCDD (A critical view) Tognoni G.; Bonaccorsi A. Ist. Ric. Farmacol. 'Mario Negri', 62-20157 Milan ITALY DRUG METAB. REV. (U.S.A.) ,1982, 13/3 (447-469), Coden: DMTRA Toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) Kociba R.J.; Schwetz B.A. Toxicol. Res. Lab., Dow Chem. USA, Midland, MI 48640 U.S.A. DRUG METAB. REV. (U.S.A.) ,1982, 13/3 (387-406), Coden: DMTRA Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on serum concentratic and the uterotrophic action of exogenous estrone in rats Shiverick K.T.; Muther T.F. Dep. Pharmacol. T h e r ., Univ. Florida, Gainesville, FL 32610 U.S.A. TOXICOL. APPL. PHARMACOL. (U.S.A.) ,1982, 65/1 (170-176), Code TXAPA 6 Differential effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on nuclear Rt\ polymerase activity in the rat liver and thymus Kurl R.N.; Lund J.; Poellinger L.; Gustafsson J.A. Dep. Med. Nutr., Karolinska Inst., S-104 01 Stockholm SWEDEN BIOCHEM. PHARMACOL. (ENGLAND) ,1982, 31/15 (2459-2462), Coden: BCPC Tetrachlorodibenzodioxin : A survey of subjects ten years after exposure May G. UNITED KINGDOM BR. J. IND. MED. (ENGLAND) ,1982, 39/2 (128-135), Coden: BJIMA Assessment of myelotoxicity caused by environmental chemicals Boorman G.A.; Luster M.I.; Dean J.H.; Campbell M.L. Natl. Toxicol. Program, Natl. Inst. Environ. Health Sci., NIH, Triangle Park, NC 27709 U.S.A. ENVIRON. HEALTH PERSPECT. (U.S.A.) ,1982, V o l . 43 (129-135), EVHPA Approaches to assessing host resistance Bradley S.G.; Morahan P.S. Dep. Microbiol., Virginia Commonw. U n i v . , Richmond, VA 23298 U.S.A. ENVIRON. HEALTH PERSPECT. (U.S.A.) ,1982, Vol. 43 (61-69), EVHPA Researc Coder Coder Cell-mediated immunity and its application in toxicology Luster M.I.; Dean J.H.; Boorman G.A. Lab. Environ. Chem., Natl. Inst. Environ. Health Sci., Research Triang: Park, NC 27709 U.S.A. ENVIRON. HEALTH PERSPECT. (U.S.A.) ,1982, Vol. 43 (31-36), Coder EVHPA Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin and phénobarbital on tl occurrence and distribution of four cytochrome P-450 isozymes in rabb: kidney, lung, and liver Dees J.H.; Masters B.S.S.; Muller-Eberhard U.; Johnson E.F. Dep. Biochem., Univ. Texas Health Sci..Cent., Dallas, TX 75235 U.S.A. CANCER RES. (U.S.A.) ,1982, 42/4 (1423-1432), Coden: CNREA Immunoteratology of chlordane: Cell-mediated and humoral immune response in adult mice exposed in utero Spyker-Cranmer J.M.; Barnett J.B.; Avery D.L.; Cranmer M.F. Dep. Pharmacol., Univ. Arkansas Med. Sci., Little Rock, AR 72205 U.S.A. TOXICOL. APPL. PHARMACOL. (U.S.A.) ,1982, 62/3 (402-408), Coder TXAPA 7 Toxicology of the immune system Davies G.E. Cent. Toxicol. Lab., Imp. Macclesfield, Cheshire UNITED KINGDOM HISTOCHEM. J. (ENGLAND) ,1981, Chem. Industr. 13/5 (879-884), Ltd, Alderley Pa Coden: HISJA Enhanced suppressor cell activity as a mechanism of immunosuppression 2.3.7.8- tetrachlorodibenzo-p-dioxin Clark D.A.; Gauldie J.; Szewczuk M.R.; Sweeney G. Dept. Med., McMaster Univ., Hamilton, Ontario L8N 3Z5 CANADA PROC. SOC. EXP. BIOL. MED. (U.S.A.) ,1981, 168/2 (290-299), Cod PSEBA Studies on the mechanisms of action of modifiers of skin carcinogenesis Slaga T.J. Biol. D i v ., Oak Ridge Nat. Lab., Oak Ridge, TN 37830 U.S.A. POSTEPY MIKROBIOL. (POLAND) ,1981, 20/1-2 (113-129), Coden: PMKMA Influence of inducers of monooxygenases on cytotoxic efficiency ellipticine on leukemia L1210 cells Lesca P.; Monsarrat B.; Cros S.; Paoletti C. Lab. Pharmacol. Toxicol. Fond., Toulouse Cedex 31078 FRANCE J. NAT. CANCER INST. (U.S.A.) ,1981, 67/4 (871-876), Coden: JNCIA Pentachlorophenol and liver function: A pilot study on occupationa exposed collectives PENTACHLOROPHENOL UND LEBERFUNKTION: EINE UNTERSUCHUNG AN BERUFL BELASTETEN KOLLEKTIVEN Zober A.; Schaller K.H.; Gossler K.; Krekeler H.J. Inst. Arbeits- Soz. Med., Univ. Erlangen-Nurnberg, D-8520 Erlangen GERMANY, WEST INT. ARCH. OCCUP. ENVIRON. HEALTH (GERMANY, WEST) ,1981, 48 (347-356), Coden: IA0HD Ultrastructural alterations in the liver of rats (8-monohydromirex) Singh A.; Valli V.E.O.; Ritter L.; Villeneuve D.C. Dept. Biomed. Sci., Univ. Guelph, Ontario CANADA PATHOLOGY (AUSTRALIA) ,1981, 13/3 (487-496), Coden: fed photomir PTLGA Rapid vertical tube rotor gradient assay for binding 2.3.7.8- tetrachlorodibenzo-p-dioxin to the Ah receptor Hing Wo Tsui; Okey A.B. Div. Clin. Pharmacol., Dept. P aed., Hosp. Sick Child., Toronto M5G 1X8 CANADA CAN. J. PHYSIOL. PHARMACOL. (CANADA) ,1981, 59/9 (927-931), Code CJPPA 8 135GB Selective suppression of cytotoxic T cell (CTL) generation by halogenat aromatic hydrocarbons Clark D.A.; Gauldie J.; Sweeney G.; Szewczuk M.R. Host Resistance Program, McMaster Univ., Hamilton, Ontario L8N 325 CANADA FED. PROC. (U.S.A.) ,1981, 40/311 (No. 4918), Coden: FEPRA Immunosuppression in mice induced by dioxin (TCDD) in feed Hinsdill R.D.; Couch D.L.; Speirs R.S. Dept. Bacteriol., Univ. Wisconsin, Madison, W i s . 