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THE TOXICOLOGY OF PCS* An Overview with Emphasis on Human Health Effect! and Occupational Exposures Prepared by the Hazard Evaluation System Ipldiwlological Studies Section State of Calflorn la Department of Health Services/Department of Industrial Relations 2151 Berkeley Vay Berkeley, California 9*70* (915) 590-2115 January, 1981 HONS 010655 THE TOXICOLOGY Of POE'S Table ol Content* I. INTRODUCTION.......................................................................................1 II. GENERAL BACKGROUND INFORMATION........................................ 3 III. PHARMACOKINETICS........................................................................... 5 Absorption.......................................................................... 3 Distribution, Accumulation (Mammals)................................................... .3 Transplacental Exposure, Secretion in Milk ..............................................6 Metabolism............................. ..... ...............................................................7 IV. ANIMAL TOXICOLOGY........................................................................... 10 Acute......................................................... 10 Sub>acute, Chronic............................. ..... 11 Reproductive Effects................................................... 12 Other - Immunosuppresive, Endocrine........................................................14 V. CARCINOGENICITY/MUTAGENICrTY....................................................... 16 Carcinogenicity. .......................................................................................... 16 Test Results....................... ..... ?-- ....................... 16 Mutagenicity ......................................................... IS VI. BIOCHEMICAL EFFECTS........................................................................... 21 Enzyme Induction....................... ..... ......................................................... 21 Porphyria ..................................................................................................... 22 VII. HUMAN TOXICOLOGY AND EPIDEMIOLOGY...................................... 2* Dermatologic Effects .................................................................................... 2* Systemic Symptoms..................................................................................... Liver Damage......................................................... 25 Yusho................................................................................ 25 Neurotoxicity ................................................................................................27 Cancer............................................. ...... ................................................... 27 Ongoing Occupational Studies .... . ....................... 21 VIII. MEDICAL SURVEILLANCE ANDBIOLOGIC MONITORING ... 31 IX. SUMMARY AND CONCLUSIONS................................................................33 HONS 010656 i Table of Contents REFERENCES............................................................................................................34 Table 1.Dose-Response for Animal Toxicology............................................... 39 Table n. Occupational Exposure to PCBs......................................................40 Table 111. Percent Distribution of Symptomsof Yusho Reported by 149 Patients Examined Before October 3, 1944 ...... 44 Figure I.............................................................................................................. .45 Figure II..................... ................................................................... 46 Figure ni...................................................................................................................47 Figure IV...................................................................................................................46 HONS 010653 Li - L INTRODUCTION As a consequence of the EPAban on further manufacture of PCB's* in 1977, occtgjat ional exposures to these compounds have been 4-astically reduced. However, significant exposures may remain for particular occupational groups. Utility workers, for example, may experience sporadic but potentially massive exposures when cleaning up spills, or when servicing and dismantling transformers and capacitors that still contain PCB fluid. Electricians, appliance service workers and firefighters also may have continued occupational exposure. NIOSH estimates that 12,000 workers have potential exposure as a result of current uses of PCB's (NIOSH, 1977). Despite the vast scientific literature on the toxicology of PCB'S, the human health effects likely to result from such exposure remain ill-defined. The Hazard Evaluation System has reviewed the literature on PCB toxicology in response to inquiries about worker health. Requests for information have come from unions and workers who handle PCB fluids in dean-up of spills, in maintenance work, and in transportation, storage and disposal of used equipment. Toxicology information has also been requested by medical professionals evaluating the