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CHRONIC TOXICITY OF HALOGENATED BIPHENYLS AND RELATED COMPOUNDS IN ANIMALS AND HEALTH EFFECTS IN HUMANS RENATE D. KIMBROUGH, M.D. TOXICOLOGY BRANCH BUREAU OF LABORATORIES CENTER FOR DISEASE CONTROL PUBLIC HEALTH SERVICE DEPARTMENT OF HEALTH AND HUMAN SERVICES ATLANTA, GEORGIA 30333 DSW 033352 STLCOPCB4017314 1 Some isomers and congeners of several aromatic halogenated hydrocarbons cause similar toxic syndromes (Kimbrough 1974). These are chlorinated and brominated biphenyls, naphthalenes, dibenzodioxins and dibenzofurans. The 3, 3',4, 4' - tetrachloroazobenzene and 3, 3',4, 4' - tetrachloroazoxybenzene cause similar effects but may be generally less toxic because they are more easily metabolized (Hsia.et al. 1980). Of the compounds mentioned the chlorinated naphthalenes, the brominated biphenyls, and the chlorinated biphenyls have been used commercially while the halogenated dibenzofurans, dibenzodioxins and the chlorinated azobenzenes and aaoxybenzenes are contaminants of commercial products. Polychlorinated biphenyls may be contaminated with chlorinated dibenzofurans (Bowes et al. 1975). Pentachlorophenol may be contaminated with chlorinated dibenzodioxins and chlorinated dibenzofurans (Goldstein et al. 1977), and hexachlorobenzene (Villanueva et al. 1973), has been shown to contain the same compounds. The 2,3,7,8 -tetrachlorodibenzodioxin is a contaminant of 2,4,5 -trichlorophenol, and the derivatives made thereof, which include the herbicide 2,4,5-T and hexachlorophene. Further more, it ha6.recently been shown that 2,4-D if made by the same company using the same equipment, that was used for the production of 2,4,5-T may then also be contaminated with 2,3,7,8-tetrachlorodibenzodioxin (Fed. Register 1979). * DSW 033353 STLCOPCB4017315 2 The commercial products are mixtures of isomers and congeners and as the different components of the mixture are studied more extensively it is recognized that they vary greatly in their toxicity (Table 1). The most toxic of the entire group of chemicals i.6 the 2,3,7,B-tetrachlorodibenzodioxin. The amount of compound necessary to produce the same chronic toxic effect differs also, for different chemicals. A marked species variation exists in the response to these chemicals. Mink, guinea pigs and sub-human primates are more susceptible to the toxic effects than rats and mice. The types of diseases reported in different animals and the symptoms related to these different compounds in men are summarized in Tables 2, 3, and 4. Although many of these compounds were introduced into commerce in the 1940s and some of them earlier than that, their toxicity was not studied extensively until the 1960s and 1970s. The first compounds of this entire group to cause illness in people were the chlorinated naphthalenes. During the first World War, chlorinated naphthalones were used in the production of gas masks which resulted in outbreaks of occupational chloracne (Wauer, 1919). It was not until the second World War that it was recognized that mixtures of chlorinated napthalenes and chlorinated diphenyls may produce liver toxicity in workers (Jones, 1941; Sulzberger, 1934; Flinn et al. 1936). Such cases were isolated and it has been speculated that additional factors such as infectioijs viral hepatitis may have contributed to the disease. DSW 033354 In addition to the effects observed in laboratory animals, farm animals have also suffered a variety of illnesses from these different compounds. Among farm animals, cattle and chickens