Unified States Environmental Protection Agency ____ ÂEPA Office of Water 4301 Great Lakes Water Quality Initiative Criteria Documents for the Protection of Human Health R EP R O D U C ED B Y : N f|& U .S. Department of Com merce " National Technical Information Service Springfield, Virginia 22161 EPA-820-B-95-006 March 1995 PB95187308 PB95-187308 BIBLIOGRAPHIC INFORMATION PB95-187308 Report Nos: EPA/820/B-95/006 Title: Great Lakes Water Quality Initiative Criteria Documents for the Protection of Human Health. Date: Mar 95 Performing Organization: Environmental Protection Agency, Washington, DC. Office of Water. Supplemental Notes: See also PB95-187290 and PB95-187316. NTIS Field/Group Codes: 57U (Public Health & Industrial Medicine), 57Y (Toxicology), 68D (Water Pollution & Control), 68G (Environmental Health & Safety), 43F (Environment), 91A (Environmental Management & Planning) Price: PC A05/MF A01 Availability: Available from the National Technical Information Service, Springfield, VA. 22161 Number of Pages: 89p - Keywords: *Water pollution effects(Humans), ^Exposure, ^Health effects, *Toxic substances, Public health, Risk assessment, Toxicity, Neoplasms, Benzene, Chlordan, Chlorobenzenes, Cyanides, DDT, Dieldrin, Toxaphene, Toluene, Mercury(Metal), Dinitrophenols, Hexachlorobenzene, Lindane, Benzene hexachloride, Methylene chloride, Polychlorinated biphenyls, Trichloroethylene, Tetrachlorodibenzodioxin, *Great Lakes Water Quality Guidance, Great Lakes Region(United States), Carcinogenicity, Dimethyl phenols, Hexachloroethane, Water quality criteria. Abstract: The document presents the dangers to human health for several Great Lakes pollutants. < Form Approved OMB No. 0704-0188 REPORT DOCUMENTATION PAGE Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the collection of information. Send comments regarding this burden estimate or any other aspect of this " ---- - n i - . r x i n m A t i n n inri.,/4¡r>~ f QT reducing this burden, to Washington Headquarters Services. Directorate tor Information Operations and Reports, 1215 Jefferson 102, and to the Office of Management and Budget, Paperwork Reduction Project (0704-0188), Washington, DC 20503. PB95187308 2. REPORT DATE 3. REPORT TYPE AND DATES COVERED Moat, i})] = ________, _________ 1.30 x IQ' 6 mq/kq/d x 70 kQ_____________ 0.01 1/d. + [(0.0036 x 520,900) + (0.0114 x 1,871,000)] = 3.9 x 10-6 ug/L References: Hiremath, C. 1991. Toxicologist, U.S. EPA Office of Research and Development. Personal communication with R. Sills, Michigan Department of Natural Resources. Kimbrough, R.D. et al. 1975. Induction of liver tumors in Sherman strain female rats by Aroclor 1260. J. National Cancer Institute. 55(6):1453. Norback. D. and R.H. Weltman. 1985. Polychlorinated biphenyl induction of hepatocellular carcinomas in the Sprague-Dawley rat. Env. Health Persp. 60:97-105. 64 U.S. Environmental Protection Agency (EPA). 1987. Integrated Risk Information' System (IRIS database). Chemical file for polychlorinated biphenyls (PCBs) (1336-36-3). Verification Date 4/22/87. Last Revised 1/1/90. 65 GREAT LAKES WATER QUALITY INITIATIVE TIER 1 HUMAN HEALTH CRITERIA FOR 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (2,3,7,8-TCDD). CAS NO. 1746-01-6 Tier 1 Bin««" Honeancer Criterion Of the many subacute and chronic studies available for 2.3.7 . 8 - TCDD, a few stand out as supporting Tier 1 criterion derivation. In a two-year toxicity and oncogenicity study, rats were administered doses of 0 , 0 . 001 , 0.01 and 0.1 ug/kg bw/day of 2.3.7.8 - TCDD via diet (Kociba et al., 1978). Animals given the high dose exhibited increased mortality, decreased weight gain, slight depression of erythroid parameters, increased urinary excretion of porphyrins and delta-aminolevulinic acid and increased serum levels of certain enzymes. Histopathologic or gross effects were seen in liver, lymphoid, lung and vascular tissues. An increased tumor incidence was also seen. Similar effects, but to a lesser degree, were seen in mid-dose animals. A NOAEL of 0.001*ug/kg/day (1 ng/kg/day) was reported in this study. A NOAEL of 0.001 ug/kg bw/day via feed exposure was also reported in a three-generation rat reproduction study (Murray et al., 1979). At 0.1 ug/kg/day, decreases in F0 generation fertility and F, generation litter size were reported. At 0.01 ug/kg/day, significant decreases in fertility were seen in the F, and F2 generations; other effects included decreased litter size at birth, decreased gestational survival and decreased neonatal growth and survival. The reproductive capacity of the low dose ra^s did not appear to be significantly affected in any generation. However, a réévaluation of these data using different statistical methods indicated that both lower dose levels resulted in significant reductions in offspring survival indices, increases in liver and kidney weight of pups, decreased thymus weight of pups, decreased neonatal weights and increased incidence of dilated renal pelvis (Nisbet and Paxton, 1982). Nisbet and Paxton (1982) concluded that 0.001 ug/kg/day (1 ng/kg/day) was not a NOEL in the Murray et al. (1979) study. Kimmel (1988) considered the data of Murray et al. (1979) to be suggestive of a pattern of decreased offspring survival and increased offspring renal pathology even at 0 . 