clinical significance of PCB exposures, and public health officials who are attempting to set standards for occupational and environmental exposures. Our primary goal has been to review the data relevant to the human health effects of PCB's especially those resulting from occupational exposires. Since the published epidemiologic evidence is limited we have utilized animal toxicology studies where appropriate in anticipating potential biologic effects in humans. We have not attempted to summarize the extensive literature on PCB toxicology, but the reader is referred to a number of recent reviews (DHEW, 197! IARC, 197*; Fishbein, 197*; Kimbrough, 1974; EPA, 1977; Nelson, 1972; NIOSH, MONS 0l065fl I- 1977), PCBs: Polychlorinated Biphenyls HONS 010659 2 0. GENERAL BACKGROUND INFORMATION In all animal species that have been studied PCB's have a very low acute toxicity. They are readily absorbed across biological membranes, poorly metabolised and only very slowly eliminated. Because PCB's persist In the environment and accumulate in living tissue, they are concentrated ("biomagnified") in the food chain in a similar manner to other organochlorine compounds like DDT. Concern about exposure to PCB's has, therefore, focused on their resistance to biodegradation with the consequent potential for long-term or delayed health effects. A number of published reports have established "background levels of PCB's In the blood and tissues of hunan populations with no previous history of exposure. Surveys in various geographical areas have found detectable residues in blood, fat and mothers' milk. Measurable levels of PCB's are typically found in greater than 70% of subjects tested with maximum blood levels generally less than 20 ppb (Finkiea, 1972). The levels reported lrom adipose tissue are typically somewhat higher, in the range of 1-2 ppm (Kutz, 1975). Residues of PCB's in human milk have ranged from 40-100 ppb in whole milk (New York State Health Council, 1977X Two facts complicate the documentation of the human and animal toxicology of PCB's: 1. Commercial products are rarely single agents, but rather are complex mixtures of chlorinated biphenyls with different numbers and arrangements of attached chlorine atoms (see Figure 1). The metabolism and toxicology of PCB's seem to vary with the percent of chlorination and with the isomeric structure of the pcb moiecuie. 2. All commercial products are potentially contaminated with chlori nated naphthalenes and polychlorinated dibenzofurarts (PCDFs). The degree of this contamination varies with different commercial mixtures (see Figure in). MONS 010660 3 Contamination by dlbenzofurans (PCDF's) is oi particular concern because of the structural similarity of these compounds to the highly toxic dibenzodioxins (see Figure II). The pattern of observed effects in animals exposed to PCDF's closely resembles that seen following exposure to 2,3,7,S tetrachlorodibenzodioxin (TCDD). In comparative animal studies the toxicity of PCDF's is much greater than the PCB's, particularly in the thymus, skin (acne), liver and hematopoetic system (Oishl et al., I97gj Moore et al., 1979). In addition, PCDPs are 1000 times more potent than PCB's as enzyme inducers (see Section VI). Uncertainties in the analytic methods used for detection of PCB's must be considered when reviewing the published data on PCB toxicology! Monitoring PCB's in environmental or biological samples by gas-liquid chromatography/mass spectrometry (GC/MS) is made difficult by the presence of other chlorinated hy^-ocarbons (eg., pesticides) which are commonly present at similar concentrations (Stalling et al., 1979). Because of the difficulties in the interpretation of GC/MS spectra, the PCB levels reported from different laboratories may show considerable variation. MONS 010061 6 UL PHARMACOKINETICS Absorption There is relatively little information on the rate or degree of absorption of PCB's by any route for any species of animal. Since similar systemic toxicity has been observed in rodents after dermal, oral and inhalational adminstration of comparable doses, it is likely that PCB's are easily absorbed by all routes. The few quantitative measurements of relative absorption rates indicate that most, if not all, PCB's whitti contain six or fewer dtlorine atoms are efficiently absorbed from the GI tract (Albro and Fishbein, 1972; Van Miller et ai., 1975). Distribution. Accumulation (Mammals) As with other heavily chlorinated chemicals the major storage tissue for PCB's is body fat. The concentration in adipose tissue is 10-1000 timet that found in other tissues, both following single oral doses (Grant et al., 1971) and after dtronic administration. (Curley et al., 1971) The lowest concentrations are found in whole blood and plasma where levels are usually several fold lower than in other tissues examined. This preferential distribution of PCB's into fat has been well documented after i.v. dosing in the rat (Lutz et al,, 1977). Results are consistent with the high distribution coefficient of PCB's in fat and low perfusion of adipose tissue compared to skin, liver, muscle and blood (Anderson et al., 1977). Two important pharmacokinetic questions cannot