53706 U.S.A. J. ENVIRON. PATH. TOXICOL. (U.S.A.) ,1980, 4/2-3 (401-425), JEPTD Code Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on macrophage and natur killer cell-mediated cytotoxicity in mice Mantovani A.; Vecchi A.; Luini W . ; et al. 1st. Ricerche Farmacol. Mario Negri, 20157 Milan ITALY BIOMEDICINE (FRANCE) ,1980, 32/4 (200-204), Coden: BIMDB Examination of bone marrow, immunologic parameters and he susceptibility following preand postnatal exposure 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) Luster M.I.; Boorman G.A.; Dean J.H.; et al. Nat. Inst. Environm. Hlth S c i ., Research Triangle Park, N.C. 27709 U.S.A. INT. J. IMMUNOPHARM. (ENGLAND) ,1980, 2/4 (301-310), Coden: IJIMD The effect of acute administration of 2,3,7,8-tetrachlorodibenzo-p-dio> (TCDD) on humoral antibody production and cell-mediated activities in mic Vecchi A.; Mantovani A.; Sironi M.; et al. 1st. Ric. Farmacol. Mario Negri, 20157-Milan ITALY ARCH. TOXICOL. (GERMANY, WEST) ,1980, 45/SUPPL.4 (163-165), Code ARTOD Immunotoxicity assessment: Screening and function studies Vos J.G. Nat. Inst. Publ. Hlth, Bilthoven NETHERLANDS ARCH. TOXICOL. (GERMANY, WEST) ,1980, 45/SUPPL.4 (95-108), ARTOD Code Identification of the form of cytochrome P-450 induced in neonatal rabfc liver microsomes by phénobarbital Schwab G.E.; Norman R.L.; Muller-Eberhard U.; Johnson E.F. Dept. Biochem., Scripps Clin. Res. Found., La Jolla, Calif. 92037 U.S.A. MOL. PHARMACOL. (U.S.A.) ,1980, 17/2 (218-224), Coden: MOPMA 9 13570 Effect of acute exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin humoral antibody production in mice Vecchi A.; Mantovani A.; Sironi M.; et al. 1st. Ri c . Farmacol. 'Mario Negri', 62-20157 Milan ITALY CHEM.-BIOL. INTERACT. (NETHERLANDS) ,1980, 30/3 (337-342), Code CBINA Role of the endocrine system in the action 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the thymus Van Logten M.J.; Gupta B.N.; McConnell E.E.; Moore J.A. Nat. Inst. Environm. Hlth Scis, Research Triangle Park, N.C. 27709 U.S.A. TOXICOLOGY (NETHERLANDS) ,1980, 15/2 (135-144), Coden: TXCYA Acute human exposure to TCDD in Seveso, Reggiani G. Hoffmann-La Roche Ltd., Basel SWITZERLAND J. TOXICOL. ENVIRON. HEALTH (U.S.A.) JTEHD Italy ,1980, 6/1 (27-43), Cod Effect of polychlorinated biphenyl, dibenzofuran and dibenzo-p-dioxin the susceptibility of male mice to endotoxin Oishi S . ; Hiraga K . Dept. Toxicol., Tokyo Metropol. Res. Lab. Pub l . Hlth, Tokyo JAPAN J. ENVIRON. SCI. HEALTH (U.S.A.) ,1980, 15/1 (77-85), Coden: JPFC Series: PART B PESTIC. FOOD CONTAMIN. Extrapolating carcinogenesis data from animals to humans Falk H.L. Office Hlth Hazard Assessment, Nat. Inst. Environm. Hlth S c i . , Triangle Park, N.C. 27709 U.S.A. FED. PROC. (U.S.A.) ,1980, 39/1 (76-80), Coden: FEPRA Resea Comparative toxicology of chlorinated compounds on mammalian species Allen J.R.; Hargraves W.A.; Hsia M.T.S.; Lin F.S.D. Dept. Pathol., Univ. Wisconsin Med. Sch., Madison, W i s . 53706 U.S.A. PHARMACOL. THER. (ENGLAND) ,1979, 7/3 (513-547), Coden: PHTHD The Seveso accident: Its nature, extent and consequences Homberger E.; Reggiani G.; Sambeth J.; Wipf H.K. ANN. 0CCUP. HYG. (ENGLAND) ,1979, 22/4 (327-367), Coden: A0HYA Structural gene products of the Ah locus: Genetic and immunochemi evidence for two forms of mouse liver cytochrome P-450 induced 3-methylcholanthrene Negishi M.; Nebert D.W. Developm. Pharmacol. Branch, Nat. Inst. Child Hlth Hum. Developm., N Bethesda, M d . 20205 U.S.A. J. BIOL. CHEM. (U.S.A.) ,1979, 254/21 (11015-11023), Coden: JBCHA1 10 1 *3?ITU's ì Symptoms in Vietnam veterans exposed to Agent Orange Bogen G. U.S.A. 242/22 ( 2 3 9 D : J. AM. MED. ASSOC. (U.S.A.) ,1979, , Coden: JAMAA Induction , enzymological inhibition, and some properties of hydrocarbon hydroxylase in fresh mitogen-activated human lymphocytes Gurtoo H.L.; Parker N.B.; Paigen B . ; et al. Dept. Exp. Therapeut., Roswell Park Mem. Inst., New York State D H l t h , Buffalo, N.Y. 14263 U.S.A. CANCER RES. (U.S.A.) ,1979, 39/11 (4620-4629), Coden: CNREA Induction, inhibition, and biological properties of aryl hydroca hydroxylase in a stable human B-lymphocyte cell line, RPMI-1788 Freedman H.J.; Parker N.B.; Marinello A.J.; et a l . Dept. Exp. Therapeut., Roswell Park Mem. Inst., New York State C Hlth, Buffalo, N.Y. 14263 U.S.A. CANCER RES. (U.S.A.) ,1979, 39/11 (4612-4619), Coden: CNREA1 11 1 O VJ i 73058434 A-' ■ RECURRENT ENVIRONMENTALLY TRIGGERED THROMBO PHLEBITIS A 5 YEAR FOLLOW-UP. REA W J; PETERS D W; SMILEY R E; EDGAR R; GREENBERG M; FENYVES E 8345 WALNUT HILL LANE, SUITE 205, DALLAS, TEX. 75231. ANN ALLERGY 47 (5 PART 1). 1981. 338-344. CODEN: ANAEA 1/3/2 23017587 CONTROLLED STUDIES ON FOOD SENSITIVITY USING INJECTION THERAPY. REA W J; WILLIAMS M L; SPRAGUE D E DALLAS, TEXAS. 37TH ACA (AMERICAN COLLEGE OF ALLERGISTS) SCIENTIFIC CONGRESS, WASHINGTON, D.C., USA, APRIL 4-8, 1981. ANN ALLERGY 47 (2). 1981. 139. CODEN: ANAEA 1/3/3 23017576 CHEMICAL SENSITIVITY AMD THROMBO PHLEBITIS. REA W J; EDGAR R T; FENYVES E J DALLAS, TEX. 37TH ACA (AMERICAN COLLEGE OF ALLERGISTS) WASHINGTON, D.C., USA, APRIL 4-8, 1981. ANN ALLERGY CODEN: ANAEA SCIENTIFIC CONGRESS, 47 (2). 1981. 132. 1/3/4 23017569 CHEMICAL SENSITIVITY IN PHYSICIANS. JOHNSON A R; REA W J; SMILEY R E; SPRAGUE D E; FENYVES E J; EDGAR R T DALLAS, TEXAS. 37TH ACA (AMERICAN COLLEGE OF ALLERGISTS) SCIENTIFIC CONGRESS, WASHINGTON, D.C., USA, APRIL 4-8, 1981. ANN ALLERGY 47 (2). 1981. 129CODEN: ANAEA 1/3/5 23011227 CHEMICAL SENSITIVITY RELATED TO PESTICIDE OVER EXPOSURE. REA W J; KAHN A A; JOHNSON A R; FENYVES E J; SMILEY R E; SPRAGUE D E; EDGAR R T DALLAS, TEXAS. 37TH ACA (AMERICAN COLLEGE OF ALLERGISTS) SCIENTIFIC CONGRESS, WASHINGTON, D.C., USA, APRIL 4-8, 1981. ANN ALLERGY 47 (2). 1981. 124. CODEN: ANAEA 1/3/6 23011226 THE EFFECTS OF ENVIRONMENTAL CONTROL AND FASTING ON HEAD ACHES. GREENBERG M R; REA W J; STROUD R M DALLAS, TEXAS. 37TH ACA (AMERICAN COLLEGE OF ALLERGISTS) SCIENTIFIC CONGRESS, WASHINGTON, D.C., USA, APRIL 4-8, 1981. ANN ALLERGY 47 (2). 