0 0 1 ug/kg/day, although the pooling of data from different generations by Nisbet and Paxton (1982) was considered biologically inappropriate. Studies by Schantz et al. (1979) and Allen et al. (1979) suggest that rhesus monkeys are more sensitive to 2,3,7,8 -TCDD than rats. When, monkeys were administered 50 ppt 2,3,7,8 -TCDD in feed for 7 to 20 months, decreases in fertility, increases in abortions and other toxic effects (alopecia, hyperkeratosis, weight loss, decreased hematocrit and white blood cell count and increased serum levels of SGPT) were noted. The 50 ppt dietary 66 residue level corresponds to a daily dose of 1.5 ng/kg bw/day (EPA, 1984). Therefore, 1.5 ng/kg/day can be considered a LOAEL for rhesus monkeys from these studies. In a continuation of the rhesus monkey studies by Schantz et al. (1979) and Allen et al. (1979), Bowman et al. (1989a, 1989b) have evaluated the effects of 5 and 25 ppt 2,3,7,8-TCDD in feed on reproduction and on behavior, respectively. Breeding of the animals after 7 and 24 months of exposure resulted in impaired reproductive success at 25 ppt but not at 5 ppt (approximately 0.67 and 0.13 ng/kg bw/day, respectively). The exposures were discontinued after 4 years, and a third breeding ten months post­ exposure did not indicate reproductive impairment (Bowman et al., 1989a). The offspring from these breeding experiments were evaluated for development and behavioral effects utilizing several testing methods (Bowman et al.-, 1989b). Although there were no significant effects of TODD exposure on birth weight, growth, or physical appearance of the offspring, some behavioral test results were interpreted to be indicative of TCDD effects. These included alterations in the social behavior between the mothers and their infants and of peer groups of the offspring after weaning. However, the study groups were very limited in size and the statistical and biological significance of the findings are unclear. This study may be interpreted to provide only suggestive evidence of possible behavioral effects. The reproduction study of Bowman et al. (1989a) provides much clearer evidence of a LOAEL at 25 ppt (0.67 ng/kg/day) and a NOAEL at 5 ppt (0.13 ng/kg/day). The EPA has used the equivocal evidence for a rat LOAEL at 1 ng/kg/day, supported by an unequivocal rhesus monkey LOAEL at 1.5 ng/kg/day, in the development of an Acceptable Daily Intake (ADI) (EPAr 1984; 1985a) and Drinking Water Equivalent Level (DWEL) (EPA, 1985b; 1990). In light of the more recent rhesus monkey study of Bowman et al. (1989a), there is improved resolution of the threshold for the sensitive effect of reproductive impairment in this species. The Human Noncancer Criterion is based on the NOAEL of 0.13 ng/kg/day (1.3 x 107 mg/kg/d) for reproductive effects from this study. The entirety of the rhesus monkey studies, supported by the evidence m rats cited above, is judged sufficient for Tier 1 criterion development. ADE = 1.3 X 10-7 mcr/kg/d = 1.3 x 10"9 mg/kg/d 100 Where: Uncertainty Factor = 100, composed of: lOx for interspecies variability lOx for intraspecies differences Drinking Water Sources: 67 APE x BW x RSC ___________ WCd + [ (FC jl3 x BAF t ij ) + (FC jl4 x BAF jj^) ] HNV = 1.30 x IQ' 9 ma/ka/d x 70 ka x 0.8 2 1/d + [(0.0036 x 48,490) + (0.0114 x 79,420)] = 6.7 x 10‘ 8 ug/L Non-Drinking Water Sources: HNV - ___________APE x BW x RSC____________ WCr + [(FCru x BAFt u ) + (FC^ x BAF^) ] = 1.30 x 10~9 mq/kq/d x 70 kg x 0.8 0.01 1/d + [(0.0036 x 48,490) + (0.0114 x 79,420)] = 6.7 x 101* ug/L References: Allen, J.R. et al. 1979. Reproductive effects of halogenated aromatic hydrocarbons on nonhuman primates. Ann. NY Acad. Sci. 320:419-425. Bowman, R.E., et. al. 1989a. Chronic dietary intake of 2,3,7,8 -tetrachlorodibenzo-p-dioxin (TCDD) at 5 or 25 parts per trillion in the monkey: TCDD kinetics and dose-effect estimate of reproductive toxicity. Chemosphere. 18(1-6): 243-252. Bowman, R.E., et al. 1989b. Behavioral effects in monkeys exposed to 2,3,7,8 -TCDD transmitted maternally during gestation and for four months of nursing. Chemosphere. 18(1-6):235-242. Kimmel, G.L. 1988. Appendix C. Reproductive and DevelopmentalToxicity of 2,3,7,8 -TCDD. Reproductive Effects Assessment Group, OHEA/ORD, EPA. In: EPA. 1988. A Cancer Risk-Specific Dose Estimate for 2,3,7,8-TCDD. Appendices A-F. Review Draft. EPA/600/6-88/007Ab. Kociba, R. J. et al. 1978. Results of a two-year chronic toxicity and oncogenicity study of 2 ,3,7,8 - tetrachlorodibenzo-pdioxin in rats. Toxicol. Applied Pharmacol. 46:279-303. Murray, F. J. et al. 1979. Three-generation reproduction study of rats given 2,3,7,8 -tetrachlorodibenzo-p-dioxin (TCDD) in the diet. Toxicol. Applied Pharmacol. 50:241-252. Nisbet, I.C.T. and M.B. Paxton. 1982. Statistical aspects of three-generation studies of the reproductive toxicity of TCDD and 2,4,5-T. The American Statistician. 36 (3) :290-298. 68 Schantz, S. L. et al. 1979. Toxicological effects produced in nonhuman primates chronically exposed to 50 ppt TCDD. Toxicol. Applied Pharmacol. 48:A180. (Abstract No. 360). U.S. Environmental Protection Agency (EPA). 1984. Ambient Water Quality Criteria for 2,3,7,8 -Tetrachlorodibenzo-p-dioxin. Office of Water Regulations and Standards. EPA 440/5-84-007. U.S. Environmental Protection Agency (EPA) . 1985a. Health Assessment Document for Polychlorinated Dibenzo-p-dioxins. Office of Health and Environmental Assessment. EPA/600/884/014F. U.S. Environmental Protection Agency (EPA). 1985b. Drinking Water Criteria Document for 2,3,7,8 - Tetrachlorodibenzo-p-dioxin. ECAO/ODW. EPA-600/X-84-194-1. PB 86-117983. U.S. Environmental Protection Agency (EPA). 