Environmental Institute for Waste Management Studies Polychlorinated Blphanyla a Toxicological Analyala Open File Report No. 17 MOMS 22S062 Escalation of raaaareh aborts regarding hazardous wastes and thatr manage* mant will bo an essential prerequisite toward the attainment of regulations founded upon sound technical data. To help meet the need for data, mombera and staff of The University of Alabama Environmental Institute) for Watte Management Studies have prepared a series of open file reports related to the treatment and disposal of solvents. The authors gratefully acknowledge support of this work by the Environmental Institute for Waste Management Studies, The Uni verity of Alabama, Or. P. E. LaMoreaux, Director. Any opinions, findings, and conclusions or recommendations expressed In this open file report are those of the Environmental Inatltute for Waste Management Studies. This open file report is currently under technical review and subject to change prior to final publication. The Environmental Institute for Waste Management Studies is a division of The University of Alabama, a state*supported Institution of higher education. The Institute Is committed to the advancement of knowledge related to the safe manage* ment of hazardous waste. Institute Members Philip E. LaMoreaux, D.Sc. University of Alabama Charles J. Mankln, Ph.D. Oklahoma Geological Survey Arthur C. Benke, Ph.D. University of Alabama James K. Mlteheil. Sc.D. University of California, Berkeley Gary P. Bennett, Ph.D. University of Toledo Carl A. Silver, Ph.D. Drexel University William J. George, Ph.D. Tulano University James V. Walters, Ph.D. University of Alabama Robert A. Griffin, Ph.D. Illinois Stats Cadioglcsl Survey Rae Zimmerman, Ph.D. New York University Institute I. AtJa Jefcoat, Ph,D. Travis H. Hughes, Ph.D. Robert L. Wells, Ph.D, Tola B. Moffett, Ph.D. James W. LaMoreaux. Ph.D, Bernadette N. Roche Susan I. Rutledge. The University of Alabama P.O. Bex Z488 Tuscaloosa, Alabama 35488 HONS 225063 POLYCHLORINATED BIPHENYLS A TOXICOLOGICAL ANALYSIS Open FI I* Report Prop*rod For The Environmental Institute for Waste Management Studies The University of Alabama BY 3 Caml lla J, George1, Cary F. Bennett, Ph.D.* Deni so Simoneaux1 and William J, Ceorge, Ph.D i ,3 Tulene University School of Medicine Department of Pharmacology New Orleans, LA 70112 2 Department of Chemical Engineering The University of Toledo Toledo, OH *3<0! Snvlronmental ^Member of the Board Institute for Waste Management Studies The University of Alabama Tuscaloosa, AL 3SSI7 Accepted For Publication, February 19S7 HQNS 225064 table of contents I Summary 1 II Introduction 2 HIitory 2 m Comnorclal Production and Application 3 Relation 7 IV Physical and ChMlcal Properties 3 V Environmental Exposure a VI 81oaceuaulatlon/01strlbutIon in Animal Tissues ii vtt VIII Exeretlon/Hetabollsa 12 Mechanism of Metabolism 14 Toxicity and Effects of PCSs 16 PCDFs 17 ATPase Enxyme Activity IB Chloracne IB Animal Experiments 19 Vapor Exposure 21 Reproductive Effects 22 Human Exposure 23 Physiological Effects 24 Neurological Effects 25 Carcinogenicity 26 IX Case Studies of Accidental Exposures 29 X Regulations of PCts 32 XI Elimination of PCBs from the Environment 33 XII Permissible Human Exposure 35 XIII Bibliography 37 HONS 225065 I. SUMMARY Polychlorinated biphenyli (PC3i> ars a dan of compounds which have. for naarly 60 yoari, b«n used ai insulating fluids, hydraulic and lubricating fluids, boat axchangtr fluids and as additives In adhesive inks and paints. The very properties that made PCBs attractive to industry, such as resistance to fire and persistence in the environment, are the same properties that have resulted in their perceived toxicological problems. Mixtures of these compounds which have groat environmental persistence and are contaminated with other agents, have been shown to produce adverse organ and system effects on a variety of animals. However, aside from occurrences of a chloracne, no significant chronic adverse health effects have been found In humans In a number of reported studlei. Nonetheless, since the mid 1970's. production and use of PCI's have been curtailed based on chronic animal toxicity data and concern about the environmental persistence of these highly lipophilic compounds which tend to bloaccumulate In living tissues and the food ehaln. This report discusses the chemical and physical properties of PCIs, their biological disposition, and their reported toxicologic effects Including carcinogenic potential. Specific comparisons are made between toxicity of PCIs In animals with effects observed In humans following exposure. Other areas covered Include governmental regulation and permissible levels of exposure. Indeed, as a result of passage of the Toxic Substances Control Act in 1976, Congress singled out PCBs for regulation as required by law and the U.S. EPA banned further production In 1979. HOMS 225066 It 1* concluded that there are significant adverse effects of Pc9s when administered to animals under laboratory conditions. However, with the exception of the development of chloracne, there is little evidence suggesting toxicity to min from the chronic exposure to PC8s including carcinogenic effect! in the workplace or environment. II. IKTROOUCTION History Polychlorinated biphenyls, PC8s, are chlorinated aromatic hydrocarbons which were discovered In 1881. Effects of PC8s on the environment were noted more than 75 years later when accumulations of PC3s were found In aquatic life of the Baltic Sea (34). The conwerclal production of PCBs began in 1929, and during the following decade, cases of poisoning were reported among workers involved in the manufacturing of PCBs (77). Ensuing safety precautions prevented further PCS poisoning until 1953 when cases were reported In Japanese factories. Widespread distribution of PCBs Irt the environment was not recognized until 1984 when S. Jensen began to search for an explanation for appearance of mysterious elution peaks during gas>11qu1d chromatographic separation of organochlorlne pesticides from environmental samples (50). He later attributed these peaks to the presence of PCBs In the samples which resulted In worldwide studies that revealed the widespread distribution of PCBs In the environment. More recent outbreaks of poisoning In men and domestic animals from accidental food contamination with PCBs stimulated an Interest In the toxic effects of PClf and have resulted In the cessation of the commercial production of PCBs and a regulation of their residues In food. MOWS 22506? ] III. commercial production ANO APPLICATIONS The basic structure of PC8s Is as follows: •denote# position occupied by olthor a hydrogen or chlorine Atoo. PCBs have tlio general forayla Cl where the nuabor of chlorines * 12 10-x x substituted on the biphenyls can range from one to ten resulting In ten forms of polychlorinated biphenyls. possible (Table 1). Two-hundred nine PCI Isoners are theoretically The nuabor of chlorines In each Isoaor determines its classification and noaenclature (Table 2). HONS 225068 1 Tabic 1 Isomers of PCSs Empirical Formula Molecular Weight 154 189 Per Cent Chlorine 0 222 258 290 324 353 392 428 480 494 ho. of isomers 18 31 41 48 54 58 62 65 3 12 24 42 46 42 24 68 3 12 79 Total . . 