now be resolved on the basis of available data*. HONS 010662 5 1. Does the concentration of PCB's reach steady state with constant exposure? and 2. Will mobilization ol adipose tissue alter starvation or illness lead to a transient increase in PCB concentrations in blood and other tissues ? Like most heavily chlorinated hydrocarbons the hall-Ule ol PCB's in animal tissue is quite long. In a chronic feeding study with Aroclor 1245 at 100 ppm In the diet ol rats, a steady build-up of PCB's occurred in all tissues analyzed without a plateau level even alter 240 days of treatment. By comparison, in a similar rat dietary study using DDT, plateaus in fat were attained after 90-140 days (Curley et al., 1971). In dairy cows a steady state was reached in 40-60 days (Fries, 1972), probably due to mobilization into fat micelles and secretion into milk. Thus, PCBs are unlikely to reach steady state levels in non-iaetatlng animals; and fat mobilization or lactation may be expected to result in release of stored PCBs. Transplacental Exposure, Secretion in Milk Transplacental exposure of PCB's has been documented in mammals. Term fetuses taksi from rats exposed to 10 mg/kg/day during days 7-15 gestation contained 0.63 ppm PCB, or about 1/60 the maternal dose. Yhen the dose to the mother was increased five fold, the concentration in the fetuses increased two fold (Curley et al., 1973). The hyperpjgmented babies observed In the Yusho incident (see Section vil) represent additional circumstantial evidence ol transplacental passage of PCB's. Secretion of PCB's into milk has also been observed. In mice, little passage of PCB's occurred across the placenta once PCB's had been sequestered into maternal adipose tissue, but they were readily transferred to suckling offspring through the milk (Vodicnik and Lech, 1980). These observations suggest that secretion of PCB's into milk may be quantitatively much more important as a source of exposure In newborns than is MONS 010663 6 transplacental passage. This has recently been documented in a prospective study of Japenese mothers and their infants. (Hirokadzu and Ota, 19S0) Metabolism PCB's are metabolized primarily by hydroxylation and conjugation with glucuronic acid. The primary site of biotransfarmation Is assumed to be the liver, although no data is available currently on the possible role of peripheral metabolism, e.g., skin. Many experimental feeding studies In both mammals and birds have shown an inverse relationship between percent chlorination and rates of metabolism. Less chlorinated PCB's are more readily metabolized than are more chlorinated ones, the rate of metabolism and excretion decreasing sharply as the number of chlorine atoms increases above five (EPA, 1977). The metabolism of the higher chlorinated biphenyls is also dependent on the position of chlorine atom substitution. The presence of two adjacent, unsubstituted carbon atoms is needed for the rapid enzymatic hydroxylation reaction (Jensen and Sundstrom, 1979). Since the more highly chlorinated biphenyls have a very much slower metabolic rate and longer half-life, they are more generally found as residues in human and animal tissues. This relationship alters with PCB's above 59% chlorination, presumably as a result of lower absorption from the gastrointestinal tract. Arene oxide intermediates have been described in a major pathway of the metabolic transformation of PCB's by hepatic mixed function oxidases (Safe et al., 1975; Gardner et al., 1975). These intermediates are of particular concern since they are capable of direct interaction with DNA and may be the active form of carcinogenic polyacyclic hydrocarbons. (Jerina and Daly, 1979) The PCB molecules which are more readily metabolized and excreted also are more likely to form these arene oxides. It does not necessarily follow, however, that those compounds which persist In tissue and are more MONS 010669 7 likely to be measured In population sampling are less important in terms of their carcinogenic potential. From the limited data available, it appears that significant differences exist between non-human primates and rodents in the metabolism and pharmacokinetics of PCB's. The marked variation observed in PCB toxicity between rodents and primates may be explained by such differences. Primates appear to be more susceptible to the toxic effects of PCB's than are rats or mice (see Section IV and Figure IV). When single doses of radiolabeled PCB were administered by gastric intubation to infant monkeys, the metabolites measured in trine, tissue (liver) and serum included hydroxylation products derived from arene oxide intermediates (Allen et al., 1976); while in the rat, direct hydroxylation is the rule (Hsu et al., 1975). There is virtually no pharmacokinetic data in humans. A few generalizations can be made, however, based on studies reporting PCB blood levels: The higher the exposure levels, the higher blood concentration of PCB's (Hara et ad., 1975; lnoue et al., 1975; Karppanen and Lotho, 1973; Baker et al., I960); and the higher the environmental concentration and/or the longer the period of exposure, the longer the blood levels of PCB's remain elevated (Hara et al., 1975; Baker et al., I960). However, there are a lew reports which are inconsistent with this latter trend (Bumgarrer et al., 1975; Hasegawa et aL, 1972; Kitamura et aL, 1973). PCB levels have also been correlated with race and geographic residence (NIOSH, 1977) and with age and dietary intake of fish (Kimbrough, 1910) Comments Certain generalizations can be made from the limited pharmacokinetic data that is available: HONS 010665 I 1. Absorption occurs by all routes (skin, Gl, inhalation). 