1990. 55 Federal Register No. 143. Wednesday, July 25, 1990. National Primary and Secondary Drinking Water Regulations; Synthetic Organic Chemicals and Inorganic Chemicals. Proposed rule. Tier 1 Human Canter Criterion The EPA (1984) evaluated the available epidemiological and animal bioassay data on the potential carcinogenicity of 2 ,3,7,8TCDD. They determined that some case-control studies provide limited evidence for the human carcinogenicity of phenoxy acids and/or chlorophenols, which contain impurities including 2 ,3,7,8TCDD. They concluded that the evidence for the human carcinogenicity of 2,3,7,8 -TCDD based on the epidemiologic studies is only suggestive due to the difficulty of evaluating the risk of 2,3,7,8 -TCDD exposure in the presence of the confounding effects of phenoxy acids and/or chlorophenol. Recently published epidemiology studies may be interpreted to provide suggestive evidence of carcinogenicity (Zober et al., 1990; Fingerhut et al., 1991). The potential use of these new studies for quantitative risk assessment has not yet been fully explored. With regard to animal bioassays, the EPA (1984) concluded that several rodent studies establish that 2,3,7,8 -TCDD is an animal carcinogen in multiple species and organs and is probably carcinogenic in humans. The weight of evidence of carcinogenicity is sufficient for Group B2 classification (probable human carcinogen), and satisfies the database requirements for Tier 1 criterion derivation. Among the carcinogenicity bioassays, NTP conducted bioassays with both Osborne-Mendel rats and B6C3F1 mice (NTP, 1982a). Groups of 50 mice and 50 rats of each sex were given 2,3,7,8 -TCDD in corn oil-acetone by gavage twice per week for 104 weeks. Doses of 0, 0.01, 0.05 or 0.5 ug/kg/week were administered to 69 rats and male mice while female mice received 0, 0.04, 0.2 or 2.0 ug/kg/week. Controls consisted of 75 rats and 75 mice of each sex. Animals were killed at weeks 105-107. 2,3,7,8-TCDD caused an increased, dose-related incidence of follicular-cell adenomas or carcinomas of the thyroid in male rats. A significant increase in subcutaneous tissue fibromas was also seen in high­ dose males. High-dose female rats exhibited increased incidence of hepatocellular carcinomas and neoplastic nodules, subcutaneous tissue fibrosarcomas and adrenal cortical adenomas. In male and female mice, 2,3,7,8 -TODD induced an increased dose-related incidence of hepatocellular carcinomas. High-dose female mice also exhibited increased incidence of thyroid follicular-cell adenomas. In a dermal study also conducted under contract for NTP (NTP, 1982b), 30 male and 30 female Swiss Webster mice were treated with 2,3,7,8-TCDD in acetone for 3 days/week for 104 weeks. Doses of 0.005 ug and 0.001 ug 2,3,7,8 -TCDD were administered to the clipped backs of males and females, respectively. A similar group was pretreated with one application of 50 ug dimethylbenzanthracene (DMBA) one week before 2,3,7,8-TCDD administration. 2,3,7,8-TCDD induced a statistically significant increase of fibrosarcomas in the integumentary system of females given both 2,3,7,8-TCDD alone and following a single application of DMBA. Van Miller et al. (1977) administered diets containing 0, 0.001, 0.005, 0.05, 1, 50, 500 and 1000 ppb 2,3,7,8-TCDD to groups of 10 male Sprague-Dawley rats. Animals received the diets for 78 weeks and were then placed on control feed until they were killed, at week 95. All rats fed the higher concentrations (1-1,000 ppb) died early. A variety of tumors were produced and the total number of animals with tumors generally increased, but the small number of animals limits the value of the data. Kociba et al. (1978) administered 2,3,7,8-TCDD via the diet to groups of 50 male and 50 female Sprague-Dawley rats for 2 years. Control groups consisted of 8 6 animals of each sex. The doses administered were 0 , 0 .0 0 1 , 0 . 0 1 and 0 . 1 ug/kg/day. 2,3,7,8-TCDD induced an increased incidence of hepatocellular carcinomas and hepatocellular hyperplastic (neoplastic) nodules in female rats at the two highest dose levels. The highest dose of 2,3,7,8-TCDD also induced an increase in the incidence of stratified squamous cell carcinomas of the hard palate and/or nasal turbinates in both males and females, squamous cell carcinomas of the tongue in males and squamous cell carcinomas of the lungs in females. Kociba et al. (1978) is chosen as the basis for quantitative cancer risk assessment. The Kociba study found that the principal target organ for 2,3,7,8 -TCDD-induced tumors was the liver in female rats, demonstrating a dose-related statistically significant increase of hepatocellular carcinomas and hyperplastic (neoplastic) nodules. For quantitative risk assessment, the data were adjusted for early mortality by 70 eliminating those animals that died during the first year of the study. Also, in the mid-dose group, two of the reported 20 females with tumors had both nodules and carcinomas; 18 affected animals were used as the input for the dose group. Using the linearized multistage model, the resulting slope factor for 2,3,7,8 -TODD is 1.51 x 105 (mg/kg/day)'1. However, an independent pathologist (Squire) was engaged by EPA to reevaluate the histopathologic slides from the Kociba study (EPA, 1984). Squire reported higher tumor incidence than Kociba, generating a slightly higher slope factor of 1.61 x 105 (mg/kg/day)*1. EPA (1984) used an average