1981. 124. CODEN: ANAEA 1/3/7 23005903. ACUTE LARYNGEAL EDEMA. REA W J DALLAS, TEXAS. 37TH ACA (AMERICAN COLLEGE OF ALLERGISTS) SCIENTIFIC CONGRESS, 13573 W SHINGTON, D.C CODEN: ANAEA 1/3/8 20055067 COMPREHENSIVE ARTHRITIS USA, APRIL 4-8, 1981. ANN ALLERGY 47 (2). 1981. 119p?'*'■?v ENVIRONMENTAL CONTROL AND ITS EFFECT ON RHEUMATOID O i HU U u A ri j ; \ A \J rv i l i\ u A il n *i u j on x i_ i *v u n it n a u w BULLOCK T M; MARSHALL R i; RANDOLPH T G UNIV. ALA. MEETING OF THE AMERICAN RHEUMATISM ASSOCIATION, CENTRAL REGION, CHICAGO, ILL., USA, NOV. 7, 1980. CLIN RES 28 (4). 1980. 791A . CODEN: CLREA ? B55 $1.65 $0.20 $1.12 $2.97 20feb84 20:49:11 User55273 0.025 Hrs File5 1 Descriptor Tymnet 8 Types Estimated Total Cost File55:BIOSIS Previews - 1977 thru 1980 (Copr. BIOSIS 1980) See Files 5,255 Set Items Description ? E AU=REA W J Ref Items Index-term E1 28 AU=REA T H E2 1 AU=REA W A 7 *AU=REA W J E3 E4 8 AU=REACH G 1 AU=REACH I E5 E6 1 AUrREACH R C 1 AU=READ A D E7 E8 30 AU =READ A E 2 AU=READ A P E9 E 10 1 AU=READ A R E 11 1 AU=READ B C E 12 3 AU=READ B D -more? TSSE3 1 0 SE3 2 7 AU=REA W J ? T2/3/1-7 2/3/1 68025129 AIR POLLUTION ANALYSIS USED IN OPERATING AN ENVIRONMENTAL CONTROL UNIT EDGAR R T; FENYVES E J; REA W J SUITE E 305, 12110 WEBB CHAPEL RD., DALLAS, TEX. 75234, USA. ANN ALLERGY 42 (3)- 1979- 166-173CODEN: ANAEA 2/3/2 67031938 FOOD AND CHEMICAL SUSCEPTIBILITY AFTER ENVIRONMENTAL CHEMICAL OVER EXPOSURE CASE HISTORIES REA W J; BELL I R; SUITS C W; SMILEY R E SUITE E305, 12110 WEBB CHAPEL RD., DALLAS, TEX. 75234, USA. ANN ALLERGY 41 (2). 1978 101-1 10. CODEN: ANAEA 135^^ 2/3/7 ENVIRONMENTALLY TRIG. .RED CARDIAC DISEASE REA W J 8345 WALNUT HILL LANE, SUITE 240, DALLAS, TEX. 75231, USA. ANN ALLERGY 40 (4). 1978 243-251. CODEN: ANAEA 2/3/4 64024295 ENVIRONMENTALLY TRIGGERED SMALL VESSEL VASCULITIS REA W J ANN ALLERGY 38 (4). 1977 245-251. CODEN: ANAEA 2/3/5 63005822 ENVIRONMENTALLY TRIGGERED THROMBO PHLEBITIS REA W J ANN ALLERGY 37 (2). 1976 101-109CODEN: ANAEA 2 / 3/6 77075477 ECOLOGIC ORIENTATION IN THORACIC AND CARDIO VASCULAR SURGERY REA W J DICKEY, LAWRENCE D. (ED.). CLINICAL ECOLOGY. XVI+807P- ILLUS. CHARLES C THOMAS PUBLISHER: SPRINGFIELD, ILL., USA. ISBN 0-398-03409-51976 650-661 CODEN: 05358 2/3/7 77075423 RELATIONSHIP OF FOOD AND CHEMICAL SENSITIVITIES TO ACUTE RESPIRATORY FAILURE REA W J DICKEY, LAWRENCE D. (ED.). CLINICAL ECOLOGY. XVI+807P- ILLUS. CHARLES C THOMAS PUBLISHER: SPRINGFIELD, ILL., USA. ISBN 0-398-03409-5. 1976 180-183 CODEN: 05358 ? B255 $1.58 $0.19 $0.98 $2.75 20feb84 20:50:31 User55273 0.024 Hrs File55 1 Descriptor Tymnet 7 Types Estimated Total Cost File255:BIOSIS Previews - 1969 thru 1976 (Copr. BIOSIS 1976) See Files 5,55) Set Items Description ? E AU=REA W J Ref Items Index-term E1 1 AU=REA V E E2 E3 E4 E5 E6 E7 2 AU=REA W 12 *AU=REA W J 1 AUrREACTIVITY OF TYROSIN E RESIDUES IN THE 1 AU=READ A 1 AU=READ A D 35 AU=READ A E E9 E 10 Ell 1 AU=READ A J 1 AU=READ A T 3 AU=READ B A N ? SS E3 1 12 AU=REA W J ? T1/3/1-12 1/3/1 57047351 CROSS LINKED HEPARIN BINDING OF A MEMBRANE OXYGENATOR SYSTEM EBERLE J W; MANTON J R; MEALS C R; WHITLEY D E; REA W J J BIOMED MATER RES 7 (2). 1973 145-153CODEN: JBMRB 1/3/2 56017058 HYPER ALIMENTATION IN PULMONARY SURGERY REA W J; ECKER R R; EBERLE J W; SUGG W L CHEST 62 ((5 PT 1)). 1972 577-580. CODEN: CHETB 1/3/3 55029919 ZINC IN CARDIAC SURGERY REA W J; ECKER R R; SUGG W L J SURG RES 12 (3)- 1972 164-167- CODEN: JSGRA 1/3/4 55021777 DIAZEPAM AS AN ADJUNCT TO BRONCHOSCOPY ECKER R R; SUGG W L; REA W J CHEST 62 (3)- 1972 259-262. CODEN: CHETB 1/3/5 73015673 MANAGEMENT OF INJURIES OF THE INNOMINATE AND PROXIMAL LEFT COMMON CAROTID ARTERIES ECKER R R; DICKINSON W E; SUGG W L; REA W J J THORAC CARDIOVASC SURG 64 (4). 1972 618-624 CODEN: JTCSA 1/3/6 73009410 LONG-TERM MEMBRANE OXYGENATION WITHOUT SYSTEMIC HEPARINIZATION REA W J; WHITLEY D; EBERLE J W AM SOC ARTIF INTERN ORGANS. TRANSACTIONS AMERICAN SOCIETY FOR ARTIFICIAL INTERNAL ORGANS, VOL. 18. SEATTLE, WASHINGTON, APRIL 17-18, 1972. XII+634P. ILLUS. AMERICAN SOCIETY FOR ARTIFICIAL INTERNAL ORGANS: WASHINGTON, D.C., U.S.A. 1972 316-320 CODEN: 02735 1/3/7 53059137 CONTROL OF INTRACTABLE VENTRICULAR TACHY CARDIA BY CORONARY RE VASCULARIZATION ECKER R R; MULLINS C B; GRAMMER J C; REA W J; ATKINS J M CIRCULATION 44 (4). 1971 666-670. CODEN: CIRCA loo * * 1/3/8 72096498 IMPORTANCE OF VENTRICULAR FUNCTION IN PREDICTING OPERATIVE MORTALITY tm » « w 11 ¿ iJ X C , i t r 1 o REA W J; ECKER R R; ..JLLINS C B; SHAPIRO W; POMBO CIRC SUPPL 44 (4). 1971 11-215 CODEN: CISUA J F; SUGG W L 1/3/9 72084252 HYPER ALIMENTATION IN CHEST SURGERY REA W J INTRAVENOUS COWAN, GEORGE S. M. JR. AND WALTER L. SCHEETZ (ED.). PHILADELPHIA, PA., HYPERALIMENTATION. XXIII+225P. ILLUS. LEA & FEBIGER: U.S.A. 1972 176-184 CODEN: 02504 1/ 3/10 72060043 GAS TRANSFER IN A HEPARINIZED MEMBRANE OXYGENATOR REA W J; EBERLE J W; WATSON J T; ECKER R R; SUGG W L SURG FORUM 22. 1971 188-190 CODEN: SUFOA 1/3/11 71073996 INTRA VENOUS HYPER OSMOLAR ALIMENTATION REA W J; WYRICK W J JR; MCCLELLAND R N; WEBB W R ARCH SURG 100 (4). 1970 393-398 CODEN: ARSUA 1/ 3 / 1 2 71051715 NECROTIZING FASCIITIS WYRICK W J JR; REA W J REV SURG 28 (2). 