2. Distribution is primarily into fat. 3. Metabolism and excretion are dependent on specific molecular structure, varying inversely with percent chlorinatioa <*. Excretion is in general quite slow so that bio-accumulation occurs even at low exposure levels. 5. Transplacental transfer occurs but may be quantitatively leu significant than secretion into milk, 6. Arene oxide metabolites are found in the metabolic transformation of PCBs. There compounds are highly reactive and may represent the active car cinogens. (see Section V) 7. The relationship between percent chlorination and potency as carcinogen has not been established. S, There are essentially no pharmacokinetic data in humans; it is not taown, for example, if intermittent high doses are more or less hazardous than low level chronic exposures to the same total dos& HONS 01066b 9 IV. ANIMAL TOXICOLOGY Acute Toxicity When given u a jingle dose, the acute oral LDJQ of PCB's In rats, rabbits and mice ranges from 1-10 grams/kg of body weight According to the American Industrial Hygiene Association classification system for acute toxicity, PCB's are classified as "slightly toxic" (0.5 - 5 f/kg), or "practically non-toxic" (5-15 g/kg). There is some evidence that young animals are more sensitive than adults, and that females we more susceptible than males to the acute effects of PCB's (Kimbrough et al,, 1978). In rodents, the acute oral toxicity appears to decrease with increasing chlorine content of the administered PCB's. This may bar secondwy to decreased absorption of the higher chlorinated compounds or to the differences in metabolic transformation previously discussed. Although few clinical signs of toxicity have been reported In experimental animals, pathologic findings are extensively documented. CNS depression (decreased pain response and diminished exploratory behavior), anorexia and oliguria followed by ataxia, coma and death have been observed in rats following acute administration of large doses of PCB's (Brackner et al., 1975). Consistent pathologic findings associated with death in rats, rabbits and guinea pigs indude liver damage with fatty infiltration, centrolobulw atrophy, and in some cases necrosis. Pathologic changes in other organs in these species are not often described, except for chloracne-like lesions which occur at the site of skin or intradermal application. Comments The low order of acute toxidty in experimental animals is consistent with the lack HONS 010667 iO of acute effects observed in workers exposed to PCB's. Reported symptoms after occupational exposures include mild irritation of the skin and eyes at levels above 0.1 *1 mg/m with unbearable irritation occurring above 10 mg/m (ACG1H, 1976). Systemic symptoms of nausea and headache have been reported but may be secondary to the solvents (such as trichlorobenzene) in the PCB mixtures. Sub-acute and Chronic Toxicity In contrast to the low order of acute toxicity, effects from chronic exposures to relatively low doses of PCBs have been consistently observed end are of far greater concern. These sub-acute effects show appreciable variation among species, but liver damage is again the prominent finding. The major changes in rats fed Aroclor 1248, 1234, and 1262 at 100 ppm in their diet for six weeks included liver hypertrophy, marked fatty infiltration and degeneration of parenchymal cells. As in acute toxicity studies PCB mixtures with lower chlorine content were more toxic (Allen and Abrahamson, 1973). In 8-12 month feeding studies increased serum lipids and focal areas of liver damage were observed (Allen et al., 1976; Kimbrough et al., 1972). Non-human primates are more sensitive than rodents to the toxic effects of PCB's (see Table I and Figure IV). Adult female monkeys exposed to dietary levels of 2.5 ppm for 12 months (*0.08 mg/kg/day) developed facial edema, alopecia, acne, gastritis with ulceration, anemia, hypoproteinemia and bone marrow hypoplasia. At 100 ppm (10 mg/kg/day) there was considerably more evidence of tissue damage than in rats, including marked hepatic hypertrophy with ultrastruetural abnormalities (Alien, 1973). Based on extrapolation from the Yusho data, PCB's may cause symptoms to humans at levels (0.2 mg/kg/day) which are comparable to the lowest doses which produce effects in non-human primates (see Table l), HONS 010668 11 Most of the animal data are derived from feeding or oral Intubation studies. There are relatively few reports of dermal or inhalation experiments. Inhalation studies again revealed liver damage to be the prominent finding in rodents. For summary of inhalation data see the NIOSH criteria document, page 125 (NIOSH, 1977). Dermal toxicity studies in rabbits have produced