209 •not a PCS: not added In total Table Source: Ourfee et al. (1976). The commercial production of PCSs Is carried out by the chlorin­ ation of biphenyls with anhydrous ehlorine In the presence of a catalyst, usually Iron filings or ferric chloride. This reaction occurs at extremely high temperatures resulting In a crude product that must subsequently be refined by an alkali wash or sometimes be distilled (47). The final commarclal products are PCS mixtures that vary In chlorine concentration, PCS isomers as well as Impurities. Table 2 Chlorine Content of Selected PCSs Arochlor f Pen Cent Chlorine 1221 21 1018 1242 1254 1260 42 42 54 60 Kanechlor # 300 400 500 Per Cent Chlorine 43 48 53 HONS 225069 5 In addition, related chemicals, polychlorinated dibenzofurans (PCOFJ and polychlorinated quaterphenyls (PCQ) art alio formed (Figure 2) and art prtitnt In some mixtures (3S). These different PCB mixtures are marketed throughout the world under a variety of trade names: Arochlor, Chloretol, DyKanol, Inerteen, and Pyranol (United States); Phenochlor (France); Clophen (West Germany); Kantelor and Satatherm (Japan); Fenclor (Italy), and Soval (Soviet Union). The varied compositions of Isomers In the different PC8 mixtures can be Illustrated by two of the Kanechlor products. Kanechlor S00 is composed of 55* pentachloroblphenyl, 26.5* tetrachloroblphenyl, 12.8* hexachlorobi phenyl, and 5.0* trlchioroblphenyl while Kanechlor 400 contains 43,8* tetrachloroblphenyl, 32.8* trlchioroblpheny1, 15.8* pentachloroblphenyl, 4.6* heptachloro­ bl phenyl, and 3.0* dlchloroblphenyl (32). Figure 2 Byproducts Found In PCI Mixtures Polychlorinated dlbenzofuran (PCOF) Polychlorinated quaterphenyl . Cl Cl —■. (PCQ) MOMS 225070 5 Sine* the Monsanto Company began production of PCBs in 1929, they had boon used In Increasingly different capacities until the regulation of their use m There were three categories of PC8 usage: closed uses, nominally 1971 {70). closed uses, and open-ended uses. The closed uses of PCBs Include insulation for electrical wire, cables, and condensors as well as coolant/dielectric in transformers and capacitors. environment. These applications Isolate PCBs from the The nominally closed uses of PCBs Include hydraulic fluids, heat transfer fluids, and high pressure lubricants. These uses do not totally isolate PCBs from the environment, but for the most part do not allow direct contact. Open-ended uses of PCBs Include additives to paints. Ink dyes, platlclters, protective coatings for woods when low flammability Is neeessary, dedusting agents, adhesives, pesticide extenders. Ink and dye carriers, and for alcroeneapsulatlon of dyes for carbonless duplicating paper (34). These applications exposed PCBs directly to the environment. From 1971 until 1974, Monsanto produced an average of 27.000,000 lb/year of PCBs with sales to fewer than 40 customers. PCB production ceased In 1977, nearly 2 years before the Toxic Substances Control Act (TSCA) required It. Of the documented production of approximately 1.4 billion 1b of PCBs In the United States (as of 1981), estimates are that 50 million 1b have been destroyed, 300 million 1b are In landfills, 154 million 1b are In the environment, ISO million 1b were exported, and 750 million 1b are still In use (122). In 1971, U.S. producers voluntarily limited the sale of PCBs to those applications that minimized Introduction of the chanleals Into the environment. Table 3 Illustrates that applications of PCBs have been limited to closed systems since 1971 (34). MOMS 225071 7 Table 3 Type of System In Which PCS* Have Seen employed Appl1 cations of PCIs Prior to 1971 After 1971 61% 13% 26% 100% 0% 0% Closed electrical systems Nominally closed systems Open end applications The major producer of PC8s In the U.S. was the Monsanto Industrial Chemical Co. which had two plants, one at Anniston, Alabama (closed In 1970) and the second at Sanget, Illinois. The Sanget plant produced 99% of the PC3s (trade namm, Aroclor) used In U.S. Industry. Seventy percent of these PCBs were used in capacitors while the remaining 30% were utilized In transformers (4«). Peculation Oesplte uncertainty about the health effects of PCIs, Congress singled them out for regulation under the Toxic Substances Control Act (TSCA) of 1976­ In 1979, the U.S. CPA banned further production of these compounds. However, utilItle^jwere allowed to contlnuo to uso existing transformers and capacitors containing PCSs for the duration of their normal service lift,, although certain uses have been banned. Under new rules Issued by the U.S. CPA In July, 1985, utilities must phase out the use of PCS transformers In or near buildings by 1990. Ultimately, they must destroy all PCIs In equipment and clean up or contain any PC8contamlnatad sites that are environmental hazards. (Disposal regulations for PCI's are quite restrictive. ppm range, the U.S. CPA allows landfilling. In the 50 to 500 However, when PCI levels are greater than 500 ppm, materials must be Incinerated. Below the 50 ppm level disposal is unregulated by the U.S. CPA, but, States' rules may mandate otherwise. HOMS 225072 3 Ironically, PCS* are still manufactured by Germany, France. Spain, and Italy and certain Eastern European countries and they contfnue to be used throughout the world (122). IV. PHYSICAL AHO CHEMICAL PROPERTIES PCS* have physicil end chemical properties that make them valuable in the previously mentioned applications of electrical insulations, l.e. stability and fire resistance. Pure PCS* are solids at room temperature (25°C), and 0 0 their melting points range from S4 C for 2-chloroblphenyl to 310 C for 2,3,4,S.6,2',3',4',S',S' decachloroblphenyl increase with the complexity of the compound. Generally, PCS melting points The chemical mixtures of PCBs used in industry are usually colorless to lightly tinted oils. Densities of such mixtures as Arochlors an Kanechlors are approximately 1.2 to 1.5 g/cm3 and have refractive Indices of approximately 1.62 (32). PCS* are fat-soluble, water-insoluble, and very stable. They are very resistant to degradation, oxidation, and other chemical agents such as acids and bases. They can withstand extremm temperatures up to 1600°? (870°C) and are fire resistant (32). PCBs may dimerize and when they do they form polychlorinated guaterphenyls (PCQs) (Figure 2) (120). Another property of PCBs that make them attractive to Industry is their low vapor pressures. This property also reduces the probability of exposure even with concentrations of several thousand parts per million (37). V. ENVIRONMENTAL EXPOSURE There Is no evidence that PCBs occur naturally In the environment. Apparently, all PCBs present in nature can be attributed to dissemination by humans. The majority of PCBs in the environment Is found In surface marine waters, mainly of the North Atlantic Ocean (34). However, since restrictions HONS 225073 3 of PCS use and production, the North Atlantic surface water has shown a 40-fold decrease In PCS concentration since 1972. Tasts In September, 197} indicate a disappearance of 20,000 tons of PCBs In the upper 200 meters of water during that one year time span (34). In 1972, the rivers of the United States were tested for presence of PCSs. The concentrations of PCSs found ranged fro* less than 0.01 to 0.4S ug/l (107). These are low concentrations compared to that found In Japanese drinking water and North Atlantic surface water which contained 10*100 ug/1 and 1* 35 ug/l, respectively (70,104). The Hudson River is a prime example of PCS pollution as a result of unregulated discharge. Between 1942 and 1970, two General Electric plants (fort Edward and Hudson Falls) discharged an average of 14 kg of PCSs per day into the river. Sedlaent samples fro* the river bed have been found to contain concentrations of 540 to 2,9tO ug/kg. river daaonstrated PCS concentrations Fish taken fro* the of 02 to US eg/kg (55). These concentrations have greatly decreased since the cessation of PCS discharge Into the river. Sedimentation testing during the early 1970's In Lake Erie (1971), Lake St. Clair (1970 and 1974), and the Detroit River (1974) revealed residues of PCSs which were 1 times higher than those of all organochlorlne insecticides. These levels have also decreased since the restrictions of PCBs (15). An important environmental concern about PCBs Is their incorporation into the feed chain. Benthic Invertebrates feeding on the lake bottom consume PCBs and later pan them on in the food chain to fish, birds, man, and other creatures. As PCSs pass through the food chain, concentrations accumulate and are transferred fro* one organise to another. As a result, the upper trophic levels are most prone to PCS accumulation (34), and freshwater fish are the major source of PCSs In the diet of humans (47). It has been HONS 225074 Z' indicated that adults consuming ISO g par weak of Coho salmon from Lika Michigan also ara Ingesting IS mg/kg of PCSs whereas In Japan. 