of the two slope factors, 1.56 x 105 (mg/kg/day)*1, to generate surface water criteria. In March 1990 a panel of seven independent pathologists referred to as the Pathology Working Group (PWG) blindly reevaluated the female rat liver slides from Kociba et al. (1978). Liver lesions were classified according to the National Toxicology Program's 1986 liver tumor classification scheme (Sauer, 1990; Goodman and Sauer, 1992). Using the linearized multistage model, the liver tumor incidence rates reported by the PWG result in a slope factor of 5.1 x 104 (mg/kg/day)*‘ for liver tumors only, and a slope factor of 7.5 x 104 (mg/kg/day) * 1 for pooled significantly increased tumors of the liver, lung or nasal turbinates/hard palate. The latter method avoids double-counting of tumor-bearing animals (Bayard, 1990). The Human Cancer Criterion is based on the pooled significant tumors in female rats of Kociba et al. (1978) with the liver tumor réévaluation of the Pathology Working Group (Sauer, 1990). The linearized multistage model generates a slope factor of 7.5 x 104 (mg/kg/day) * 1 from these data. RAD = Risk Level = ______ 1 x 10~5 _______ ql* 7.5 x 104 (mg/kg/d) * 1 = 1.33 x 10' 1 0 mg/kg/d Drinking Water Sources: HNV = _________________ RAD x BW___________________ WCd + [(FCru x BAFt u ) + (FC™ x BAF^) ] = : __________ 1.33 x IQ* 1 0 ma/ka/d x 70 ka__________ 2 1/d + [(0.0036 x 48,490) + (0.0114 x 79,420)] = 8 . 6 x 10' 9 ug/L Non-Drinking Water Sources: HNV = _______________ RAD x BW____________ ; _______ WCr + [(FCnj x BAF^) + (FG^ x BAFTM)] 71 = = ___________ 1.33 x IO' 1 0 mq/kq/d x 70 kg___________ 0.01 1/d + [(0.0036 x 48,490) + (0.0114 x 79,420)] 8 . 6 x IO' 9 ug/L References : Bayard, S. 1990. Toxicologist/Statistician with the U.S. EPA Office of Research and Development, Human Health Assessment Group. Personal communication with R. Sills, Michigan Department of Natural Resources. Fingerhut, M. et al. 1991. Cancer mortality in workers exposed to 2,3,7,8-tetra.chlorodibenzo-p-dioxin. The New England Journal of Medicine. 234(4):212-218. Goodman, D. and R.M. Sauer. 1992. Hepatoxicity and carcinogenicity in female Sprague-Dawley rats treated with 2.3.7.8 - TCDD: A pathology working group réévaluation. Reg. Toxicol. Pharamcol. 15:245-253. Kociba, R.J. et al. 1978. Results of a two-year chronic toxicity and oncogenicity study of 2 ,3,7,8 - tetrachlorodibenzo-pdioxin in rats. Toxicol. Applied Pharmacol. 46:279-303. National Toxicology Program (NTP). 1982a. Bioassay of 2.3.7.8- tetrachlorodibenzo-p-dioxin in Osborne-Mendel Rats and B6C3F1 Mice (Gavage Study). NTP-TR-209. National Toxicology Program, U.S. DHHS, Research Triangle Park, NC. National Toxicology Program (NTP). 1982b. Carcinogenesis Bioassay of 2,3,7,8 -tetrachlorodibenzo-p-dioxin in Swiss-Webster Mice (Dermal Study). NTP-TR-201. National Toxicology Program, U.S. DHHS, Research Triangle Park, NC. Sauer, R.M. 1990. Pathology Working Group: 2,3,7,8Tetrachlorodibenzo-p-dioxin in Sprague-Dawley Rats. Pathco, Inc. Submitted to the Maine Scientific Advisory Panel. U.S. Environmental Protection Agency (EPA) . 1984. Ambient Water Quality Criteria* for 2,3,7,8 -Tetrachlorodibenzo-p-dioxin. EPA 440/5-84-007. Van Miller, J.P. et al. 1977. Increased incidence of neoplasms in rats exposed to low levels of 2 ,3,7,8 - tetrachlorodibenzo-pdioxin. Chemosphere 6 (10):625-632. Zober, A., P. Messerer and P. Huber. 1990. Thirty-four-year mortality follow-up of BASF employees exposed to 2,3,7,8 -TCDD 72 after the 1953 accident. 62 (2):139-157. Int. Arch. Occup. Environ. Health. 73 GREAT LAKES WATER QUALITY INITIATIVE TIER 1 HUMAN HEALTH CRITERIA FOR TOLUENE CAS NO. 108-88-3 Tier 1 Truman Noncancer Criterion A review of the available literature indicates inadequate human data for quantitative risk assessment of toluene based on human health effects. Occupational exposure, cigarette smoking and deliberate inhalation of solvents found in various preparations ("glue sniffing") are common means of human exposure to toluene (NTP, 1990). Chronic exposure to toluene vapors at levels of approximately 200-800 ppm have been associated primarily with CNS effects, possibly peripheral nervous system effects, hepatomegaly and hepatic function changes, and renal function effects (EPA, 1987). Although these findings provide qualitative evidence of the human toxicity of toluene, specific exposure levels were not provided and these data do not provide a dose-response relationship (EPA, 1987; EPA, 1990; NTP, 1990). The majority of the subchronic-chronic studies on toluene are inhalation studies determining behavioral or histopathologic effects of toluene exposure. The most appropriate basis for HNV derivation for toluene is the NOAEL from a 13-week rat gavage study (NTP, 1990). In this study, toluene in corn oil was administered by gavage to groups of weanling F344/N rats and B6C3F1 mice (10/sex/group) at dose levels of 0, 312, 625, 1250, 2500 or 5000 mg/kg, 5 days per week for 13 weeks. All rats at 5000 mg/kg died during the first week, and 8/10 rats at 2500 mg/kg died, two of which were due to gavage errors. Histopathologic changes were observed in the liver, kidney, brain and urinary bladder at a 1250 mg/kg. The NOAEL for the rats is 312 mg/kg/day with a LOAEL based on liver and kidney weight changes in male rats at 625 mg/kg. Because the exposure was for 5 days/week, these doses are converted to time-weighted-average doses of 223 and 446 mg/kg/day, respectively (EPA, 