skin lesions at the site of application as well as systemic effects including liver and kidney damage, thymic atrophy, lymphopenia and increased fecal porphyrins (Vos and Beems, 1971). Comments Liver damage, documented histologically, is the consistent finding among various laboratory animals exposed to low dironic levels of PCB's. It has not been observed in the limited surveys of exposed workers. This may be an artifact, however, of the relative insensitivity of the standard liver function tests (such as serum levels of SCOT, SGPT) as compared to biopsy and histologic analysis. Reproductive Effects Adverse reproductive effects of PCB's have been noted in many mammalian and avian species. The pattern of reproductive effects include alterations In estrus cycles, failure of implantation, increased frequency of spontaneous abortions, low birth weight offspring and decreased post-natal survival. No specific teratogenic effects of PCB's have been observed in a variety of avian species. Transplacental effects, however, have been documented in both animals and humans (see Section VU). PCB's given to mice for 10 weeks at dosage of 1.0 mg/kg/day lengthened the estrus cycle by more than two days and decreased the number of successfully implanted ova (Orberg and Kihlstrom, 1973). Similarly, mice that received PCB's as sucklings in a HONS 010669 12 long-term transgenerational study showed subsequent alterations in estrus cycles, decrease in implantations, and when mated to each other (FI studies), reduced number of offspring per litter (Kihlstrom et al.r 1975), In rats, studies suggest that reproductive effects of PCB's decrease as chlorination increases. No reproductive effects have been found with Arodor 1260 (60 percent chlorination) at 1, 10, 100 ppm, but significant effects have been noted with Arodor 1242 and 1254 (42 and 54 percent chlorination, respectively) at doses of 20 and 100 ppm. Arodor 1260 began to exert toxic effects at doses of 500 ppm. Rats chronically fed from 20 to 100 ppm Arodor 1242 and 1254 had reduced numbers of offspring. Surviving newborns showed increased mortality, with only 30 percent surviving to weaning. Five ppm of either Arodor 1242 or 1254 produced no effects over two generations. Thus, the minimum effective doses ranged from 20 ppm for the lower chlorination mixtures to 100-500 ppm of the more highly chlorinated compounds. (Keplinger et al., 1971; Linder, et al., 1974) Evidence of adverse reproductive effects is also available for non-human primates. Rhesus monkeys fed 2.5 and 5.0 ppm Arodor 1248 for 18 months in the diet showed changes in menstrual cycles in addition to other systemic signs of toxidty. Evidence was also obtained for frequent resorptions and spontaneous abortions following breeding to normal males. In all, six infants were carried successfully to term out of 14 pregnancies. The offspring were of low birth weight and by two months began to show evidence of PCB toxidty, presumably from PCB's in the maternal milk; only three infants survived to six months. Behavioral tests in the three surviving animals showed marked deficits in several learning tasks, with increasing errors correlated with increasing body burdens of PCB's (Allen and Barsotti, 1976; Bowman et al., 1978; Barsotti et al., 1976). HONS 010670 13 The effect of PCB's on the male reproductive system is not known. There is one report of four male Rhesus monkeys exposed to 5.0 ppm Aroclor 1248 In the diet for 18 months. After 12 months, one of four animals developed clinical signs of PCB intoxication, showed marked sperm count depression and was functionally sterile. A testicular biopsy revealed an absence of spermatogonia. A second biopsy one year after exposure showed complete recovery (Allen et al., 1979). PCB's are negative in the mouse sperm morphology assay (Heddle and Bruce, 1977). Comments PCB's show significant effects on reproductive competence In a variety of species. These effects increase in intensity with increasing dosage and decrease with increasing chlorination of the PCB isomers. PCB's do not appear to be mammalian teratogens. A reasonable explanation for most of the reproductive effects of PCB's could be based on their estrogenic activity (see below). PCB's have been detected in human semen (Dougherty et al., 1980), but there have been no studies of semen quality in relation to PCB exposure in humans. The effects of PCBs on the male reproductive system in animals or humans has not been ade<jately studied. The only other evidence to date on reproductive toxicity in humans come from the Yusho incident and is summarized in Section VII. Other 1. Immunosuppressive Effects A number of reports implicate PCB's as immunosuppressants (Fishbein, 1974). Lymphoid atrophy has been observed in rabbits, chickens and guinea pigs. Suppression of humoral immune responses to several antigens was observed in rabbits and guinea pigs, and decreased cell-mediated immune response HONS 010671 14 followed PCB exposure in guinea pigs. A decreased tolerance to hepatitis virus was seen in ducklings without apparent intoxication. In monkeys exposed traru pi seen tally and through contaminated milk, the lymph nodules of the spleen were extremely small and without germinal centers (Allen and Barsotti. 