80 g of fish contains the same quantity of PCSs (70). Studies of 70-79 y**r old Japanese men revealed S.1 mg/kg of PCSs in fat tissue. Japanese women of the same age bracket had 2.4 mg/kg PCSs in fat tissue (49,70). a 1972 survey by Yobs of 637 Americans from 18 states indicated that 25% had 1-2 mg/kg PCSs in fat tissue (98). In the samu year, a report by the U.S. Department of Agriculture listed PCS presence In many common foods such as cheese (0.2S mg/kg), milk (2.27 mg/kg), and eggs (O.SS mg/kg) (32). There are four major routes by which PCSs enter the environment: Industrial accidents or discharges, imcomplete destruction of PCS containing products, natural weathering of PCS containing products, and leaking from land-fills (32). Most PCS leaks result from pump leaks Into the cooling water used in capacitor and transformer production resulting In the Introduction of the PCSs into municipal savors (48). Once In the environment, PCSs can be transported by leaking, diffusion, rain, snow, and dust (32). Oomostlc sources of PCSs In the U.S. are: 1) industrial and municipal sewage disposal, 2) paper recycling plants, 3) PCSs In the soil, 4) Incineration, and S) municipal (solid waste) landfills. The PCBs put in carbonless copy paper from 19S7 to 1971 contaminated the paper products which have subsequently been recycled and put back Into the environment. PCBs have found their way Into sell from disposal sites and equipment servicing as well as oils used In dust control which may have been contaminated with PCBs. Incineration Is probably the best method for destruction of PCSs, but if not properly executed, Incineration can release PCSs and their by-products back Into the environment. Incineration can bo accomplished in a number of HONS 22507S II thermal devices Including industrial boilers, cement kilns, and hazardous waste incinerator*. All appear, if properly operated, to sat 1sfactorily destroy the chemical (1). U.S. EPA regulations governing Incinerators require 99,99% destruction, thus allowing a maximum of 0.01% to escape. Chemical landfills are presently effectively used to Isolate PC3s from the environment, but the danger of erosion and leaking is present (47). PCSs are also introduced Into the U.S. by atmospheric currents from other parts of the world, but the amounts are nominal compared to domestic sources (34). VI. BI0ACCUHULATI0M/9ISTXIBUTI0N IN ANIMAL TISSUES Environmentally, the bloaccumulatlon of PCBs Is very important. Due to their low solubility in water and high accumulation coefficients, PCSs display high bloaccumulatloir values In animal tissue. Aquatic organisms, such as fish, experience the greatest amount of PCS accumulation, for instance, the concentration of PCSs In Lake Michigan averages approximately O.OOS ug/kg while PCS concentrations found In the lake trout are approximately 28 mg/kg (10S). This concentration is over 3 million times that of the external environment. Different species of fish collected from the same environment In Lake Michigan contained different amounts of PCSs. Lake trout and carp both have approximately 10% body fat and contained more than five times as much PCS as yellow perch with only 4% body fat. It appears that species of fish with higher amount* of body fat (such as carp or catfish) contain more PCBs than other specIts of fish having less body fat (such as yellow perch or northern pike) (M). This difference In the bloaccumulatlon of PCSs Is mainly dependent upon adipose tissue and under stress this may present a release MONS 225076 mechanism as PCB-contalnlng lipids arc mobilized (34). accumulate In skin and muscle tissue. PCSs also may After PCSs reach the bloodstream, they become located within the liver and muscle. From these locations they are redistributed and become incorporated within other tissues such as adipose tissue and skin which, although they have lower blood perfusion rates (137), also have higher affinities for PCSs. This distribution of PCSs primarily in adipose tissue Is displayed In feeding experiments with Sherman rats (69), ppm of Arochlor 1254 for 5 months. These rats were fed a diet of 500 After 10 months, the rats were sacrificed and PCS concentrations were determined. Adipose tissue contained 1200 ppm of PCSs while liver tissue contained only 22 ppm (69). In another such feeding experiment, rats were fed diets of 1000 ppm Arochlor 1254 for 98 days. The adipose tissue contained 11.27ft ppm while other tissues had less than 200 ppm (36). Experiments with pheasants Indicate that as wch as 82X of the PCSs are absorbed via the gastroenteric tract (112). Additional absorption, though reduced In amount. Is by way of the respiratory tract (123). Excrotlon/Hetabol1sm Although adipose tissue accumulates more PCSs than other tissue types, the liver still must be considered an Important target organ because of its importance in the excretion of such toxins In the body. Furthermore, liver tissues still can accumulate concentrations of PCSs at levels twice that seen in the rest of thm body (128). Mlcrosomes of the human liver transform certain PCSs Into less lipophilic compounds to facilitate excretion (139). However, the nature of the PCSs In question dictates the fate of these toxins because their excretion is associated not only with the rate of metabolism, but also with their llpophlllclty. MOMS 225077 n In vitro experimentation involving the metabolism of PCSs by human liver mlcrosomes indicates that PC3* must have two adjacent unsubstltuted carbons to b« metabolized. Any unmetabolized PCBs appear to accumulate in adfposo tlssut (139). Chi orIn# atoms on the biphony1 compound also affect the rate of metabolism in both number and position on the biphenyl group, in mice, the rate of metabolism and excretion decrease as chlorination increases in orally administered PCSs (137). Similarly, studies by Sunyan and Page dealing with quail suggest that absorption, metabolism and excretion become increasingly impaired as chlorination increases on the biphenyl compounds (1SI). However, the amounts of chlorination alone are not the only thing to affect metabolism. Olfferent Isomers seem to affect hepatic enzymes differently. biphenyls seem to have yielded the-strongest results. The hexachloro- This study Indicates that activity of PCS Isomers differs sufficiently to warrant individual studies on each Isomer to determine metabolism and excretion. Testing with rhesus monkoys demonstrated that the majority of PCBs from a diet of Aroclor 1Z4S accumulate within liver and adipose tissue and decrease slowly following discontinued exposure. In fact, the PCSs appeared to have a half-life of at least 3 to 4 months. ________ Beagles were used In an experlmont In which both 2,3.B-heptachlorobiphenyU results Indicated that 70% of the 2.3,6-HCS was excreted in 3 days while only 14% of the Z,3,5-HC8 was excreted In 20 days. The 2,4,S-HC8 was 64% excreted In IS days while only 8% of the 2,4,S-H88 was excreted in 25 days (142). Thus, the rate