have primarily been affected. In cattle the so-called hyperkeratosis STLCOPCB4017316 3 or X disease is characterized by excessive lacrimntion, diarrhea and discharge from the nostrils. In addition, such animals develop a chronic cough, poor appetite, numerous red maculae in the buccal mucosa, and hyperkeratosis of the skin. The abomasum may become inflamed with many superficial ulcers (Olafson, 1957; Sykes et al. 1952}. After numerous investigations it was established that X disease could be produces in cattle by the ingestion of highly chlorinated naphthalenes. In the late 1950s, outbreaks of a disease occurred among chickens which caused extensive losses throughout the southeastern part of the United States. One of the leading symptoms was fluid accumulation in the pericardial sac and the peritoneum. The disease was therefore called chick edema(Simpson et al. 1954; Sanger et al. 1958). Following extensive research it was finally determined in 1967 (Cantrell et al. 1967), that 1,2,3,7,8,9-hexachlorodibenzodioxin was one chemical responsible for chick edema disease. The source of this compound was fat which had been obtained from fats and tallows of hides treated with chlorophenols. When these fats were heated to produce fatty acids some of the chlorophenols may have, been converted to chlorinated dlbenzodioxins. In addition, the chlorinated phenols were also contaminated with chlorinated dibenzodipxins and dibenzofurans. It was later established that chick edema could also occur following exposure of chickens to chlorinated naphthalenes and chlorinated biphenyls (Kimbough, 1974). Thus far the only extensive outbreak of acute illness among the general population following exposure to these types of chemicals occured in Japan in 1968. There rice oil become contaminated with chlorinated biphenyls and also chlorinated dibenzofurans DSW 033355 STLCOPCB4017317 and quarter-phenyls. Since the disease was caused by rice oil it was termed Yusho the. Japanese word for rice oil (Kimbrough, 1974; Cordell et al. 1978). Another group of compounds, 3,3', 4, 4'-tetrachloroazobenzene and the tetrachloroazoxybenzene are contaminants of 3,4-dichloroaniline and its derivatives, (Sundstrom et al. 1978). The only illness linked to human exposure to 3,3', 4, 4'-tetrachloroazobenzene and 3, 3',4, 4'-tetrachloroazoxybenzene is chloracne (Taylor et al. 1979; Morse et al. 1979). One such chloracne outbreak was investigated by the Center for Disease Control (Morse et al. 1979). A particular chemical company made propanil, N-(3,4-dichlorophenyl) propanamide, from 3,4-dichloroaniline. The 3,4-dichloroaniline used in this factory contained 51 mg/kg tetrachloroazobenzene and the propanil t* yV^ contained over 1000 mg/kg tetrachloroazobenzene. Other commercial y ,, \ Yr herbicides that are also made from 3,4-dichloroaniline usually contain 3,3',4,4'-tetrachloroazobenzene at concentrations of less than 100 mg/kg (Hill et al. Arch. Environ.i Healtlh in press). Most of these chemicals are not readily metabolized and excreted. Since they are all lipophilic they are stored in adipose tissue and may be excreted in milk. Certain isomers of chlorinated and brominated biphenyls are the most persistent in this group. When rats were given a single dose of a polybrominnted biphenyl mixture (Kimbrough et al. 1978), the polybroroinated biphenyls did not decline appreciably in blood and' adipose tissue over a 14 month period once they were equilibrated in the different tissue compartments. OSW 033356 STLCOPCB4017318 5 Similarly certain congeners of the