1976); morphologic changes were indicative of reduced Immunologic compe tence. 2. Endocrine Effects Subcutaneous administration of Aroclor compounds with lower chlorination produced an estrogenic effect on the rat uterus which was not shown with Aroclors of higher chlorination (Bitman and Ceal, 1970). Female primates fed Aroclor 1241 for six months showed an increase In concentration of urinary ketosteroidi and a prolongation of their menstrual cycles with increased bleeding (Barsotti et al., 1976). Antiandrogenic effects have been described in birds although the mechanism is not clear. It may be secondary to an increased rate of androgen metabolism in the liver by induction of microsomal enzymes (see Section VI), or by virtue of PCB's exerting estrogenic effects. Comments The effect of PCB exposure on immune and endocrine system function has not been carefully studied in humans, so the relevance of these animal observations to human health remains inknown. There is one cross-sectional study of occupational exposure to PCB's which will include analysis of serum hormone levels and urinary metabolites, but results have not yet been published (Selikoff et al., in progress). MOMS 0106 72. 15 V. CARC3NOGEN1CITY/MUTAGENICITY Cardnogenidty Several PCB mixtures ere dearly cardnogenic in rodent bioassays, producing liver tisriors (hepatocellular cardnomasl Kanechlor 500 and Arodor 1254 are cardnogenic in male mice (Ito et al., 1973; Kimbrough and Linder, 1974); and Arodor 1260 is cardnogenic in separate studies in two strain* of female rats (Kimbrough et al., 1975; Norback et aJ., 19&0). In addition, a purified component of a PCB mixture, 2,4,5,2*,4',5' -hexachlorobiphenyl, has recently been found to be cardnogenic in female rats, causing hepatocellular car doomas (Norback et al., 19S0). Because high doses of PCB's are known to cause extensive injury to liver tissue it is important to consider the dose levels at which liver card nomas were produced in the rodent bioassays. In two studies in rats, significant increases in hepatocellular carcinomas were present at doses which did not produce gross histologic changes. Hepatocytes were somewhat enlarged (probably due to microsomal enzyme induction), but no extensive fatty infiltration or necrosis occurred, as was characteristic of bioassays at higher dose levels (Kimbrough et al., 1975). Test Results 1. Mice (Male) A. Kanechlor 300, 400, and 500 fed to groups of 12 eight-week-old male mice at 100, 250, and 500 ppm in the diet for 32 weeks produced hepatocellular car doomas in 5 of 12 survivors in the high dose group fed Kanechlor 500. The remaining 7 mice in this group had noduiar HONS 010673 16 hyperplasia (neoplastic nodules). No metastases or other tumors were present in this or other dosed groups. The control group (6 mice) was likewise tvsnor-free (Ito et al., 1971). B. Arodor 1274 administered to groups of 50 five to six-week-old male BALBc/3 mice at dietary levels of 0 or 300 ppm (about 50 mg/kg body weight during the exposure) for 11 months produced neoplastic nodules (hepatomas or hyperplastic nodules) in 9 of 22 survivors In the dosed group. Other liver lesions (adenofibrosis) were present in all 22 survivors. Additional morphological changes In the livers of these animals included pleomorphism and areas of necrosis. Such changes and tumors were absent among survivors (24) in the control group (Kimbrough and Linder, 1974). A. Kanechlor 400 administered to ten-week-old Donryu rats (10 males and 10 females) at dietary levels which varied from *0-600 ppm during the 400-day study produced liver tumors (multiple adenomatous nodules) in 6/10 treated female rats. Such lesions were absent from the controls (5 males and 5 females) and the treated males (Kimura and Baba, 1973). B. Kanechlor 300, 400, or 500 administered to groups of 30 eight-week-old male Wistar rats at dietary levels of 0, 100, 500, or 1000 ppm produced increases in the incidence of cholangiofibrosis at the highest dose level of all Kanechlors (2/15, 2/10, and 4/13, respectively). All three compounds also produced hepatic nodular hyperplasia, the incidence of which increased with dose and extent of chlorination (Kanechlor 300 at 100 ppm: 1/22; Kanechlor 400 at 100 ppm: 2/16, and 1000 ppm: 3/10; Kanechlor 500 st 100 ppm: 3/25, st 500 ppm: 5/16, and at 1000 ppm: 5/13>, (Ito et al., 1974). HONS 010674 17 C. Aroclor 1260 administered to groups of 200 three to four-week-old female Sherman rats at 0 and 100 ppm in the diet (varying between 5-10 mg/kg body weight during the 2J month exposure) produced at 23 months among the dosed survivors clearly significant increases of hepatocellular carcinomas (controls 0/173; dosed group 164/186) as well as neoplastic noAiles (hyperplastic nodules: controls 0/173; dosed group 26/186). The incidences of non-hepatic tumors did not differ between the dosed and control groups (Kimbrough et at., 1975). O. Aroclor 1256 administered to groups of 26 eight-week-old Fisher 366 rats of either sex at dietary levels of 0, 23, 50, or 100 ppm for 105 weeks was not carcinogenic to any of the treated groups under the test conditions. It is