of elimination was dtttrmlned by chlorine position, probably by HONS 225078 controlling tho rate of metabolism. Th# amount of metabolism and rata of •aeration Is also determined by the specific halogen. Another experiment involved beagles treated with an Intravenous dose of 0.6 mg/kg of CU labelled 4,4'-PC8. Excreta, bile and tissues were collected from IS minutes to 23 days following treatment. These specimens oxidized and was quantitated by scintillation counting. The results Indicated that 50% of the dose of 4,4'.PCS was excreted as metabolites within the first 24 hours. Urine contained 7% of these metabolites, while feces contained the remelnlng 43%. muscle and skin, Any remaining 14C In the dogs was present mostly In fat. By S days after the termination of exposure, more than 90% of the original dose of the 4,4'-PCS was excreted. exposed to PCSs In an identical experiment. excreted within the first 24 hours. Cynoaolgus monkeys were However, only 15% of the dose was At 24 hours, the blood and bile contained 75% and 100%, respectively, of their original values.The remaining PCSs were located mainly In the adipose tissue (33%) as the parent compound. muscle contained lesser amounts. excreted. Skin and After 2B days, only 59% of the dose was Hence, with 4,4'PCS, the beagles appear to be capable of eliminating highly chlorinated PCSs more quickly than the monkeys due to metabolic differences In the organisms (13S). Mechanism of Metabolism Biphenyls are hydroxylated then conjugated before Incorporation In rat bile for excretion. After doses of 2,2'*;2,4-;2,3*;3.4-; 3,3'*; and 4,4'- dlchloroblphemyls, the primary metabolites were d1 chiorodihydroxy biphenyls (69). PCSs have been Indicated In some cases as the toxins responsible for mutagenicity and liver damage In animals and humans. It seems that these adverse effects result from electrophilic Intermediates produced during the MQNS 225079 IS metabolism of PCBs (139). Hydroxylatlon, the major pathway of metabolism for PCBs, may sometimes Involvt arene oxidos at Intermediates. l«ad to carcinogenic, cytotoxic, or mutagenic affects. Aran* oxides may Increased arena oxide production may b« duo to the activity of both PCBt and PS8t working addltivtly together (75). Furthermore, hydroxylatod_chlorob1phenylt are more hazardous then the starting PCBt (34). It also hat been Indicated that rats exposed first to PCBt or PBBs have an increased likelihood of toxicity from other chealcals such as carbon tetrachloride, chloroform, and bromobonzene. Certain Insecticides are also more toxic when given with PCBs (72,74,99). Since degree and position of chlorination dictate the rate of PCB metabo­ lism, it nay suggest that the 11m1t1n9 factor is the rate at which arena oxide intermediates are produced (4). The production of these highly reactive, elec­ trophilic arena oxides may be due to the activity of hepatic and extrahepattc aryl hydrocarbon hydroxylase (AMI). The metabolism of 4-dlchloroblphenyl often yields 4,4'd1ch1oro-3*b1pheny1ol, This is probably due to a rearrange­ ment of a 2,3-epoxide or a 3,4 epoxide using an arena oxide as an Intermediate. If a 2,3 epoxide Is rearranged, the metabolite Is 4,4'-d1chloro-2*b1phenylol. However, If a 3,4 epoxide Is rearranged then a 3,4' dlchloro-4-blphenylol is the metabolite (16). A mixture of the two is most probable. A major concern with PCB metabolism Is the effect resulting metabolites may have on the young of exposed pregnant adults. Arochlor 1254, In doses of 10 or SO mg/kg, was administered to rats from the 7th to the 15th day of pregnancy (38). These doses resulted in average PCS concentrations In fetuses excised on the 20th day of 0.83 and 1.38 mg/kg for the above doses, respectively (38). These values, although low, Indicate a definite transfer occurring from parent to fetus. Laboratory studies indicate that greater quantities of PCBs NQNS 225080 .3 arc transferred by breast feeding after birth than prenatal!/ through th* plactrta. Thu nay be due to the fact that PC3s accumulate more readily and in greater quantity In tha fat of maternal milk r«thar than In maternal serum (92). Tettt of blood, milk, and adipose tUsua of infant* and mothers yielded data which damomtPati that tha loading maternal in fact, natarnal nllk fat (Tabla 4). soupc* of PCS* fop infant* ft. Additionally, tha fttus accumulates the majority of PCS* in adlposa tluua. Tibia 4 Natapnal Sources of PCS* and Olitrlbutlon Pound In Infants Holoolctl Source Natarnal milk Matarnal milk fat Natarnal blood Infant blood Fat only Total adlposa tissue Liver Adrenal Concantratlon of PC8s foobl 13 ISO 1.4 2.S 470 ISO 7.3 26 VII. TOXICITY AND EFFECTS OF PCSs Toxicity of PCSs Is a valuable consideration whan dealing with living organisms. Tha lethal doses of PCSs such as Arochlor 1242 and Arochlor 1260 administered orally are 4.25 g/kg and 9.S g/kg, respectively•'flSS)*' In laboratory rats, oral toxicity decreases with Increased chlorination; however, there Is no slallar correlation with rabbits and toxlelty (40,41). Tha exact effects of PCSs are difficult to ascertain because the eixtures often contain impurities. PCS eixtures have also been deaonstrated to contain several other types of chlorinated compounds such as polychlorinated naphthalenes and polychlorinated dlbenzofurans (PCOFs) (140). The presence of these PCOFs in PCS mixtures may arise from the distillation process during purification (Figure 3) (34). HONS 225081 17 Figure 3 Conversion of PCBs to PCOFs Ourlng Purification Process PCOFs The offsets of PCOFs hove boon widely studied beceuse of their possible connection with PCS toxicity. food consumption. Rats on diets of PCOFs displayed inhibition of PCSs also caused reduced food consumption but the decrease was far less than that demonstrated by PCOFs. In addition, chloracne-Ukt lesions appeared on the ears of these rats. Low levels of PCOFs cause the hemoglobin hematocrit and mean corpuscular volume to decrease. At higher concentrations, 10 ppm or more, PCOFs cause additional erythrocyte count decreases (Iff). PCOFs have also been demonstrated to decrease serum glutamic- pyruvic transaminase activity as well as testosterone concentrations within the testes. Concurrently, an increase in serum glutamic-oxaloacetic acid transaminase activity is typical for these PCOF treatments. Mixtures of PCBs and PCOFs cause a variety of symptoms In treated animals Including Increased MQNS 225082 13 serum cholesterol levels, elevated cholinesterase activity, and decreased triglyceride end amlnopaptidase activity <154). ATPase Enzyme Activity PCBs are also capable of altering ATPase enzyme activity In organisms, [t appears that the lipophilic properties of PCBs are the dominating factor in PC8 Inhibition of ATPases. The Inhibitory activity of PCS decreases as Its aqueous solubility Increeses. It seems that the lipid portion of the ATPase enzyme readily associates with PCSs. An allosteric change probably occurs in the ATPase enzyme by the lipophilic separation and results in decreased activity of this ATPase (130). In fact, studies by laAocca and Carlson Indicate Arochlors and other chlorinated hydrocarbons are equally capable of inhibitory activity on both Mg (ATPases). -and Na /K • adenosine trlphophatases More specifically, it was determined with in vitro experimentation that a concentration of 30 ppm of PCSs Inhibits the MgATPase activity of brain and heart tissue (8,4S,64,121,121). The activity of each of the 209 isomers of PCS as ATPase Inhibitors varies according to each compound and its corresponding association with a given ATPase (130). Chi oracne Chi oracne, a coaaon symptom of human PCS poisoning. Is a shin disorder associated with poisoning by any chlorine-containing compound. It occurs