1990). As described above, NTP (1990) also conducted a 13-week gavage study in B6C3F1 mice. All mice that received 5000 mg/kg died during the first week, and 40% of those that received 2500 mg/kg died before the end of the 13-week gavage study. Clinical signs observed in mice at a 2500 mg/kg included sub-convulsive jerking, prostration, impaired grasping reflex, bradypnea, hypothermia, hypoactivity and ataxia. The final mean body weight of males at 2500 mg/kg was lower than that of vehicle controls. At a 1250 mg/kg, relative liver weights were increased for mice, but this increase was not statistically significant. The NOAEL for this study was 1250 mg/kg and the LOAEL was 2500 mg/kg. Adjusting the doses for 5 days/week exposure provides timeweighted- average NOAEL and LOAEL doses of 893 and 1786 mg/kg/day, respectively. Another subchronic oral toxicity study was conducted by Wolf et al. (1956), in which female Wistar rats were administered 74 toluene by stomach tube at doses of 0, 118, 354 and 590 mg/kg/day, 5 days/week for a total of 138 doses (converted to time-weighted-average doses of approximately 0, 18, 253, and 422 mg/kg/day per EPA, 1990). No adverse effects were observed at any dose level in any of the parameters monitored: growth, appearance and behavior, mortality, organ/body weight, blood urea nitrogen levels, bone marrow counts, peripheral blood counts or morphology of major organs. The NOAEL for this study was 422 mg/kg/day as the time-weighted-average dose. NYLAR mice were exposed pre- and post-natally to toluene provided in the drinking water at concentrations of 0 , 16, 80 and 400 ppm (Kostas and Hotchin, 1981). Rotorod performance was measured at 45 and 55 days of age. An inverse dose-response relationship in the effects was noted in which rotorod performance was improved with increasing dose. No effects were observed for the following reproductive measurements: maternal fluid consumption, offspring mortality rate, development of eye or ear openings,« or surface-righting response, resulting in a NOAEL of 400 ppm. Assuming mice consume water at appoximately 0.24 1/kg bw/day (EPA, 1988), the NOAEL was approximately 96 mg/kg/day. Nawrot and Staples (1979) administered 0.3, 0.5 or 1.0 ml/kg bw toluene, 3 times/day (equivalent to approximately 780, 1300 and 2600 mg/kg/day, per EPA, 1990) to pregnant CD-I mice from days 6-15 of gestation. No method of exposure was mentioned in this limited information abstract. Teratogenic effects were reported at 2600* mg/kg/day and increased embryolethality was reported at a 780 mg/kg/day, therefore the LOAEL for this study was 780 mg/kg/day. No other subchronic-chronic oral toxicity studies were identified in the available literature for toluene. Chronic inhalation studies include NTP (1990), in which F344/N rats and B6C3F1 mice (60/sex/dose) were exposed to vapors of toluene, 6.5 hours/day, 5 days/week for 2 years. Dose levels were 0, 120 (mice only), 600 or 1200 ppm. Ten animals/group (except male mice) were remov'ed at 15 months for toxicologic evaluation. At 15 months, there was an increased incidence and severity in the erosion of olfactory epithelium, and degeneration of respiratory epithelium was increased in the exposed rats. At the end of the study inflammation of nasal mucosa and metaplasia of olfactory epithelium were increased in exposed females rats. Nephropathy was seen in almost all rats with a severity somewhat increased in exposed rats. For mice, no biologically relevant increase in any nonneoplastic lesion was observed. Chronic inhalation of toluene was studied in F344 rats exposed to 30, 100 or 300 ppm (113, 377 or 1130 mg/m3) toluene 6 hours/day, 5 days/week for 24 months (Gibson and Hardisty, 1983; CIIT, 1980, as cited in NTP, 1990; EPA, 1990; and EPA, 1987). A dose-related reduction in hematocrit values was reported in female rats exposed to 100 and 300 ppm. Increased corpuscular hemoglobin concentration was reported in females at 300 ppm. 75 In a perinatal study with CD-I mice (Courtney et al., 1986), toluene was administered by inhalation at 200 and 400 ppm (750 and 1500 mg/m3, respectively) to pregnant female CD-I mice 7 hours/day from days 6-16 of gestation. Fetotoxicity was observed at 400 ppm with a significant shift in the fetal rib profile. An increased body weight in the neonates on day 1 postpartum was observed at 400 ppm. At 200 ppm, there was an increase in dilated renal pelves which the authors concluded might reflect desynchronization of maturation with respect to development and growth. Assuming that mice breathe appoximately 1.7 m 3 /kg/day (EPA, 1988), the 7 hours/day 200 ppm LOAEL and 400 ppm FEL convert to approximately 370 and 740 mg/kg/day, respectively, as daily administered doses. The Tier 1 HNC is derived from the NOAEL dose of 312 mg/kg (converted to 223 mg/kg/day for 5 days/week administration) from the 13-week oral rat study by NTP (1990) with an uncertainty factor of 1000. The uncertainty factor accounts for interspecies variation, intraspecies differences, and subchronic exposure duration. This approach should be protective of developmental effects, as suggested by the limited developmental toxicity data. This approach is consistent with the risk assessment of toluene for the oral RfD and the drinking water health advisory developed by EPA (1990; 1987). ADE = 223 mo/ko/d = 2.23 x 10' 1 mg/kg/day 1,000 Where: Uncertainty Factor = 1,000, composed of: lOx for interspecies variability lOx for intraspecies differences lOx for subchronic exposure duration Drinking Water Sources: HNV = ____________ADE x BW x RSC____________ WCj + [(FC tt 3 x BAFttg) + (FCX L 4 x BAFfu) ] = 2.23 x 10' 1 mg/kq/d x 70 kg x 0.8 2 1/d + [(0.0036 x 11) + (0.0114 x 17)] = 5.6 x 105 ug/L Non-Drinking Water Sources: HNV = ___________ADE x BW x RSC____________ WCr + [(FCtt^ x BAFn ^) + (^Cry x BAF*^) ] = 2.23 x 10' 1 mq/kq/d x 70 ko x 0.8 0.01 1/d. + [(0.0036 x 11) + (0.0114 x 17)] 76 5.1 x 104 ug/L References: Chemical Industry Institute of Technology (CUT). 