important to note that two of the dose levels used were lower than those which produced a positive response in Sherman rats. Rare adenocarcinomas and carcinomas of the gastrointestinal tract appeared in both sexes and may be related to the administration of the PCBs (males: historical controls 6/600, dosed group 2/26). In addition a high incidence of non-neoplastlc liver hyperplasia was present among the dosed groups (males: controls 0/26, low-dose 5/26, mid-dose 8/26, high-dose 12/26; females: controls 0/23, low-dose 6/26, mid-dose 9/22, and high-dose 17/26); (NCI 1978). E. Aroclor 1260 administered to groups of 50 male and female SpragueDawley rats at dietary levels of 0 and 100 ppm for 103 weeks was carcinogenic in female rats, causing significant increases in liver hepatocellular carcinomas (Norback and Veltman, 1980). HONS 010675 18 -#V F. A purified component of a PCB mixture, 2,4,3,2\*,,5-hexachlorobiphenyJ administered to groups of 50 mate and female Sprague Dawley rats at dietary levels of 0 and 100 ppm far 105 weeks was carcinogenic in female rats, producing an increased incidence of liver hepatocellular carcinomas among tha dosed animals (Norbeck and Weltman, 19S0). Mutagenicity PCB mixtures have not been observed to have mutagenic activity nor to measurably affect chromosomes In repeated studies using a variety of in vitro or in vivo test systems Evidence of genetic damage from PCB's in laboratory test systems including chromosomal aberrations, non-djsjwction, loss of sex chromosomes or increased frequency of sister chromatid exdvange has not been observed. Report of a weak effect of Aroclor 1221 and of a stronger effect of O-chlorobiphenyl in Salmonella using PCB-induced rabbit liver homogenate as a liver activation system appears unfounded (Wyndham et al., 1976). Further attempts to repeat these results have been unsuccessful using a variety of Salmonella tester strains and liver activation systems (Katzenellenbogan and Ames, 19$0; Sale, 197S). However, PCB's belong to the dass of heavily chlorinated animal carcinogens, most of which are not positive In short-term tests for mutagenicity. Examples in this class include dieldrin, chlordane, kepone, mirex, TCDO,* chloroform^and carbon tetrachloride. Whether this is because the In vitro metabolic activation systems do not produce the same spectrum of metabolites that occur in vivo or because heavily chlorinated compounds such as PCB's are carcinogenic by non-mutagenic mechanisms is not known at this time. TCDD: Tetrachlorodibenzodioxin 19 HONS 010676 Validation ol the carcinogenic effects in rodents is provided by a positive cell transformation assay using C3H10TI/2 clone eight mouse fibroblast ceils in culture by two separate PCB mixtures (Aroclor 1254 and 1260) and a purified component 2,4,5,2\4'5' -hexachlorobiphe-iyl (Norbaek and Weltmtn, 1910), Comments A wide variety of PCB mixtures have been subjected to rodent cancer bioassays and to numerous in vitro and In vivo short-term tests for mutagenicity. Several of these PCB mixtures are carcinogenic. None of the PCB mixtures are active in short-term tests for mutagenicity, a finding that holds true far most heavily chlorinated carcinogens. However, substantial confirming evidence lor carcinogenicity is provided by positive cell transformation assays using these same PCB mixtures. Thus, under OSHA published ft criteria, PCB mixtures should be considered Category I carcinogens. Both 1ARC (1ARC, 197S) and EPA (EPA, 1971) have concluded that based on available animal data PCB's should be considered as potential human carcinogens. Category 1: Human evidence or two positive mammalian bioassays or 1 positive mammalian bioassay with sia>porting results in short term tests. Category lb One positive mammalian bloassay. (Source: Occupational Health and Safety Letter Vol. 9, No. 24 November S, 1979) HONS 010677 20 VL BIOCHEMICAL EFFECTS OF PCB'S Enzyme Induction The principal biochemical effect of PCB's is the stimulatioa_and induction of certain enzyme systems. Enzyme induction occurs in both the microsomal monooxygenase or cytochrome P-430 system and the aryl hydrocarbon hydroxylase or cytochrome P-448 system, and it has been observed in both man and experimental animals. Induction is not restricted to the liver. It occurs in numerous other organs including kidney, adrenal, lung, gut, skin, and testes. Fetal enzyme induction may occur via transplacental exposire, and induction may also occur by exposure to contaminated milk, (ref) Identification of structure-activity relationships for enzyme Induction Is difficult because of the large number of isomers in commercially prepared PCB's and because all commercial products contain trace amounts of polychlorinated dibenzofurans (PCDF's) which are orders of magnitude more potent as enzyme inducers than PCB's. (ref) In early studies using commercial Aroclors, potency for enzyme induction was found to be dependent on chlorination of the PCB mixture. Later, when purified isomer* were tested, potency was found to vary with the position of chlorine atom substitution (see Section ni). (ref) Since rate of metabolism is also known to vary with isomeric configuration of the PCB molecule, it