1971 143 CODEN: RESUA ? LOGOFF $1.45 $0.18 $1.68 $3*31 20feb84 20:51:46 User55273 0.022 Hrs File255 1 Descriptor Tymnet 12 Types Estimated Total Cost LOGOFF 20:51:49 TYMNET: call cleared by request please log in: 13578 P E T E R I. O R R I S , M . D . QUALIFICATIONS Dr. Orris is a practicing physician, specializing in internal medicine. His practice is based in Chicago, Illinois where he is a member of the Division of Occupational Medicine at Cook County Hospital, Southwest Physicians Limited in Chicago, and part of NIOSH Region V. His curriculum vitae is attached. He is currently involved in a research study of truck drivers in the St. Louis, Missouri area through the Teamsters Central States Fund for potential exposure to dioxin at Times Beach and a study through the Veterans Administration of Wisconsin in surveying approximately 61 veterans twin pairs wherein one of the twins served in Vietnam and the other did not. He is participating in these separate studies of potential dioxin-related health effects from the clinician's point of view in preparing an initial survey questionaire to be followed by examinations. His clinical practice has involved the hands-on diagnosis and treatment of veterans who had served in Vietnam. II. SUBJECT MATTER The subject matter of Dr. Orris' testimony will include his clinical evaluation of Vietnam veterans in his own practice, a methodology for the assessment of TCDD intoxication and the diagnosis of symptoms and/or syndromes of TCDD intoxication. He will testify that the diagnosis of TCDD intoxication rests upon three categories of evidence, i.e. a history of exposure, a clinical syndrome consistent with that exposure history and chronologically appropriate, and laboratory evidence consistent with the exposure history and clinical syndrome. His testimony will finally include a review of the representative plaintiffs' medical records and clinical evaluations. 13579 I I I . S C I E N T I F I C P R I N C I P L E S See General Statement of Scientific Principles and Assumed Facts Attached. IV SUBSTANCE OF OPINIONS A. Dioxins are extremely toxic particularly 2,3,7,8 -TCDD. B. That TCDD is extremely toxic at extremely low levels. C. That TCDD is acneogenic. D. That TCDD is teratogenic. E. That TCDD is fetotoxic. F. That TCDD is capable of transmitting genetic damage. G. That TCDD is capable of causing liver dysfunction. H. That TCDD can cause peripheral neuropathy. I. That TCDD is carcinogenic, specifically causing soft tissue sarcomas and lymphomas. J. That TCDD as a carcinegen does not affect one organ, but many. K. That additional sites of cancer may be caused by exposure to TCDD. L. That TCDD may cause neuropsychiatric disorders. V. GROUNDS FOR OPINIONS* 1 A. General The bases or grounds for such facts and opinions include Dr. Orris' educational and professional experience; personal research; review of the applicable medical and scientific literature; and a review of the medical records and/or data of the representative plaintiffs. B. Specific For several of the opinions articulated above, Dr. Orris will rely in part on the following references: 1. Van Miller, J. T., Lalich and Allen, 1977, Increased incidence of Neoplasm in Rats Exposed to Low Levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin, Chemosphere 6(9, 10), 537-544 and 625-632. Kociban, R. M., Keyes, and Beyer, 1978, Results of a twoyear Chronic Toxicity and Oncogenicity of 2,3,7,8-tetrachlorodibenzop-dioxin in Rats, Toxicology and Applied Pharmacology, 46 (2): 279-303. -2- J Esposito, M. P., Tiernan and Dryden. 1980. Dioxins. Prepared for industrial pollution control division, U.S. EPA, Cincinnati, Ohio Contract Nos. 68-03-2577, 68-03-2659, and 68-03-2579. EPA 600/2-80-197. The EPA Advisory Committee and Criteria Documents. The additional specific references for the specific opinions articulated are being compiled by Dr. Orris but as of this submission, because of the require­ ments of his clinical practice, has been unable to compile the entire list of references but he shall forward those references within two weeks. -3- CüP.'îir.: ■ Tr -c t.'ü'.i.M'ber 13, 1983 i'i/u.c Peter Orri ADDRESS Resi donee: bìil.'-y South Kenwood C!i i ..;tc;o, I l l i n o i s 6 Ob.15 O i l : ) 7G2-76S0 B u siness: Ili vi si en o f Occupati oral Ted ici ne Coo!: County Hospital 720 S. Wolcott Chicago, 111. 60512 (312) 633-5310 HI OSH Regien V. 300 S. Wacker, Chicago, 111. 60606 (312)885-3651 Southwest P h y sicia n s L td . 3214 I/. 63 S tre e t Chicago, I l l i n o i s 60629 (312) 434-0556 n i M ï w n . v r ; October 7, 1945 B 7 r,T:: l .o'- Angeles, C a li forni a ed u c a ti 1-uv.u: rrj .■u a ce r ra Poso C (Aiate Addi LI1 a I June, 1967 Bachelor of A rts ( B .A . ) harvard College Cambridge, Massachusetts J u r r , 1970 Master of P u b lic Health (M.P.M.) Yale U n iv e r s it y New Haven, Connecticut 1 Kj lin Doctor of Medicine (H .D .) Chicago Medical School Chicago, I l l i n o i s 1975 1975-19 Intern al Medicine Resi do,icy Cook County Hospital Chicago, I l l i n o i s 1977-1979 Occupational Medicine Residency Cook County Hospital Chicago, I l l i n o i s J u l y , 1965 Bio-medical Cl a c t r o n ics He. r v r-d U;li v e r s i ty Cambridge, Massachusetts 1i!v•7-19ci3 Advanced E l e c t r i c a l Thoor” Circuit Depart: t of Engineering and Applied Th ysics Harvard U n iv e r s it y Cambridge, Massachusetts Ja n u a ry , 1979 UICC/ILO System of Radiographic Evaluation o f Ptieumocconiosi s NIOSH approved American College Chest P h y s ic ia n s Continuing Medical Education Course. 