1980. A 24Month Inhalation, Toxicology Study in Fischer-344 Rats Exposed to Atmospheric Toluene. CUT, Research Triangle Park, NC. As cited in EPA, 1987; EPA, 1990; NTP, 1990. Courtney, K.D., J.E. Andrews, J. Springer, M. Menache, T. Williams, L. Dailey and J.A. Graham. 1986. A perinatal study of toluene in CD-I mice. Fundam. Appl. Toxicol. 6:145-154. Gibson, J.E. and J.F. Hardisty. 1983. Chronic toxicity and oncogenicity bioassay of inhaled toluene in Fischer-344 rats. Fundam. Appl. Toxicol. 3:315-319. Kostas, J. and J. Hotchin. 1981. Behavioral effects of lowlevel perinatal exposure to toluene in mice. Neurobehav. Toxicol. Teratol. 3:467-469. National Toxicology Program (NTP). 1990. Toxicology and Carcinogenesis Studies of Toluene (CAS No. 108-88-3) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). NTP-TR. No. 371, NIH Publication No. 90-2826. Nawrot, P.S. and R.E. Staples. 1979. Embryo-fetal toxicity and teratogenicity of benzene and toluene in the mouse. Teratology. 19:41A (abstract). U.S. Environmental Protection Agency (EPA). 1990. Integrated Risk Information System (IRIS database). Chemical file for toluene (108-88-3). Verification Date 6/20/90. Last Reviewed 6/20/90. U.S. Environmental Protection Agency (EPA). 1988. Recommendations for and Documentation of Biological Values for Use in Risk Assessment. PB88-179874. U.S. Environmental Protection Agency (EPA). 1987. Drinking Water Criteria Document for Toluene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. ECAO-CIN-408. Wolf, M.A., V.K. Rowe, D.D. McCollister, R.L. Hollingsworth and F. Oyen. 1956. Toxicological studies of certain alkylated benzenes and benzene. A.M.A. Arch. Ind. Health. 14:387-398. Tier 1 Human Cancer Criterion Toulene is not considered carcinogenic. 77 GREAT LAKES WATER QUALITY INITIATIVE TIER 1 HOMAN HEALTH CRITERIA FOR TOXAPHENE CAS NO. 8001-35-2 Tier 1 wi«n»n Wfmr»nr»«»r Criterion EPA is currently reviewing the RfD for toxaphene. Because there is no EPA verified RfD that can be used for derivation of a Tier I human noncancer, the final Guidance does include a noncancer criterion for toxaphene. Tier 1 Biiman ff»nnftr Criterion According to EPA (1985; 1987), there are inadequate data available to ascertain whether toxaphene is a human carcinogen. However, two chronic studies have shown that toxaphene induces the formation of liver tumors in B6C3F1 mice. One of these studies also found that toxaphene induces the formation of thyroid tumors in Osborne-Mendel rats. Toxaphene was mutagenic for Salmonella typhimurium strains TA98 and TA100 (Hill, 1977 as cited by EPA, 1985) and was also found to induce the formation of sister chromatid exchanges in Chinese hamster lung (DON) cells (Steinel et al., 1990). However, toxaphene produced a negative response in a modified dominant lethal assay which used male ICR/Ha Swiss mice (Epstein et al., 1972). According to EPA (1985; 1987), the weight-of-evidence for toxaphene carcinogenicity is sufficient for B2 classification (probable human carcinogen)» The data are sufficient to derive a Tier 1 HCC. . In a study conducted by NCI (1979), 50 Osborne-Mendel rats/sex/group and 50 B6C3F1 mice/sex/group were administered toxaphene in their diets for 80 weeks. Male rats received timeweighted average (TWA) doses of 112 and 556 ppm, while females received TWA doses of 540 and 1080 ppm. Both male and female mice received TWA doses of 99 and 198 ppm. Both rats and mice had 10 matched controls/sex with an additional 45 pooled controls/sex for rats and 40 additional pooled controls/sex for mice. Male and female rats exhibited a statistically significant dose-related increased incidence of thyroid tumors (adenomas and carcinomas), whereas treated mice exhibited a statistically significant dose-related increased incidence of liver tumors (NCI, 1979). In a study conducted by Litton Bionetics (1978, as cited by EPA, 1987), toxaphene was administered to B6C3F1 mice (54 mice/sex/group) in the diet for 18 months at doses of 0, 7, 20 and 50 ppm. Animals were observed for a period of 6 months after treatment. An increased incidence of hepatocellular tumors (adenomas and carcinomas) was seen in both sexes and was statistically significant in males administered 50 ppm. This 78 study, rather than the NCI study, was used for cancer risk assessment because it utilized more dose levels and a lower range of doses while still eliciting a tumorigenic response in the liver. EPA (1987) recommends the same key study and slope factor (1.1 (mg/kg/d)'1) as utilized for HCC derivation. RAD = Risk Level = ql* 1 . 1 = 1 x 10' 5 (mg/kg/d) ' 1 9.09 x 10"6 mg/kg/d Drinking Water Sources: HNV = ________ ; ________ RAD x BW___________________ WCd + [(FCpjj x BAFt u ) + (FC-TL4 X BAF-pj^j) ] = __________ 9.09 x 10- 6 mcr/kcr/d x 70 kg________ _ 2 1/d + [(0.0036 x 498,100) + (0.0114 x 665,600)] = 6 . 