as severe acne but does not disappear as quickly as it appears and can be severe enough to leave facial scarring. The effect of PCSs on skin is manifested as typical chloracne In addition to hyperpigmentation, loss of hair, and yjrpbyr-4-e(90). The acnelfona eruptions of chloracne form both closed comedones (cysts) and open comedomes. The cause of these acnelfona eruptions appears to be the MOWS 225063 13 follicular excretion of PC3i with tho sebum. Thttt excretions continually stimulate the litln and result in tho acnelfons characteristic of PCS poisoned patients (1*9). Anliitl Experiments On tho Acuto Toxicity Chart, PCBs aro only ranitod slightly toxic to non-toxic (37). Recent studios Indicate that short-term exposure to PC8s does not sees to be particularly toxic (134). The short-tone toxic effects seen in laboratory aniuls would appear to require dosages in terms of pints or quarts to cause corresponding effects in humans (25). Experiments with rhesus monkeys on a diet of 300 ppa of Arochlor 1248 resulted In diloraene, loss of eyelashes, and subcutaneous edeoa (119). Longer teres of exposure In eale monkeys resulted In slight periorbital edema and erythema (9). Oral adnlnlstrati on of a 83* chlorinated biphenyl to laboratory anleals resulted In atrophy and lesions of the liver (158). More specifically, Hie dogs on a diet of 100 ug/g of PCBs have experienced observable reductions In growth rates while displaying an enlargement of the liver. Serve levels of alkaline phosphates are also elevated (84). Studies on the effects of PCBs on microorganisms such as the fvg/ena and the Scenedesmu* also demonstrate reduced growth rates. Other microorganisms that contain chlorophyll, the cyclosteriue and thalosslosloa. also display suppressed growth (14,42,43,127). Guinea pigs, rats, and rabbits that were topically treated on a daily basis with 0.025 ml (34.5 mg) of undiluted chlorinated biphenyl all demonstrated fatty degeneration and central atrophy of the liver. addition, tho epidermis thickened at the site of application (123). In Testing with Ulster rats fed 1000 ppm of Kanechlor 300, 400 or 500 resulted in MOMS 225084 the development of cholangloflbrosls. symptoms. lower doses did not dljplay such In addition. Increasingly larger concentrations of PCSs with greater chlorination caused higher occurrences of medullar hyperplasia (63). Sherman rats fed high doses of Arochlor 1254 exhibited adenofibrotlc lesions. Mice also demonstrated liver changes when given highly chlorinated com­ pounds In concentrations of 300-500 ug/g (34). 1234 mas administered to two groups of mice. A 300 ppm dosage of Arochlor Group one was exposed for LI months while group two was exposed for 9 months. Histological examinations of these mice indicated that one of the 24 mice in group two developed hematomas. Furthermore, of the 22 mice In the first group, all displayed adenoflbrosls (85). Birds also suffer adverse effects from long-term exposure to PCBs. For example, chickens display reduced egg production and fertility over long-term exposure to PCBs (125). Chickens have also displayed slight morphological deformities and a decline In reproductivity which is accompanied by subcutaneous edema when doses of 20-30 ug/g of PCSs were administered (34). Chickens treeted orally with 100 ppm of Arochlors 1242 and 1234 display decreased rates of hatching eggs (34). Qualls exposed for 2 months to Arochlor 1242 showed discontinued production of eggs and displayed decreased levels of Vitamin A in the liver with as much as SOS of the original level of Vitamin A being decreased (20). Wild fowl. In general, display reproductive changes when exposed to PCS concentrations of 50-200 ug/g (34). American kostlels exposed to PCBs demonstrated nominal increases in the thickness of egg shells. Higher doses 80 mg/kg were necessary to cause decreased egg production and a 12S decrease In eggshell thickness. Ring doves fed 10 ppm MONS 225085 21 of Arochlor 1234 dlsplayad lowar hitching rata*. Cytoganatlcil tasting on th« tmbryos of thasa PCS ftd dovas ylaldtd hlghar than normal chromosomal raarrangamants and abarratlons whan Irradlatad with X-rays (131). Of all bird spaclts studlad. ring dovas appoar to ba tha most suscaptlbla to PCBs. A 10 mg/kg dost of PCSs has baan raportad to graatly Incraasa ambryonlc mortality ratas in tha sacond ganaration as wall as causa chromo­ somal abarratlons. In addition, bahavloral changas hava baan obsarvad in tha parant birds (117). It Is apparant that dlffarant spaclas of birds hava varying tolaranca and raactlons to PCBs. Birds alsa damonstrata many symptoms axparlancad by laboratory mammals. Chlckans as wall as othar spaclas show anlargad kldnays, splanlc atrophy, and congastlon and Infiltration of fat In tha llvar (11,143). Pal leans hava baan shown to axparlanca soma hapatocallular altaratlons whan axposad to PCB dosas of 100 ug/g (34). Vapor Cxposuro Vapor axposura to PCBs saam to rasult In an Incraasa In tha occurranca of advarsa affacts on animals. Vapor axposura of mica damonstratas that chlorlnatad dlphanyls could causa Injury whan usad In small concantrations. PCB axposura, In this fashion, may bo mora dangarous than axposura to chlorlnatad napthalanot (42,43). Howavar, gulnaa pigs that undarwant vapor axposura to PCI concantrations of 818 ug/1 of air for tha 7 hr/day ovar 14 days showad na toxic affacts. This concantratlon was naar saturation and did causa poor growth, but nothing so profound as indlcatad by tha axparlmant with mica (42,43). Skin axposura, as mantlonad pravlously, can causa chloracna. high dosas of PCBs may causa systamlc affacts. In addition, Thasa affacts incraasa in MOMS 225086 severity with the amount of chlorination of the 61 phony 1 (Wo). Systemic effects wort observed In rats given five skin applications of Arocftlor (1 ml of 20% solution mixed In olive oil). These rats displayed general mala is*, rough fur, loss of body weight, death with and without convulsions and coma (10). Reproductive Effects One of the loading concerns regarding PCBs today is tho effect on mannal reproduction and the reproductive systea. With regard to the endocrine systea. PCBs can cause irregularity in tho menstrual cycle (90). In monkeys, saall doses of 2.3-9.0 ug/g will cause an erratic menstrual cycle as well as an Increase In abortion rates (76). Reproductivity tests In feaale rhesus monkeys with PCI doses of 2.S-S.0 ppa were carried out over a 6 month period. The monkeys on the 9.9 ppa dosage demonstrated Irregularities in the menstrual cycle. Six of the eight feaales tested were capable of conceiving. Of the six animals that conceived, five had abortions or experienced early fetal resorption. The eight feaales receiving dosages of 2.9 ppa were all capable of conceiving. However, three did not carry to full tens and the surviving Infants showed reduced site and dark skin plgaentatlon (119). Studies by Klhlstrom et al. determined that a decrease In Implantation capability occurred In alee when both the aether and father were nursed froa PCI or OOT-treated mothers. When the mothers alone were treated with PCBs, Implantations dropped to 79% froa a control rate of 94%. The control rate dropped to 79*when the mothers were triated with DOT. However when only one parent was nursed froa a treated mother, there was no noticeable decrease in the implantation rate. It seems that the milk on which the mice nursed, contained PCBs and was capable of Increasing standtrd catabolism. The end result was an alteration of normal sexual development of these mice (124). MOMS 225087 23 A similar experiment was cirri ad out by Burke and Fitzhugh with rats. rats wars fad dlats of Arochlors 1Z42, 7254, and 1260. 