1979 Diplomat, American Board of Preventive Medicine in Occupational Medicine 1976 State of I l l i n o i s , Ph ysician and Surgeon, #36-52014 J u l y , 1979- Attending P h y s ic ia n , D iv is io n s o f General and Occupational Medicine Department of Medicine Cook County Hospital Chicago, I l l i n o i s CERTIFICATION AMD LICENSES CURRENT EMPLOYMENT R e s p o n s ib ilit ie s in clud e: 1) In te rn a l Medicine H ousestaff su pervisio n and d i r e c t p a tie n t care in. the o u t- p a tie n t c l i n i c and on a general medicine ward s e r v i c e . 2) Occupational Medicine h o u se s ta ff supervisio n and d ir e c t p a tie n t care on the in p a t ie n t c o n su lta tio n s e rv ic e and in the o utpatien t c lin ic . 3) D id a c tic sessions with the h o u se s ta ff on both In te rn a l and Occupational Medicine t o p ic s . 4) C l i n i c a l research in Occupational Medicine. 51 Supervision of the Epidemiologic Research of the Occupational Medicine H o u sesta ff. 1358 o1-7% J i Region . Nations n s t it u t e For Occupational Safety and Health U .S . P u b lic Health Service Chicago, I l l i n o i s R e s p o n s ib ilit ie s in clu d e : 1) Conducting epidemiologic stu d ies to evaluate in d u s t r ia l health hazards in the States of Ohio, Ind iana, I l l i n o i s , Michigan, W isconsin, and Minnesota. 2) Providing Occupational Medical c o n s u lta tiv e s e r v ic e s to the medical community. 3) Le ctu rin g management, la b o r, and medical groups on Occupational Health to p ics as requested. ACADEMIC APPOINTMENTS 1975-1550 1930- Department of Preven tive Kedi ci ne Abraham Linco ln School of Medici ne U n iv e r s it y of I l l i n o i s Chicago, I l l i n o i s In s t r u c t o r L e c tu re r 1379-1381 1981- Department o f Community Heal tri and P reven tive Medici ne School of Medicine North.western U n iv e r s it y Chicago, I l l i n o i s Associ ate A s s is t a n t P ro fe s s o r , C l i n i c a l 1933- School o f Pu b lic health U n iv e r s it y of I l l i n o i s Chicago, I l l i n o i s L e ctu re r HOSPITAL STAFF APPOINTMENTS 1979- Dept, o f In te rn a l Medicine Cook County Hospital Chicago, I l l i n o i s 1982- Dn p t . c 'nternal Modi cine Mount Sinai Hospital Chicago, Illinois 1983- Dept, of Internal Medicine Mercy Hospital and Medical Con tor Chicago, Illinois OCCUPATIONAL MFD ICAL CONSULTANT TO: Occupational Health Program of Mercy Hospital and Medical Center Miles Laboratories, Inc. H. Kramer and Company Industrial Medical Program of Mt. Sinai Hospital TEACHING OF UNDERGRADUATE MEDICAL COURSES 1977 The Epidemiology of Cardiovascular Di sea se University of II 1inois , Abraham Lincoln School of Medicine. 1978 International Health Care Systems University of Illinois, Abraham Lincoln School of Medici ne. 1930-1983 International Comparison of HeFftirCare Systems HorfcTi\stern Uni versfty Medical School 1931,1982 Occupational Health northwestern University Medical School. 1966-19G7 Research Assistant to Dr. David T. Donhardt Dept, of Biology Harvard University Cambridge, Massachusetts 1967-1968 Research Assistant to Dr. J. A. Hobson Dept, of Psychiatry Harvard Medical School Boston, Massachusetts PAST LI'PLOYMENT 19/0 Ad r¡ n i:;tr:.ti vc inter !i111 He a 'th Carter He\/ H.iv . Cr,nn.ee tic 1970-1982 Edi torial Ccr.sol tant Ac ado ray Professional Servioes licw York, N.Y. 1971-1972 Nurse Technician Trau.na Unit Cook County Hospital 1372-1975 Research Assistant Division of Emergency Medical Services Illinois Dept, of Health Chicago, Illinois 1979-1900 Attending Physician Div. of Emergency Medicine Cook County Hospital Chicago, Illincis 1979-1960 Medical Director Hi'10 Fe a s ib i1ity Study Southeast Health Plan Chicago, Illinois. Orris, !'., Daniels, Health Hazard Report 30-201 Health Effects of 1,1_,1 , Trichloroethan^ on So"; av can AssemoTy“ íi’pToyocs U.S. Üoparcrout of Health 'íT¡7d ¡füüijtV"Seryices, *Publie ileal ch Service, Center for Disease Control, national Institute for Occupational Safety and Health, Cincinnati, Feb. 1900 Orris, P.: Unjustified Conclusion?(Letter) Journal of Occupational '!TedTcTrTc, VoT 7~?j , lio. 1, Jan. 1931, p.7. Edmonds, L., McQuilkin, S., Orris, P., Daniels, U. Health Hazard Report 80-053-874, An Evaluation of Potential Abortifactants At A PlaTit ProcuTcTTT;“ Mac !-in c To 6 fs T)e n a r tTTarTc"o7 1 fiáTtfi "a iid Uuná n Serví c o s , Pu -• ic TTsaTv.n Service, Canter for Disease Control, Ration 1 Institute for Occupational Safety and Health, Cincinnati, May, 1981. Orris, P., Daniels, W., Health Hazard Report C.l-0'.8-9o9 An Evaluation of Possible Garrir,0 'r'nir Effect:', of TTroTcftic Iiyiii-oco¡-;bio^“ljTo"7“lJJpüir :ent of TieaTuf f'7nr¿F^in7^vrü7’~ P i |U¡dc U-al th Service, Center for Disoc.-.e Control , National Institute f ;••• Occupational Safety and Health, Cincinnati, October 1931 135B6 Orris, P. , Daniels, Heal tl~ Hazard Report 80-244-992 Heal th Hazards of .. atomacious Earth and Phosphoric Acid at a Hanufacturinn Plant in ChT.r.~pn" U T S . Department or lieaich and Human SeFv :~es~7 fuo fic Health Service, Center for Disease Control, National Institute for Occupational Safety and Health, Cincinnati, Ohio, November, 1931 Orris, P., Daniels, W., Health Hazard Report 80- 025-989 Health Effects of Low Dose Sulfuric Acid U.S. Department or neTTYh and Human services, FUTITc Health Service, Center for Disease Control, National Institute for Occupational Safety and Health, Cincinnati, Ohio, November, 1981 Orris, P., Almaguer, 0., Health Hazard 81-185-1C07 Health Effects of a Spray Paint and Shot Blast Process U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety and Health, Cincinnalti, Ohio, November, 1981 Orris, P. Daniels, W., Health Hazard Report 81- 054-1035, Polychlorinated Biohenyl Exposure to Electrical V/orkers in a Steel !h iTT'U'."S’. Department otnieaftn and Human services, PuoTic Health Service, Center for Disease Control , National Institute for Occupational Safety and Health, Cincinnati, Ohio, January 1982 Orris, P. Haalth Hazard Report 80-235-1055, Cp£cer Mortal ity of Electrical Workers in a Steel Ro Ii~~ ¿T H tH 1, u.