polychlorinated biphenyls are not excreted. Rats fed Aroclor 1254 for 6 months (daily dietary intake about 5 mg/kg b.w.) after a 10 month recovery period 8ti11 had 152 ppm polychlorinated biphenyls in their adipose tissue. The PCB congeners retained this long were the more highly chlorinated ones. The 3,3',4,4'-tetrachloroazoxybenzene and 3,3*,4,4'-tetrachloro- benzene seem to be more rapidly metabolized (Hsia et al. 1980,). Not much information i6 available on the pharmakokinetics of halogenated dibenzodioxins, dibenzofurans and naphthalenes. The half life for 2,3,7,8-tetrachlorodibenzodioxin (TCDD), is 3-4 weeks (Rose et al. 1976). In rats, more TCDI) is stored in the liver than in adipose tissue (Kociba et al. 1978), while in monkeys and humans, the opposite is true. Polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo- dioxins are animal carcinogens. At daily dietary levels of 0.1 pg/kg b.w. 2,3,7,8-tetrachlorodibenzodioxin an increased t incidence of hepatocellular carcinomas of the liver and squamous cell carcinomas of the lung, hard palate/nasal turbinate or tongue was noticed (Kociba et al. 1978). Hepatocellular carcinomas have also been produced in rodents by feeding chlorinated biphenyls (Kimbrough et al. 1975), but tumors of the lung6 and upper respiratory system were not noted. In earlier studies in our laboratory, hepatic neoplastic nodules were observed in a preliminary study with polybrominated biphenyls (Kimbrough et al. 1978). Therefore, additional studies were conducted with larger numbers of rats. It was determined . OSW 033357 STLCOPCB4017319 6 that a single dose of 1000' mg/kg of PBB in corn oil given to eight-week-old female Sherman strain rats produced a 41% incidence of hepatocellular carcinomas. In addition most of these rats had hepatic neoplastic nodules, a tumor considered to represent part of the response of the rodent liver to carcinogens (1LAR 1980). Many of them also had hepatic pophyria. Repeated doses of 100 mg/kg twice a week for a total of 12 doses given to young rats produced a 67% incidence of hepatocellular carcinoma. At the end of the study these rats still had appreciable amounts of PBB in their adipose tissue and in the liver (Table 5). A lower single oral dose of 200 mg/kg given to female rats at the age of 4 months produced neoplastic nodules but no hepatocellular carcinomas (Kimbrough et al. manuscript in preparation). * Attempts to induce cancer of the skin in rodents by dermal exposure to these compounds have not been very successful. It has been suggested that most of these compounds are promoters of cancer instead of intiators of cancer (Berr.y, et al. 1979). . A number of reports in the scientific as well as public press have associated exposure to these compounds with an increased incidence of cancer in people. Some of these reports have raised suspicions but thus far no studies have been reported suggesting a definite link between cancer and exposure to these compounds. One reason for the lack of such evidence is that groups of workers exposed to these compounds ore usually small and studying them would not necessarily demonstrate slight increases in cancer rates. DSW 033358 STLCOPCB4017320 7 Unfortunately, these negative findings may create a false 6ense of security. However, other human health effects have been reported for some of these chemicals. In addition; to chloroacne, increased triglyceride and cholesterol serum levels have been associated with exposure to these type6 of compounds. Abnormal liver functions tests and a sensory neuropathy