7he Concantratlons of 1, 10 and 100 ppm wan administered. At lowar concantratlons of 1 and 10 ppm than wara no notlcaabla affacts. Howavar, whan dosages of 100 ppn of Arochlor 1242 wara used, tha anlaali dlsplayad dacraastd mating indices In tha sacond ganaratlon. Dosages using Arochlor 1254 causad tha number of pups born to bo raducad and also dacnasad tha survival rata of sacond and third pragnanclos (91). An Incraasad rata of stillbirths was only apparent whan tha dosagas wara of Arochlor 1240 (113). A dacreasa In fatal walght and prasenca of neoplastic nodules In tha liver ware apparent (21). Additional experiments with minks ware performed with PC? doses of 10 \*g/g. At this concentration, the sinks display decreased growth and reproduction (34). Studios by Tomdergs Indicate that PCBs can affect tha reproductive and adrenal hormones of animals by stimulating microsomal enzymes responsible for metabolizing the adrenal hormones (135). WII. HUM* ctrnuu The lack of sufficient data concerning PCI exposure Is tha Uniting factor In determining toxicity as wall as affects In humans. Rare accidental PCS exposures have become the major source of nearly all of the acuta health data. The first of these Is an accident which took place in 1948 whan thousands of people were orally exposed to PCIs in Fukuoka, Japan. This exposure was causad by PCI contamination of rice oil which was subseguently usad for cooking. Tha disease described by these symptoms was called Tusho rice oil disease. Tha sacond major accident leading to human exposure MONS 225088 occurred In 1978 In Tainan. Not uni fit* the Yusho caia. PCBs wart ingested by humans through uti of contamlnattd rice oil. From thtsa two specific fncident and othtr lata notad PCS exposure situations, tha affacts of PCBs on humans hava baan placad together. Physiological gffacts Gross morphological or pathological affacts art raraly ralatad to PCB axposura In humans. Instead, only minor Impairments result (34). Tha general symptoms of PC8 Ingestion are weakness, nausea, headache, Impotence, insomnia, loss of appetite, loss of weight and abdominal pains. muscular pain also may be related to PCB poisoning. Muscle spasms and Ocularly, PCBs are capable of causing inflammation and burning, edema of the eyelids, cysts of the tarsal glands and conjuctlva (90). The sebaceous gland of the eyelids, the Meibomian gland, may also become hypertrophic and result in cheese-like discharges from the eyes (M9). Autopsies of humans exposed to PCBs in the Yusho rice oil poisoning revealed typical chloracne and pigmentation of cutaneous tissue. In addition, follicular hyperkeratosis, dilation of hair follicles, and melanin Increases In the epidermis were observed In histological preparations of skin (89). Other PCS effects on the skin include xerosis, nail deformity, hair loss, and hyperldlosls. In survivors of the Yusho accident, the acnelform, follicular cysts, pigmentation, and nail change all improved dramatically or returned to normal within 1*1 years (1*9). It is possible that PCBs stimulate the melanocyte In seme fashion, but the pathogenests of pigmentation is unclear and any relation with PCB Is merely theory (1*9). Mi thin the blood, serum triglycerides have been noted to increase due to PCB Influence. A decrease In serum bilirubin Is also noted. Organ system MOMS 225089 Impairment such as fibrosis, hapatoeatlul*r ntcresls, enlargement of the liver, and reduction of air capacity in the lungs has been observad (90). appears that prolongad axposura to PCBs can causa llvar damaga. savarlty of such hapatlc damaga is not cartaln (140). It Howevar, the In addition, hypartro- phla, hyperplastle gastritis, and ulcar formation Hava baan obsarvad In tha gastrolntastlnal tract (7$). A group of woman occupationally axposad to PC3s was studlad to nota affacts in pragnaney. Tha naan birth walght of infants bom to thasa woman was S3 grams Ugh tar than tha walght of infants born to woman In a control group. Tha gastatlon parlod was raducad by s.s days in tha axposad woman and this dacraasa in tha gastatlon parlod may account for tha dacraasa In blrthwolght (145). hurolooicil Effects Tha extent of tha offacts of PCS oxposuro on tho narvous systam ara, at most, vague. Soma studlas Indlcata that both a 30ft dacraasa In motor and a SOS dacraasa In sonsory narva conduction velocity occurs In PCS axposad patients (30). In addition to narva conduction velocity decreases in tha central and perlphoral narvous systems, other sensory disturbances may also oceur. Tho senses of taste, hearing, smelling, and sight may be distorted as wall (90). Studios indicate that them Is no correlation between neurological manifestations and PCI concentration in tha blood- That Is, high PCI concentrations In tho blood do not always give rise to neurological affects (30). Speculations ara that thasa neurological symptoms are caused by soma other chemical substance or that genetic factors may make cartaln individuals more susceptible to PCI related neurological dysfunctions. MOMS 225090 :s In 1980, a neurological study was performed. with 35 of tha 2000 people •xposad to PCBs In tha 1978 accident in Taiwan (30). soma typa wara obJarvad in 31 patlants (39%). from a dull, non-pulsating haadacha. experienced by 12 patlants (34%). Neurological symptoms of Thlrtaan patlants (37%) suffarta Dizziness or 1Ight-haadadnass was Nausea and vomiting sonatinas accompanlad thasa symptoms, but no vartlgo or tlnnltls was obsarvad. Both parasthasia and hypoasthasia wara experienced, and soma patlants damonstratad sluggish or absant daap tondon reflexes. Blood tasting ravaalad no corralatlon batwaan thasa affacts and PCB concantratlons In blood. Carclnooenlclty It has baan datamlnad that larga dosas of highly chlorlnatad compounds hava tha ability to Induca tumor growth in both rats and mica, but tha spaclflc rola of raasonabla 1 avals of PCBs In promotion of tumor growth Is unclaar (34). In mica, PCI Inducad tha davalopmant of llvar tumors (78) and mica exposed to high lavals of PCBs (500 ug/g) for prolongad tlmo spans hava dlsplayad hapatocal1ular carcinomas and nodular hyparplasla (81.111). Although faw PCBs hava baan tastad for carclnoganlc affacts. Arochlor 1254 and 500.'hava baan datarmlnad to produca both banlgn and malignant tumors In tha llvars of mica (80). In a study of Kanachlor 500, 7 of 12 mica fad 500 ppm PCBs ovar a 32 waak parlod davalopad llvar nodulas. Flva of tha mica had hapatocallular carcinomas wharaas othar organs dlsplayad no traca of matastasas ar tumors (29). Thara hava baan axtanslva data collactad on tha carclnoganlc affacts of PCBs In laboratory animals, but faw concerning humans (58). limited accidental and prolongad occupational exposures are tha only.source of such data. Of tha thousands of individuals axposad In tha Yusho, Japan incident of MOWS 225091 27 1968, four deaths wart examined to det«rmlne the absence or presence of PC3 ralatad affact*. The four autopsies which wera conducted, included thraa adults and ona stillborn infant (88). All four individuals dlsplayad skin laslons that we now know ara charactarlstlc of PCS exposure. Additionally, masantarlc fatty tissua and skin contalnad high 1 avals of PCBs. This again is to ba expected slnca PCBs tand to bloaccumulate In adlposa tissua (86,87). Tha stillborn was hatvlly pigmented, being in a stata rafarrtd to as “Brown Baby*. This plgiaantatlon indlcatad transportad passaga of PCBs to tha davaloplng fatus (B6). damage. Only ona of tha four autopslas revealed any hapatlc This victim, a 48 yaar old Japanasa woman, was dlagnosad as having llvar cirrhosis with multilobular cirrhotic changas balng accompanlad by many hapatlc-call carcinoma nodulas (88). Although tha dansatltls of thasa four Individuals has baan associated with PCI