“S. Department of Health and Human Services, "Puoi ic Haalth Service, Center for Disease Control, National Institute for Occupational Safety and Health, Cincinnati, Ohio, March 1982 Orris, P. Almaguer, D. Kramkcwski, R. Health Hazard Report 81-123-1107, Low Dose TDI Exposure in a Fcam Seat Mannf ac turing Process, U. S. D e pa r' an r. c f He il11li "and Human Services, PubVicf Health Service, Canter for Disease Control, National Institute for Occupational Safety and Health, Cincinnati, Ohio, May 1932 Kahn, H.S., Orris, P., The Emerging P.olo of Salaried Physicians: An Organizational proposal Journal of PuCl ic Tiea~l th Po 1 1 cy, ToT. 3, m o . 3, 1982 Orris, P. Kennedy, M.J. Guerriero, J. Hess!, S.M. Hryhorczuk, D.O. and Hoffman, D. Activi ties O f An Emp 1o.vr Indcpen ¡ant Occupati onal iladici ne Li inic America:! Journal of Public Health, Voi. 72, No. 10, October, 1982 o i35 Q IO ti.1 i•*.10»:. :tp;1 , m 0,.Uti.y t'CL#I_*5 10•'»-.1 liiiv\ :.>v<>.iu>i Her vie*,. Irc7-New York, N .Y . 982 t Orris, P. Alme.guer, 0. Kra.aikowski, R. Hc*a 1 Lh Hazard Report S2-05‘T-1194, Lew Lazo Solvent Exposure In A S'.1 .::,11 Lngi no ?:am;fac Lurfn;)~ ¡'1 an t, IJ. S. Department of TleaTth ai;i71Ti7.iiar73orvi’ces,’ PTibnc Meal th Service, Center for Disease Control, national Institute for Occupational Safety and Health, Cincinnati, Ohio, Sept. 1002 Fagan, K. Orris, P. & Daniels, V/. Health Hazard Report Cl-239-1201 , Low Dose Carbon Monoxide E xpo sura in a Steel Mill , U. S. Department oTlleaPcn ifnd’l.uinan Services, Public Health Service, Center for Disease Control, national Institute for Occupational Safety and Health, Cincinnati, Ohio, Oct. 1932 Orris, P. Daniels, W. Health Hazard Report 81-317-1202, Health Effects of Oil Mist Exposure In A Machine Shop,- U. S. Department of Heal th and Human 'Services,' Public Health Service, Center for Disease Control, National Institute for Occupational Safety and Health, Cincinnati, Ohio, Oct. 19C2 Orris, P. Baron, S. Occupational Medicine: A Role for the Primary Care Phy sTc inn, Hospi ta~~^ra~ctTc'eVuT. 13,1,0. J7"Tiarciij TlTa. Orris, P. Danir4s, W. Health Hazard Report 0U-112-12G1, Health Effects of Iron Oxide Exposure in A Steel Tubin~~ ■•ITTl , U DeparH-rit oTTlTi crT anu ~ Human Service:., PuDlic Health. Service, Center for Disease Control, National In stitute for Occupational Safety and Health, Cincinnati, Ohio, Feb. 1933 Orris, P. Cone, ,1, Dozier, E . , McQuilkin, S. Health Hazard Report 80-096-1359, Health Effects of Va.nad:fo Pentoxide In Thermal Patt e r Tliaimfactare , U. S. Department orlleai th and Henan Services- Publ ic ilea i th Service, Cenf:r for Disease Control, National Institute for Occupational Safety and Health, Cincinnati, Ohio, Aug. 1963 Orris, P. Health Hazard Report 82-239-1355, Evajua f •'an of a Suspect:*'! Cancer Excess in an ElectricaTToiT ’ “ llanorac iwri tujliop,ir iTuuit, U. S. [)eparti'ife;:c""oT M l fth and Huine.ii Services, PunTic Health Service,' Center for Di sons o Control, National Institute for Occupational Safety and Health, Cincinnati, Ohio, Aug. 1933 13588 Lùv’iin, J. Idris, A. Narcynski,Ji. Sherer, R. L'i\v.;.i;r, D. Fateli, 0. McCulley, D. and 'is, P. Uipaire-I In:,1/,;noi oc ic Function In Hospitalized Intravedi': ~s Drug Abusers, Archives of Interna i Modici n e , Accopà~d~forr publication November, 1983. PRESENTED PAPERS OCTOBER, 1975 Orris, P., Sheaf, L. , Boyd, D., Freeland, J., & ¿yellow, S. Mobile Intensive Care Units, Cests~ ‘TT~ ITfectiveness: An Assessinent ~c Two PlTot Projf'Ci' in 11!ino i :V~ 7wTe r lc a jT T û ü T ïcTT •-.•aTcTi Association Annual Convention Orris , P., Carl son, C . , & Conibear, S. Occupational Health Education of T n d u s t n a T T'order’s : A New Approach Am.erican~P'ubl ic Health Association Annual Convention OCTOBER, 1976 Kientz, R., Orris, P. The Economic Fe a s i b i l i t y of a National Health Service /..-.encan Puohc Health Association Annual Convention. OCTOBER, 1979 Orris, P. Occupational Medicine in a Public General Hospital American Pud ilc Heal th Association Annual Convention. JULY 8, 1981 Orris, P. The Cook County Hospital Occupational i-Teciicine Clinic NIOSH Conference on Occupational Health and Safety of Miir.ority Workers NOVEMBER 3, 1931 Orris, P., Kahn, H.S., Sayres, B.B., Physician°s Forum Task Force Report: The Salaried Physi■:ian A~merican Public Health Association Annual Convention NOVEMBER 4, 1-9P.1 Orris, P., Kennedy, M.J. Guerriero, J. Nessi, S.M. Hryhorczuk, D.O. and U Tf: an, D. Activities of An Employer Tritiep onci ên t üc c u p T a T id FT ’ed ic in e Cl inic Alfieri can Pubi . :c He;, en Association Annual Convention MAY L’5, lPr-3 Snxena, K ., Johnson, 8., Ilryhorozu' D., and Orri:., F. Intitial r.. dice1 Hanaccmoot uf a Mi ni -U i so s to r w izh a T ra n sTerriiTr' FTrenTi.-.TtTfnq PolychlorinTr.