have also been reported (Kimbrough 1974). Workers exposed to high concentrations of TCDD have developed porphyria cutapea tarda (Jirasek,1976^ - Recently the Center for Disease Control studied a population of about 600 inhabitants of a smal jll rural town in the South Eastern United States. A source of protein was fish caught in a near by river system. When it was discovered that this fish contained high concentrations of DDT residues, DDT serum levels were determined in 1978 on a few fish eaters and found to be extremely high. Subsequently a study was conducted of the entire population (Kreiss et al. manuscript in preparation). This study consisted of the administration of a questionnaire, measurement of height, weight, blood pressure, clinical chemistry tests and analysis of serum for DDT levels. During the course of the serum DDT analyses it was discovered that PCB levels also seemed to be high in a number of the 6era. The sera were subsequently al60 analyzed for PCB. Several interesting findings were made in this study. First DDT and PCB residue levels increased with age and correlated well with fish consumption. Although DDT DSW 033359 STLCOPCB4017321 8 residue levels in the fish were high, the PCB levels in fish were below or close to the present JFDA guidelines, suggesting that heavy fish eaters can build up substantial PCB levels. For instance, a composite sample of 6 catfish from the area averaged 3.64 mg/kg and 4 cataco creek catfish had 4.34 mg/kg \' PCB. Catfish from other sites in the river system averaged 0.59 mg/kg. In spite of extensive environmental sampling by the EPA no point source for PCB could be uncovered. For the 458 individual PCB measurements the geometric mean serum s PCB level was 17.2 yg/L and the range was 3.2-157.9 yg/L. * This mean PCB blood level is within the same range of blood levels of the general population. Serum PCB levels correlated well with fish consumption,. Of the health indices measured in this population only cholesterol, hypertension and one liver enzyme test, Y-glutarayl-transpeptidase, were positively associated with PCB serum levels, all independent of major confounding variables. Although there wa6 a gObd correlation between total DDT and PCB blood levels there was no positive association between DDT serum levels and hypertension. Many factors affect blood pressure and cardiovascular disease such as: smoking, diet, excercise, excessive salt Intake and genetic make up. These factors are probably of greater importance than exposure to PCBs. Similar studies in other exposed groups are needed to 6tudy these various confounding variables. OSW 033360 STLCOPCB4017322 Table I Acute Oral LD^q in Rats Compound Aroclor 1240 LD50 4.25 g/Kg Aroclor 1260 4-10 g/Kg Aroclor 1254 4-10 g/Kg TCDD 44.7 pg/Kg 2,3,6,7-Tetrachloronaphthalene >11.3 mg/Kg 1-chloronaphthalene 1540 mg/Kg 2-chloronapli thalene 2078 mg/Kg Brominato.d biphenyls (Firemaster BP-6) 21.5 g/Kg Reference Kimbrough et al. 1978 Kimbrough et al. 1978 Kimbrough et al. 1978 Rowe et al, 1971 McConnell, in press NTIS PB 225-283 NTIS PB 225-283 Michigan Chemical Corp. 1974 1 DSW 033361 STLCOPCB4017323 1 Table II. Examples of Effects Produced by Compounds in Animals Compound_____ PCB Effects Reference 1. Decrease in liver vitamin A in Japanese quail and rats Cecil et al, 1973 2. Chick edema Vos and Koeman, 1970 3. Induction of liver microsomal enzymes in rats and other species Johnstone et al, 1974 4. Effect on chick embryo Cecil et al, 1973 5. Porphyria cutanea tarda (hepatic porphyria in rats chickens and quail) Goldstein et al, 1975 Vos and Koeman, 1970 Vos et al, 1971 6. Liver disease in rats,mice and chickens 7. Liver tumors in rats Kimbrough et al , 1972 Kimbrough and Linder, 1974 Vos and Koeman, 1970 Kimbrough et al, 1975 Ito et al, 1974 8. Hyperkeratosis in rabbit ears Vos and Hotenboom-Ram, 1972 9. Effects on embryo, neonatal and postnatal effects in rats.^nd minks Linder et al, 1974 Ringer et al, 1972 10. Gastric mucosal ulceration in mink and rats. Hyperplasia gastric mucosa in 6ubhuman primates Kimbrough, 1974 Allen and Norback, 1973 TCDD 1. Effects on embryo, neonatal and postnatal in rats 2. Porphyria cutanea tarda (Hepatic porphyria) in mice 3. Liver disease In rats, mice and guinea pigs 4. Thymic atrophy in rat and guinea pig Murray et al, 1978 . Moore et al. 1973 Vos et al, 1974 Gupta et al, 1973 Greig et al, 1973 Gupta et al, 1973 DSW 033362 STLCOPCB4017324 Table II. (continued) 2 Compound TCDD Chlorinated naphthalenes Erominatcd biphenyls ____________ Effects_______ __________ , Reference_______________ _ 5. Chick edema Metcalfe, 1972 6. Liver microsomal enzyme induction Poland and Glover, 1974 7. Hyperkeratosis in rabbit ears Jones and Krizek, 1962 8. Immunosuppression In mice Thigpen et al, 1975 9. Fatal liver necrosis in rabbits Milnes, 1971 1. X-disease in cattle Sikes et al, 1952 2. Chick edema Pudelkiewicz et al, 1959 3. Hyperkeratosis in rabbit ears ' and swine Hambrick, 1957 Huber and Link, 1962 4. Yellow atrophy of rabbit liver Flinn and Jarvik, 1936 5. Decreased vitamin A level in liver and plasma of cattle and swine * Olafeonj 1947 Huber and Link, 1962 1. Liver disease in cattle, rats and minks 2. Liver tumors in rats 3. Immunosuppression in rats, mice, chickens and guinea pigs ' 4. Porphyria cutanea tarda (Hepatic porphyria) in rats 5. Liver microsomal enzyme induction in rats and mice Jackson and Halbert, 1974 Kimbrough et al, 1978 Aulerich and Ringer, 1979 Kimbrough et al, 1980 Luster et al, 1978 Vos and Van Genderen, 1973 Kimbrough et al, 1978 Moore et al, 1978 Dent et al, 1976 Dent et al, 1977 DSW 033363 STLCOPCB4017325 3 Table 11. (continued) Compound__________ ___________________ Ef fccts________ _Reference 6. Behavioral and neurological effects in rats and mice 7. Hyperkeratosis in rabbit ears Tilson et al, 1978 Kimbrough et al, 1977 `% DSW 033364 STLCOPCB4017326 Compound PCB 1 Table III. Examples of Effects Produced by Compounds in Man Effects Reference 1. Chloracne 2. Mucoid discharge from eyes Umeda, 1972 Jones and Alden, 1936 Umeda, 1972 3. Pigmentation of skin and nails Umeda, 1972 4. Induction of liver microsomal enzymes Alvares et al, 1977 TCDl) 1. Chloracne 2. Porphyria cutanea tarda 3. Peripheral neuropathy 4. Elevated serum lipids Jirasek et al, 1976 Poland and Smith, 1971 Jirasek et al, 1976 Bleiberg et al, 1964 Goldman, 1972 Jirasek et al, 1976 Chlorinated naphthalenes 1. Chloracne 2. Subacute yellow atrophy of liver 3. Cable rash ., Mayers and Silverberg, 1938 Hambrick, 1957 Von Wedel et al, 1943 McLetchie and Robertson, 194 Good and Peneky, 1943 Polybroininated biphenyls 1. Hypothyroidism? Bahn et al, 1980 DSW 033365 STLCOPCB4017327 1 Table IV. Examples of Fetotoxicity and/or Teratogenicity in Different Animal Species Compound Fetotoxic Teratogenic Reference Aroclor 1248 2.5 ppm35 4 (Monkey) - Barsotti et al, 1976 Aroclor 1260 Aroclor 1254 35.4 mg/Kg/day^ (Rat) 3 1.5 mg/Kg/day (Rat) - Linder et al, 1974 Linder et al, 1974 TCDD 0,01 pg/Kg/day* (Rat) 0.125 pg/Kg/day** (Rat) Murray et al, 1979 Sparschu et al, 1971 - 3 pg/Kg/day6 * Courtney and Moore, 1971 (Mouse) 1.0 pg/Kg (Monkey) 7 Zingeser, 1979 Hexachlorodibenzodioxin 1 pg/Kg8 (Rat) 100 pg/Kg8 (Rat) Schwetz et al, 1973 Brominated biphenyls 200 mg/Kg9 . (Rat) - 800 mg/Kg9 (Rat) 1000 ppm10 (Mice) Beaudoin, 1977 ' 1 Corbett et al, 1975 Footnotes ]. Monkeys fed Aroclor 1248 at 2.5 ppm In diet for 7 months prior to breeding. 