axposura, tha stillbirth and llvar damago Is not concluslva onough to establish a causal relationship batvaan PCI exposure and thasa given effects. Furthermore, reevaluation of mixtures of the contaminated rice oil from Yusho indicate that other compounds, such as hazardous polychlorinated dlbanzofurans (PCOFs) (52) and polychlorinated quaterphenyls (PCQs) were present in tha PCS mixture (120). The major PCI*re1ated effects in humans are subtle even whan the PCBs ara present in largo concentrations. Although, acute exposure is rare for humans and wild life (34), an exception to this is the direct and cumulative occupational exposure to PCBs. Some workers In capacitor plants have baan exposed for decades to PCBs (27). Lower levels of PCBs may be linked to minor transient affects such as headaches, abnormal fatigue, and possible Joint soreness. Higher levels aay result in dermatological affects such as hyperpigmentation and chioracne (146,147). MONS 225092 13 On* occupational exposure study used 14 capacitor plant worker* who wart breathing 0.1 mg/m* of PC9f. Seven of tha 14 workers acquired chloracne which disappaarad aftar axposura to PCBs was discontinued. normal 1 iwtr function. Of these 7, S possasstd The remaining individual with chloracna, had only borderline liver abnormalItles. Within 13 months after termination of exposure, liver function returned to normal. Although chloracna appears to be related to PCS axposura, th* data suggest that It is unlikely that the liver problems ware caused by PCIs. Lack of controls and only a single liver abnormality make Its occurrence not significant (106). Tho South Carolina Oopartaant of Health conducted a study with 32 capacitor plant workers (138). axposod to PCBs. Ton of those Individuals ware regularly Tho findings revealed that there was 'no evidence of physical harm resulting from working with PCBs* (39). Tho carcinogenicity of PCBs was tasted In three additional epidemiological studios. Tho first one used 92 refinery workers. had melanomas. Of those 92 people, three However, these employees may have been exposed previously and slmultanoously to other known carcinogens (6,7). Tho second study covered a time span from 194S to 196S. In this study, 89 Monsanto workers with at least 6 months exposure were monitored. Neither liver cirrhosis nor liver dysfunction was noted In any of th* employees. Four respiratory cancer cases occurred, but were not statistically significant from controls. Furthermore, therm were additional oxposuros to known carcinogens, particularly through cigarette smoking (160). Tho last study used 2,367 capacitor plant employees In whom there appears to be an increased rate of death duo to liver cancer (II). However, the incidence of cancer was ’Inversely related to duration and latency of MONS 225093 ;9 exposure* (59), which dots not suggest occupatlcnal exposure to PCBs u tho ciusatlvo mechanism. cincar. Additionally, thtrt was in Increased rata of ractal Tha plant was. however, locitad in an arta wh«re thara it a hlghar than ivaraga ractal cincar mortality rata for all inhabitants (IQ3). Froa thata occupational itudlas, high lavalt of axpotura to PCSt hava demonstrated tha ability to cauta dermatitis, but othar clinical affacti. Including cancer, hava not baan obtarvad. Studies of Individual! who were environmentally axpotad to PCIt, not occupationally, daaonttratad no clinical affaett, Including daraatltit (S3,59). Tha taall taapla tUa and simultaneous axpotura to additional toxic coapound* makes tho cancar avaluatlon In thaaa studlas difficult. Thata studlas daaonstrata an axcasslva mortality rata pattarn that It 1ncontIttant with tha probable carcinogenic effects of PCIa (55,59). IX. CASK STUDIES OF ACCIDENTAL EXPOSURES The beat inalght into tho effects of PCI expoauro hat com from case studies of accidental and occupational exposures. In 1913 In Slaeoe County, Ontario, a material dripping from a fluorescent light fixture in a school room was found to contain 200,000 ppm of PCBs (20* PCI by weight) which was later Identified as Arochlor 1254. Tha ballast of tha light had originally contained 1 1/2 ounces of PCts and 1/3 of an ounce was lost in thm leak. Among all the students and teachers exposed to these PCBs, there were no noted symptoms except several headaches which ware attributed te the pungent odor that was present. The Yusho exposure of 19BI was caused by a leak In a heat-exchanger used in rice oil manufacturing. Kanechlor 400 was tha PCI present and tha contam- (nation level was determined to be between 1500 to 2000 ppm of PCBs. MONS 225090 Of 12 Yusho patients studied, 10 subsequently dlad. Four of thase patents (tgas 13, 23, 48, and 73) dlad froia heart failure. [t was ntvar determined if any of that# four victims had a family history of haart disaasa. patlants dlad from rasplratory fallura. Thraa othar Rupture of llvar carcinomas rasultad In tht daaths of two patlants and a tanth pat 1 ant dlad as a rasult of aspiration pnaumonla. Analytical mathods for tha datamlnatlon of PCBs wara not davalopad until 3 yaars aftar tha Yusho Incident. In 1973, gas chromatography was usad to detarmina PCI concentration In whole blood. By this time, tha Yusho patients had a mean PCS level In blood of only 7 ppb (120). Later testing verified that tha rice oil was also contaminated with PCOFs (52). Almost all Yusho patlants displayed PCQ blood levels greater than 0.02 ppb (120). Elevated concentrations of PCQs and PCOFs In tha rice oil Indicated that tha oil was heatPd first (28). Recant data concerning tha Yusho Incident seam to indicate that adverse health effects originally blamed on PCBs were really due to exposure to these toxic contaminants of the PCS mixture (37). The source of PCS In the 1978 Taiwan Incident has not been determined. However, Just as In the Yushe case there was more than one chemical in the contaminated rice oil. In addition to a PCS concentration of S3 to 99 ppm in rice oil samples, there were also PCOFs and PCQs present In concentrations of 0.18 to 0.40 ppm and 2$ te S3 ppm, respectively. One of the most hazardous PCBs, 3,4f3',*'-tetre-ch1orob1phenyl, was present In rice oil samples as well as adipose tissue of patients. Furthermore, a highly toxic PCQF.2.3,4,7,8- pentachlorodlbenzofuran, was also present in the oil sample and in liver tissue of a patient who had died (28). HONS 225095 31 Most extended exposures to PCBs have baan associated with Industrial accldants with workers who manufactured PCB-contalnlng goods. In 157!. approximately 12,000 paopla wara occupationally axposad to PCBs. Tha majority of thasa axposuras occurrad in tha production of capacitors (152). In industry, most of thasa axposuras wara dermal, not oral, so tha coonon affact was chloracna. Thara ara raports of savaral daathj Involving darnal axposura to vary high concantratlons of PCBs, but avldanca suggasts tha prasanca of chlorlnatad naphthalanas in thasa substancas (32). Tha General Electric Corporation conductad studlas on almost 200 workers at thalr capacitor plant In Hudson Falls, New York. Thasa workars had diract contact with PCB alxturas and vapors for savaral dacadas. Tha rasults of thasa studios ravaalad that no confirmed cases of chloracna or other PCB-related effects ware present In workars axposad to ordinary, unpyrolyzed American-made PCBs (27). Another study Involving occupational axposuras divided axposad workers into two oaln groups. The first group Included silk workers from Kyoto exposed to PCBs by tha oil used on tha machines. Levels of 50 ppb ware found in soma members of this group but no clinical symptoms were displayed as in the Yusho case. The PCBs present wort Identified as Kanechlor 500. levels ware lower than 0.02 ppb In blood. Furthermore, PCQ The second group In tha study included paint manufacturers who were axposad to paints containing PCBs. As in tho first group, concantratlons were found to be higher than in the Yusho patients, but no cllnclal symptoms were observed. workers was identified as Kanechlor 600. The PCB present in these Again, PCQ concentrations in blood ware lass than 0.02 ppb (1*4). MOMS 225096 X. RESULATtON OR PCBS Irr. 1976. tha manufacturing process and use of PC8t in the Uni tad Statai wart banned by tha U.S. EPA in spite of clear avfdanca indicating that long tana exposure to PCSs by numerous electrical equipment workers mis not a serious advarso health problem (102). Tha stringent regulations pUcad upon PCS use wara baiad upon tha assumption that any level of axposura to pcBs is hazardous. Tha ban regulations which wara instltutad In 1976 wara basad upon only ona human axposura Incldant (9) out of approxlaataly 2500 scltntiffc articles publlshad prior to that data. However, racant rasaarch shows that. In fact, lower-level axposuras to PCBs ara not hazardous to man (37). In tha 5 yaars following tha issua of thasa ban ragulatlons, ovar 5000 additional sclantlflc publications detailing PCS toxicity hava baan published Indicating that PCBs hava not baan shown to be significantly hazardous to man (139). It seams apparent that all scientific resources and studios wara not used In establishing regulatory bans on PCBs. The last several yaars hava provided many additional human axposura cases which need to be considered in updating the alleged toxicity of PCBs (37). A coomrittee established by the National Research Council of tha National Academy of Sciences to reevaluate PCBs In 1979 concluded: "An analysis of PCI data compiled following the criteria of FIFRA and TSCA proposed guidelines, leads to the conclusion that PCBs are persistant, and are likely to accumulate. PCSs do not appear particularly toxic for short-term exposure, but results are subject to Interpretation." (37). A reevaluation of PCI toxicity, especially in humans, revealed that human health is generally not seriously Jeopardized by PCB exposure. PCBs do not appear to be carcinogenic In humans, and there is no proof that leads us to believe that PCSs art mutagenic, teratogenic, indicative of birth defects, or HONS 225097 deterlmental to human reproduction. Only dermatitis and chloracne havo baan conclusivaly provan to ba caused by PCS axpesura. Soth of these adverse affacts ara coiaplataly ravarslbla and disappear If PCB exposure is terminated. Data comp Had In tha last dacada hava Introducad additional human axpoiura casas upon which to basa thasa conclusions (37). In Hay of 1982, tha U.S. EPA sponsorad a symposium on tha affacts of PCBs. It was concludad that PCBs thamsalvas do not promote unraasonabla risks to tha environment or human haalth. XI. ELIMINATION OF PCBS FROM THE ENVIRONMENT Thara ara savaral Mans by which PCBs can ba allalnatad from tha environmant. Hydrolysis can ba used undar extreme conditions although PC3i ara usually Inart to this raaetlon (71,118). Chamlcal degradation Is anothar mathod that can ba usad to allalnata PCBs (17). Tha stability of PC8s is so great that envIronMntal conditions ara not llfcaly to promote chamlcal reactions with tham. Howavar, undar controlled conditions, oxidation, reduction, nitration, Isomerization, and nucleophilic reactions can occur with PCBs (71). For example, PCBs hava recently baan shown to ba degraded to polyphenylene and sodium chloride by treatMnt with Mtalllc sodium (MO). Photodegradation Is anothar Mthod for destruction of PCBs. Gechlorina- tlon of PCBs as wall as tha production of potyMrlzed materials occurs In hexane whan exposed to irradiation In sunlight (100). Chlorine can ba re­ placed by hydrogen or hydroxyl groups, a condensation or raarrangpMnt may occur, or even the production of polar products can result from such a reaction. Specifically, Arochlor 1254 can ba degraded to hydroxylated and carboxylatad species by Irradiating it In the presence of hydroxylic solvent it pH 9 (100). MQNS 225098 Very little photodegradation of PCS* occur* naturally because they art usually sub-terrestrlally stared and not readily accessible to sunlight. Another natural process that can eliminate PC8s from the environment Is biodegradation. A recent report indicates that natural soil processes will degrade PC8s (19). In this process, both position and degree of chlorination of PCBs play crucial roles In determining whether or not microbial degradation will occur. Bacteria can transform biphenyls of lower chlorination, but encounter difficulty with more highly chlorinated biphenyls (122). Many PCBs are oxidized to their corresponding chlorobenzolc acids, but other mixtures of dlhydroxy compounds, meta-cleavage compounds and other unknown products are possible based upon the degree of chlorine substitution (50). Conversion of PCBs to chlorobenzolc acids Is the main process of biodegradation (figure 4). figure 4 Host Probable Reaction in llodogradatlon of PCBs Meta-cleavage Compound* Chlorobenzolc acid MONS 225099 35 Not only 4o Aclnetobacter bactorla follow this pathway, but so do othar ganan of bactarla such as Alctll i genes, ^rthrsbactar, AcArsmoOictar, Nccardn, and Pstfjdomonts (58). All pathways and products must ba considarad in blodegra* datlon bacausa It is posslbla that metabolites generated during this procais ara avan more toxic than ara tha PCBs (58). Tha final method for tha dastructlon of PCBs, as pravlously mentioned, is Inclnaratlon. As PCBs ara Inclnaratad, haxachlorobanzana Is formed. Both PCBs and haxachlorobanzana can ba dastroyad thanaally at a temperature of 950°C with a rasldua of 100 mg of haxachlorobanzana par kg remaining (101). Heating aay causa PC8s to fora dlffarant polyaarlc conpounds Incorporating o oxygon (161). Haatlng PCBs to $00*600 C will causa formation of dagradatlva products such as chlorinated dlbanzofurans (22)< Despite these aethods for allalnatlng than, PCBs raaaln a persistent 5 problea In tha anvlronmnt. Of tha 670x10 kg of PCBs produced In tha U.S. since 1930, nora than half (SOX) ara still In service and Twelve percent is aoblle In the envlroneent. Twenty-eight percent of these PCBs have bean ellalnated, 5X by Incineration or chaalcal degradation and 23X by being placed In landfills (34). XII. PERMISSIBLE HUNAN EXPOSURE It Is difficult to assartaln tha quantity of PCBs, If any, that would ba a permissible exposure limit for humans. Generally, tha concentration of 200 ug/kg ef body weight par day has been determined to ba tha minimum oral Intake of PCBs shown to produce toxicity In humans (101). Signs and symptoms of toxicity occur In humans after an oral Intake of O.S g (114). HONS 225100 This quantity represent* a fairly large dosage and would indieata that there has been an ovar-raaction to the perceived toxicity of PCBs. Tha affacts of PCBs on hunan haalth still hava not baan concluslvaly determined. Problems arlsa concerning this datarmination bacausa accldantal exposures to PCBs cannot ba claarly Idantlflad as pura PCS axposuras or as axposuras to mixtures of savaral hydrocarbons- Additionally, Intaractlons between chemicals can occur within tha body following Ingastlon of food* breathing air contaminants, as wall as siniltanaous or latar axposuras to othar chamlcals. Such Intaractlons can produca addltlva affacts making tha study of PCB affacts vary difficult. HONS 225101 XIII. BIBLIOGRAPHY 1. Ackerman, O.G.. Sclnto.L.L., 8aksh1, P.S. .Oelumyea, R.5., Johnson. R.J.. Richard, G., Takata.A.M. and Swortym, E.M.: Destruction and Disposal of PCBs by Thermal and Non-Theroal Methods, Noyes Oata Corp., p»Pk Ridge NJ 1985. 2. Ahmed, M. and 0.0. 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