-.l ~Ei piiuny ia iTiird World i¿Tigresc on Emergency and Disaster Medicine, Rome, Italy. June, 2, 1903 Orris, P. Hryhorezuk, D. Piagnosis of TCDD Intoxication, American Public Hea1th Association, Occupational ;_*alth Section Midwest Regional Meeting AUGUST 1, 1983 Orris, P. Socioeconomic Determinants of AdlilTUiseaco, national Medical /»ssociation, 88th Annual Convention, Chicago, Illinois LECTURES Graduate? Modica! Education : Moal th Effects of 2,3,7,8 TëtraciT! cro'd lb"c;'i:-:o-7T~ui pxl n . Case Western Reserve University School of Medicine, University of Tennessee Medical School , Wayne State University School of Medicine, Mt. Sinai Hospital, Chicago. Epidemioloqy as a Tool of tho Ce cup o r.al 1laa itli ProressTônaT Wisconsin Association of Occupational Health Professionals, Milwaukee, Wi sconsi n . Occupational Disoase in Pr ima ry Caro Trac ti co Anal g tod Clothing 2 Textile Workers Union, AFL-CIO, Hew York City., Grant Hospital, Chicago., Alexian Brothers Medical Center, Chicago., University of Tennessee School of Medicine . Occupational Renai Disense University of Illinois Great Lakes Educational Resource Center, United States Uavy, Virginia Beach, VA. Occupational Lead Ucphropatliy Case Western Reserve University School of Medicine, Cleveland, Ohio Respiratory Hazards of Workers in ch«.1 k TTFc of IIo’.TT.TrTTTns Hew Orleans General Hospital , Mew Orleans, La. Agent P:*ance: .rr;?n t K n ow lede a The American .dical Student Association 31st Annual Conventic--, Can Ikimanisn Survive Medicai Sai-.ooì ? State University of Maw York Medical School, Syracuse, Maw York Is Competition Heal tliy For FiëoTc"iïïëT Dept, of Preventive Medicine, Wayne State University School of Medicine, Detroit, Michigan. Occupational Medicine: ArTOvervi ew Dept, of Preventive Medicine, St. Louis University, St. Louis, Mo. Continuing Education in Occupational Health: Medical Surve il lance For "Foundry Workers Allied Industrial Workers, AFL-CIO, National Foundry Conference, Milwaukee, Wise. Health Hazards of Women in tTie~l ec tri cal Industry Health Services Seminar, Motorola, Inc., Chicago, Illinois. Infectious Disease Risks o f Fiospltal Workers American Federation of Government Employees, AFL-CIO, Chicago, Illinois. PCBs: Current Knowledge International Brotherhood of Electrical Workers, North Chicago, Il 1inoi s. TESTIMONY BEFORE GOVERNMENTAL AND CITIZENS COMMITTEES 0CT03ER, 1975 Sub Committee on Health, U. S. House of Representatives Re: National Health Insurance APRIL, 1976 Democratic National Committee Re: Housestaff Trade Unions NOVEMBER, 1976 U. S. Congressional Hearings Re: Black Lung Compensation SEPT. 25, 1981 Illinois Commission on the Status of Women. Re: Reproductive Hazards in Industry NOVEMBER 6, 1982 Illinois Legislative Study Commission on Agent Orange. Re: Health Effects of Dioxin (TODD) MARCH 21, 1983 Citizens Commission On Justice At Hanes, Chicago, Illinois. Re: Carpal Tunnel Syndrome J U; Ici 3, 1 j 8 3 minois ..'iiuTco Pubi ic l'aol th, Welfare, and Corroctitns Committee. Re: Repentine! of Parental 0c c ui a t"TonlTïïtTr7^g7b'rsïï~u?pôc i c l i 7cZ£cU?*s September 25, 1903 Illinois Legislative Siuciy Commission on Agent Grange. Re: Di agno r. i s of TCDD Intrigati on 1973 Ciba Community Affairs Award 1900- Fcllcv/, American Colics of Preventive Medicina AWARDS AND HONORS PROFESSIONAL SOCIETY KEM3ERSHIPS 1969- American Public Heal th Association 1974- 1975 American Trauma Socioî/. 1975- Physicians Forum 1970- American Occupational Sdical Association. 1970- Illinois Public Healü Association 1970- American Academy of Occupational Medici ne 1579- Chicago Medical Society 1979- Illinois State Medical Society 1379- American Medical Association 1531- American College of Preventive Medici ne 1972-1975 Executive Committee, Gricaqo Area Committee on Occupational Safety and Health. 1975-1979 Executive Medical Staff, Cook County Hospital COMMITT.I MEMBERSHIPS 19/ /-ivbü , ’1U'JC un i.c; .¡ui;.1i ; il :i Propose 1 s Modicol Care Section, The Amer n Public Heal cli Associ ati un 1978-1980 Resolutions Committee, Illinois Public Health Association 1973- Occupational Health Committee, Cook County Hospital. 1979-1982 Program Committee, Medical Care Section, American Public Health Association 1980-1932 Chairman, Sub Committee on Public Hospitals Illinois Public Health Associ ati on. 1932- Action Board, American Public Health Association. 1932- Joint Policy Committee, American Public Health Association. 1983- Member, Scientific Review Panel of the American Occunational Medical Association’s Self Assessment Examination. 13593 MARVIN A. SCHNEIDERMAN, Ph.D. I. QUALIFICATIONS Marvin A. Schneiderman of Bethesda, Maryland is a statistician and epidemiologist who is the former Chief of Statistics and Epidemiology and the former Director for Science Policy of the National Cancer Institute. He is currently a consultant. II. His curriculum vitae is attached. SUBJECT MATTER Dr. Schneiderman will testify in areas concerning mathematical models, statistics, and epidemiology particularly in the area of the determination of cancer causation. He will also discuss the epidemiology of dioxins and their contaminants specifically as that relates to cancer in humans specifically soft tissue sarcoma, stomach cancers and lymphcaas. He will further testify to the relationship of exposure to the cime of manifestation of disease, i.e. the "latency period" for the development of neoplsns. Included within his testimony will be a discussion of the aultiplication of base rates in the production of cancers; the