2. Rats fed 500 ppm Aroclor 1260 in diet for 62 or 188 days before mating showed fetotoxicity in both Fja and generations. 3. Hats fed 100 ppm Aroclor 1254 in diet for 62 or 186 or 129 days before mating showed fetotoxicity in the F-^ and F2fl generations but not in F^q. 4. Rat6 fed 120-215 ppt TCDD to give 0.01 pg/Kg/day for 90 days prior to mating. 5. Rat6 dosed with 0.125 pg/Kg/day on days 6 to 15 of pregnancy by gavage. 6. Mice dosed subcutaneously with 3 pg/Kg/day of TCDD on days 6 through 15 of pregnancy. DSW 033366 STLCOPCB4017328 Table IV. (continued) 2 7. Monkeys dosed nine times by gavage on days 20 through 40 after Insemination. 8. Rats dosed day 6 through 15 of pregnancy by gavage. 9. Rats given a single dose by gavage at varying times during day 6 through 14 of pregnancy. 10. Mice were fed 1000 ppm Firemaster BP-6 days 7-18 of pregnancy. i DSW 033367 STLCOPCB4017329 1 Table V. PBB Concentrations Range (and mean) in Liver, Adipose Tissue and Liver Lesions of Rats given Single or Multiple Doses1- at Given Times Number Number of of Rats Doses x(mg/Kg) per Dose Recovery Sex Tissue (expressed PBB mg/Kg Period as wet weight for Concentration (Months) liver and on lipid (ppm) basis for adipose tissue) * Lipids 4 1 x 1000 10 M Liver Adipose tissue Blood 21.0 - 100 (GO.3) 434 - 920 (714) 0.55 - 1.35 (0.94) 5.60 - 9.90 (7.55) 74.2 - 88.2 (81.3) 5 1 x 1000 14 M. Liver Adipose tissue Blood 32.0 - 105 (63.2) 662-1170 (866) 1.20 - 1.42 (1.34) 3.60 - 11.6 (7.00) 80.8 - 86.6 (8.35) 4 3 x 1000 10 F Liver Adipose tissue Blood 27.5 - 58.7 (37.4) * 857 - 1802 (1202) 2.00 - 4.66 (2.90) 3.40 - 5.10 (4.10) 75.1 - 88.7 (83.5) 5 1 x 1000 14 F Liver Adipose tissue Blood 11.0 - 41.0 (22.0) 479 A 1264 (783) 1.64 - 3.63 (2.92) 3.20 - 4.10 (3.80) 81.5 - 92.2 (85.5) 12 1 x 1000 26 F Li ver 8.77 - 25.8 (18.1) 1.90 - 7.30 (4.54) 6 1 x 1000 26 F Hepatocellular carcinoma 8.99 - 22.3 05.3) 1.60 - 6.80 (4.23) 7 12 x 100 26 F Liver 23.8 - 74.5 (34.2) 2.53 - 4.38 (3.04) 5 1 x 200 22 F Liver Adipose Blood 1.85 - 4.07 (2.68) 136 - 441 (244) 0.17 - 0.31 (0.22) 0.92 - 2.66 (1.68) 87.4 - 91.7 (90.0) Footnote DSW 033368 >BB concentrations were >determined for a number of control rats each time with negative results in all. STLCOPCB4017330 REFERENCES 3. Allen, J.R., and Norback, D.H. (1973) Polychlorinated biphenyl - and triphenyl - induced gastric mucosal hyperplasia in primates. Science. 179, 498-499. 2. Alvares, A.P., Fischbein, A., Anderson, K.E., and Kappas, A. (1977) Alterations in drug metabolism in workers exposed to polychlorinated biphenyls. Clin. Pharmacol. Therap. 22, 140-148. 3. Aulerich, R.J. and Ringer, R.K. (1979) Toxic effects of dietary polybrominated biphenyls on mink. Arch. Environ. Contam. Toxicol. 8, 487-498. 4. Bahn, A.K., Mills, J.L., Snyder, P.J., Gann, P.H., Houten, L., Bialik, 0., llollmann, L., and Utiger, R.D. (1980) Hypothyroidism in workers exposed to polybrominated biphenyls. New Eng. J. Med. 302, 31-33. 3. Barsotti, I).A., Marlar, R.J., and Allen, J.R. (1976).Reproductive dysfunction in rhesus monkeys exposed to low levels of polychlorinated biphenyls. Food Cosmet. Toxicol. 14, 99-10.3. 6. Berry, D.L., Slaga, T.J., DiGiovanni, J., and Juchau, M.R. 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