8 x 10; 5 ug/L Non-Drinking Water Sources: HNV = _______________RAD x BW____________________ WCr + [(FCn q x BAF-pi x BAFp^) ] = ___________ 9.09 x IQ- 6 ma/ka/d x 70 kg___________ 0.01 1/d + [(0.0036 x 498,100) + (0.0114 x 665,600)] = 6 . 8 x 10' 5 ug/L References: Epstein, S.S., E. Arnold, J. Andrea, W. Bass and Y. Bishop. 1972. Detection of chemical mutagens by the dominant lethal assay in the mouse. Toxicol. Appl. Pharmacol. 23:288-325. Hill, R.N. 1977-. Memorandum to Fred Hagemen. Off. Spec. Pestic. Rev., U.S. EPA. December 15. As cited in: EPA, 1984. Litton Bionetics. 1978. Carcinogenic evaluation in mice: Toxaphene. Prepared by Litton Bionetics, Inc., Kensington, MD for Hercules, Inc., Wilmington, DE. National Cancer Institute (NCI). 1979. Bioassay of Toxaphene for Possible Carcinogenicity. Carcinogenesis Testing Program. Division of Cancer Cause and Prevention. NCI, National Institute of Health, Bethesda, Maryland, 20014. U.S. Department of Health, Education and Welfare. DHEW Publication No. (NIH) 79­ 837. 79 Steinel, H.H., A. Arlauskas and R. S. Baker. induction and cell-cycle delay by toxaphene. 230:29-33. 1990. SCE Mutât. Res. U.S. Environmental Protection Agency (EPA). 1985. Drinking Water Criteria Document for Toxaphene. Environmental Criteria and Assessment Office. Cincinnati, OH. PB 86-118049. U.S. Environmental Protection Agency (EPA). 1987. Integrated Risk Information System (IRIS database). Chemical file for toxaphene (8001-35-2). Verification Date 3/5/87. Last Revised 1/1/91. 80 GREAT LAKES WATER QUALITY INITIATIVE TIER 1 HOMAN HEALTH CRITERIA FOR TRICHLOROETHYLENE CAS NO. 79-01-6 Tier 1 Human Noncancer Criterion EPA is currently reviewing the RfD for trichloroethylene. Because there is no EPA verified RfD that can be used for derivation of a Tier I human noncancer, the final Guidance does include a noncancer criterion for trichloroethylene. Tier 1 Human Cancer Criterion Six epidemiologic studies have been performed to investigate the carcinogenicity of trichloroethylene (TCE) in exposed workers (Axelson et al., 1978; Hardell et al., 1981; Malek et al., 1979; Novotna et al., 1979; Paddle, 1983; Tola et al, 1980). Results of those studies were inadequate to attribute cancer incidence to TCE exposure. However, because they suffer from various limitations and deficiencies, they also fail to provide adequate evidence that TCE is not a human carcinogen (EPA, 1985). Based on weight of evidence, EPA (1985, 1987, 1988) classified TCE in Group B2- Probable Human Carcinogen. The evidence reviewed by EPA (1985) for carcinogenicity of TCE in experimental animals includes increased incidence of hepatocellular carcinomas in male and female B6C3F1 mice (NCI, 1976; NTP, 1982, 1986) by gavage, malignant lymphomas in female Han:NMRI mice by inhalation (Henschler et al., 1980); and renal adenocarcinomas in male Fischer 344 rats by gavage (NTP, 1982, 1986) . Evidenr-e presented in EPA (1987) markedly strengthened the B2 classification by showing that inhalation is a second exposure route that results in carcinogenic activity in rats and mice, and by identifying diverse tumor sites (EPA, 1987). EPA (1985) developed a quantitative cancer risk assessment based on four sets of gavage bioassay data that show hepatocellular carcinomas in male and female mice (NTP, 1982; NCI, 1976). The NCI bioassay involved exposure by gavage to B6C3F1 mice. Although rats were also tested, excessive mortality in all groups cast doubt on the adequacy of those results. Mice were dosed in groups of 50 animals per sex, 5 days/week for 78 weeks. Surviving animals were sacrificed at 90 weeks and subjected to complete necropsy and histopathological examination. The time-weighted-average (TWA) doses for male mice were 1,169 and 2,339 mg/kg, and for the female mice they were 869 and 1,739 mg/kg. The study included 20 matched vehicle control animals of each sex. It was concluded that TCE induced a statistically significant (p < 0.05) increase in the incidence of hepatocellular carcinoma in both male and female B6C3F1 mice. A reduction in the time-to-tumor response was also reported among male mice at the high dose level. The presence of the trace contaminant epichlorohydrin (0.09%) in the test material for this 81 bioassay could be a cause for concern. However, it has been determined that any potential contribution of epichlorohydrin to the overall carcinogenic potency of TCE in the bioassay was negligible (EPA/ 1985) . NTP (1982) conducted a carcinogenicity bioassay on TCE in B6C3F1 mice and F344/N rats. The rats experienced reduced survival when compared to controls, and the results were therefore invalidated. Male and female mice were dosed by gavage at 1,000 mg/kg, 5 days/week for 103 weeks. Survival was significantly lower (p < 0.004) in treated males whereas survival in treated females was lower after 95 weeks, but the overall difference between vehicle controls and treated females was not significant. Male and female mice had a statistically significant increase in the incidence of hepatocellular carcinoma (p <. 