presentation ¡sf a multi-stage model for cancer induction; the age relationships and the role age plays in the various stages of cancer development as they are effected by dioxins and/or their contaminates. He will also discuss and present the pertinent animal data and the fact that the animal data in the reputable and respected medical and scientific literature is consistent with the epidemiological studies pertaining to dioxin effects in humans and that the animal data is an accurate and appropriate method for the extrapolation and prediction of disease in humans. His presentation will include a discussion of a mathematical model for the association of the multi-faceted presentation of signs and symptoms in the veteran who was exposed to Agent Orange and the correlation between those signs and symptoms and said exposure and the causal relations between those two elements. Dr. Schneiderman will, of necessity, discuss the incidence of these rare cancers in the general population for a comparison of the onset ages in the general population as compared to the ages of onset for these cancers observed in the Vietnam veterans. His testimony shall also include a discussion of the relationship of cancer induction to immune deficiencies or deficits as brought about by the immuno-suppressive effects of exposure to dioxin and will rely upon the experience with organ transplant patients and the development of lymphomas and soft tissue sarcomas which he will testify validates his opinions as to the cancer induction in the representative veterans. Finally, his testimony shall include a discussion of the question of a threshold exposure to a known carcinogen for the induction of cancer. This will include testimony to the effect that there is no "safe" level for exposure to a carcinogen, that a single exposure may cause cancer, and that there is no "no effect" level to a known carcinogen. In his testimony he will present his opinion that TCDD is the most toxic and potent carcinogen ever synthesized by man. And, finally, his testimony shall cover the widely held belief in the respected medical and scientific community that an sarcomas, lymphomas and skin cancers. 12. A carcinogen capable of causing cancer in one organ or system is more probably than not capable of causing cancer in a variety of organs or systems. 13. The cancers present in representative plaintiffs Lambiotte and / Ford are consistent with TCDD exposure. 14. It is more probable than not that the cancers present in Plaintiffs Ford and Lambiotte were caused by their exposure to Agent Orange. V. BASES FOR OPINIONS A. General Dr. Schneiderman's opinion will be based upon his education, training, experiences, participation in on-going scientific research and investigations, a review of the medical and scientific research, and a review of the zedical records of the plaintiffs. B. Specific 1. Epidemiology of Cancer 1. Hardell, L., 1981, Epidemiological Studies of Soft-tissue Sarcoma and Malignant Lymphoma and Their Relation to Phenoxy Acid or Chlorophenol Exposure, UmeS University Medical Dissertations, U Series, No. 65-ISSN 0346-6612, Ume3, Sweden, 1981. 2. Axelson, 0. and L. Sundell, K. Anderson, C. Edling, C.Hogstedt and H. Kling, 1980, Herbicide Exposure and Tumor Mortality. An Updated Epidemiologic Investigation on Swedish Railroad Workers, Scandinavian Journal of Work, Environment and Health, Volume 6:73-75. 3. Young, A.L., M.R. Flicker, H.K. Kang, 3.M. Shepard, 1583, Health Surveillance of Vietnam Veterans Claiming Agent Orange Exposure presented at American Chemical Society National Meeting, Washington, D.C., August 30, 1983 for publication in Proceedings of the Symposium "Chlorinated Dioxins and Dibenzofurans in the Total Emrironment-Il", Ann Arbor Science, 1984. 4. Back, J.A. and R.R. Suskind, 1930, The Mortality Experience of Workers Exposed to Tecrachlorodibenzo Dioxin in a Trichlorophenol Process Accident, Journal of Occupational Medicine, 22, No. 1, 11-14. 5. Cook, R.R., J.C. Townsend, M.C. Ott, L.G. Silverstein, 1980, Mortality Experience of Employees Exposed to 2,3,7,8-cetrachlorodibenzo-p-dioxin, Journal of Occupational Medicine 22 (8): 530-32. 6. Ott, M.G., D.B. Holder and R.D. Olson, 1980, Mortality Analysis of Employees Engaged in the Manufacture of 2,4,5-crichloroplienoxyaceticacid, Journal of Occupational Medicine 22 (i): 47-50. 7. Olsson, H. and L. 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Chu, Approaches to Epidemiologic Analysis of Prospective and Retrospectivie Studies: Example of Lung Cancer and Exposure to Arsenic in Environmental Epidemiology, in Environmental Epidemiology: Risk Assessment, Proceeding of a SIMS Conference, Altar, Utah, June, 1982, SIAM institute for Mathematics in Society. 13588 6. Day, N.E. and C.C. ! vn, 1980, Multi-stage Models a. Primary Prevención of Cancer, Journal or the Nacional Cancer Institute, 04:977-989. 7. Crump, K.S., D. Hoel, C. Langley and R. Peto, 1976, Fundamental Carcinogenic Processes and Their Implications for Low Dose Risk Assessment, Cancer Research 36:2973-2979. 8. Falk, H.L., 1978, Biological Evidence for the Existence of Threshold Chemical Carcinogenesis, Environmental Health Prospective, 22: 167-170. 9. Gaylor, D.W., and R.L. Kodell, 1980, Linear Interpolation Algorithm for Low Dose Risk Assessment of Toxic Substances, Journal of Environmental Pathology and Toxicology, 4: 305-312. 10. 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