0 .0 0 2 ) and hepatocellular adenoma (p < 0.05) over corresponding vehicle controls. The TCE test material for that bioassay was not contaminated with detectable amounts of epichlorohydrin. The potency of TCE with regard to the induction of hepatocellular carcinomas in mice has been determined to be very similar in the NTP (1982) bioaspay and the NCI (1976) bioassay (EPA, 1985). Additional studies were reviewed by EPA (1987) identifying positive findings by inhalation exposure in rats and mice. Maltoni et al. (1986) conducted bioassays of Sprague-Dawley rats exposed to 0, 100, 300 and 600 ppm of TCE 7 hours/day, 5 days/week for 104 weeks. Necropsy was performed on all animals. Male rats demonstrated increased incidence of renal tubuli megalonucleocytosis and renal adenocarcinomas, and a slight increase in leukemias, particularly immunoblastic lymphosarcomas. Maltoni et al. (1986) also conducted bioassays on Swiss mice and B6C3F1 mice (90 mice/strain/sex/group) exposed to 0, 100, 300, and 600 ppm TCE for 78 weeks. Statistically significant increases in hepatomas were noted among male Swiss mice at the high concentration, and significant increases in pulmonary tumors were observed among male Swiss mice at high and medium exposures. Among the B6C3F1 mice, there were increases in hepatomas in males and females, pulmonary tumors in females, and in the total number of tumors among females at all concentrations. Fukuda et a*l., (1983) reported the results of bioassays with female ICR mice and Sprague-Dawley rats (49-50 per group) exposed to airborne concentrations of 0, 50, 150, and 450 ppm of TCE for 7 hours/day, 5 days/week for 107 weeks. There were no statistically significant increases in tumors among rats, however a statistically significant increase in lung adenocarcinomas was found among the mice. Using the mice liver tumor data sets from NTP (1982) and NCI (1976), EPA (1985) calculated human slope estimates of 1.9 xlO'2, 8.0 x 10'3, 1.8 x* 10"2, and 5.8 x 10' 3 (mg/kg/day)'1. Because the slope estimates from these four data sets were found to be comparable, their geometric mean was used to derive the recommended slope factor of 1.1 x 10' 2 (mg/kg/day)'1. EPA (1987) 82 also developed slope factors from the inhalation studies of Maltoni et al. (1986) and Fukuda et al.(1983). These slope factors were found to be comparable to the qj* developed earlier from the gavage studies (EPA, 1987). EPA is currently reviewing the carcinogenicity data for trichloroethylene. Based on this review EPA may change the carcinogenicity characterization for trichloroethylene. However, until this review is completed the previously verified oral slope factor of 1 . 1 x 1 0 ‘ 2 (mg/kg/day)'* will be used. RAD = Risk Level =_______ 1 x 10' 5 ______ ql* l.l x 1 0 * 2 (mg/kg/d) " 1 = 9.09 x 10"4 mg/kg/d Drinking Water Sources: HNV = ________;________ RAD x BW___________________ WCd + [(FC tu x BAF^) + (FC™ x BAF^) ] = __________ 9.09 x 10~* mq/kq/d x 70 kg__________ 2 1/d + [(0.0036 x 7) + (0.0114 x 12)3 = 29 ug/L Non-Drinking Water Sources: HNV = _______________ RAD x BW____________________ WCr + [(FC tt 3 x BAF-n 3 ) + (FCT L 4 x BAF^) ] = ___________ 9.09 x 10"4 mq/kq/d x 70 kcr___________ 0.01 1/d + [(0.0036 x 7) + (0.0114 x 12)] = 3.7 x 102 ug/L References: Axelson, 0. et al. 1978. A cohort study on trichloroethylene exposure and cancer mortality. J. Occup. Med. 20:194-196. Fukuda, K., K. Takemoto, H. Tsuruta. 1983. Inhalation carcinogenicity of trichloroethylene in mice and rats. Ind. Health 21:243-254. Hardell, L., et al. 1981. Malignant lymphomas and exposure to chemicals, especially organic solvents, chlorophenols, and phenoxy acids: a case-control study. Br. J. Cancer. 43:169-176. Henshler, L. et al. 1980. Carcinogenicity study of trichloroethylene by long-term inhalation in the animal species. Arch. Toxicol. 43:237-248. 83 “ Malek, B., B. Kromarova, and 0. Rodova. 1979. An epidemiological study of hepatic tumor incidence in subjects working with trichloroethylene. II. Negative results of retrospective investigations in dry-cleaners. Prakov. Lek. 31: 124-126. As cited in EPA (1985). Maltoni, C., G. Lefemine, and C. Gotti, 1986. Experimental research on trichloroethylene carcinogenesis. In: Maltoni, C. M. Melham eds. Archives of Research on Industrial Carcinogenesis. Vol. V. Princeton NJ. Princeton Scientific Publishing Co. National Cancer Institute (NCI). 1976. Carcinogenesis Bioassay of Trichloroethylene. CAS No. 79-01-6. NCI-CG-TR-2. National Toxicology Program (NTP). 1982. Carcinogenesis Bioassay of Trichloroethylene. Cas No 79-01-6. NTP 81-84. NIH Publication No. 82-1799. National Toxicology Program (NTP). 1986. Toxicology and Carcinogenesis Studies of Trichloroethylene in F344/N Rats and B6C3F1 Mice. NTP TR 243. U.S. Department of Health and Human Services. National Institutes of Health. Bethesda, MD. Novotna, E., A. David, and B. Malek. 1979. An epidemiological study on hepatic tumor incidence in subjects working with trichloroethylene: I. Negative results of retrospective investigations in subjects with primary liver carcinoma. Pracovni Lekartsvi. 31(4): 121-123. As cited in EPA (1985). Paddle, G. 1983. Incidence of liver cancer and trichloroethylene manufacture: joint study by industry and cancer registry. British Medical Journal. 286:846. Tola, S., R. Vilhnuer, E. Jaruinene, and M. Korkale. 1980. A cohort study of workers exposed to trichloroethylene. J. Occup. Med. 22:737-740. U.S. Environmental Protection Agency (EPA). 1988. Health Effects Assessment for Trichloroethylene. EPA/600/8-89/097. Washington, D.C. U.S. Environmental Protection Agency (EPA) . 1987. Addendum to the Health Assessment Document for Trichloroethylene: Updated Carcinogenicity Assessment for Trichloroethylene. EPA/600/882/006. Washington, D.C. U.S. Environmental Protection Agency (EPA). 1985. Health Assessment Document for Trichloroethylene. EPA/600/8-82/006F Washington, D.C. 84