may be that potency for enzyme induction is simply a function of the relative rate of metabolism and excretion. The enzyme induction properties of PCB's are utilized in the metabolic activation system of in vitro bioassays for mutagenicity. It is unlikely, however, that enzyme HONS 010678 21 induction would consistently enhance the effects of carcinogens or pro-carcinogens: It might function synergisticaily to activate a chemical, but they also might function to deactivate reactive carcinogens. Both phenomena have been observed in rodent cancer biaassays. Porphyria Porphyria cutanea tarda (PCT> in humans is an acquired defect in hepatic porphyrin metabolism characterized by uroporphorinuria, photosensitivity and mechanical fragility of the skin. PCT can be produced experimentally by a number of drugs, including tetrachlorodibenzodioxins and PCB's. Ail of these agents have the ability to stimulate the activity of 2-aminolevulinic acid (ALA) synthetase which is the initial enzyme in the heme synthetic pathway. Experimental hepatic porphyria was observed in Sherman rats exposed to Aroclor 1276 in the diet. At doses of 100 ppm the animals became porphyric after a delay of approximately 2-6 months. The porphyria resembled hexaehlorobenzene poisoning and human PCT (Goldstein et al., 1977). In chronic feeding studies ALA-synthatase induction occurs after rats have become porphyric, although with large single doses the enzyme induction is seen almost immediately alter dosing the animals (Goldstein et al,, 1977). It has not been established whether only certain isomers in the PCB mixtures or contamination with PCDFs is responsible for the production of hepatic PCT. Porphyria has not been reported in humans exposed to PCB's. Comments Enzyme induction has two important implications for human health 22 HONS 010679 1. The occurrence of disease secondary to the increased metabolism of endogenous or exogenous substances, and 2. The interference with medical therapy due to increased metabolism of administered drugs. PCB's are more potent enzyme inducers than phenobarbetal, a drug that occasionally causes clinical problems due to its enzyme inducing effects. While the effects of phenobarbetal decline after administration ceases, enzyme induction from PCB's persists tong after cessation of exposure. HONS 010680 23 VIL HUMAN TOXICOLOGY AND EPIDEMIOLOGY Few good epidemiologic studies of the health effects of PCB's ere available. Most studies reported in the literat txe have been characterized by one or more of the following shortcomings: 1. Small study populations. 2. Lack of accurate exposure data. 3. Simultaneous exposure of workers to other potentially harmful chemicals. 4. Lack of control for confounding variables, such as alcohol consimption, 5. Inability to separate PCB's from contaminants and/or (fifficulty in comparing PCB's manufacture by different firms. In spite of these problems, some health effects have been consistently reported in studies ol workers occupationally exposed to PCB's. In addition, a large-scale poisoning which resulted from ingestion of PCB-contaminated rice oil has been well documented and resulted in multiple signs and symptoms attributable to PCB's. The health effects identified in a review of the epidemiologic literature are summarized below, and Table Q briefly describes the major epidemiological studies from 1934 through 1980. Dermatologic Changes Chi oracne, contact or allergic dermatitis, and brown chromodermatosis have been consistently reported in studies of workers exposed to PCB's (Kara et al., 1975; Hasegawa et al., 1972; tnoue et al., 1975; Kitamura et al., 1973; Baker et al., 1980; Meigs et al., 1934; Ouw et al., 1976; Schwartz, 1936). HOMS 010681 24 Systemic Symptom* Nausea, digestive disturbances, headaches, upper respiratory problems, and persistent body odor have been reported as a result of occupational exposures (Ouw et al,, 1976; Schwartz, 1936; Warshaw et al., 1979). Liver Damage This effect has been reported in some studies (Hasegawa et al., 1972; Higuchi, 1976; Meigs et al., 1939; Ouw et al., 1976). However, some investigators reporting abnormal liver function tests did not control for additional chemical exposures, previous medical problems, drinking patterns, etc. These confounding variables could explain some or all of the marginal differences encountered. Yusho (3apenese word translated as "oil disease") Both dermal and systemic health effects are well documented in the epidemiologic study of a poisoning epidemic in 3apan caused by Ingestion of contaminated rice oil in 1968 (Higuchi, 1976; Kiratsixie et al., 1972) It is not clear how much the health effects observed in Y usho victims can be extrapolated to occupational exposures tor the following reasons: 1. The average amount of PCB (Kanechlor 900) ingested was estimated to be 2 grams and the minimum, 0.3 gram (Kiratsuie et al., 1972). This is a higher dose than has been reported in most occupational exposures. In addition, the PCB's were ingested as opposed to inhaled or skin-absorbed as is the case with occupational exposures. 2. The contaminated oil contained "used" Kanechlor 900, the exact chemical compositon of which is isiknown X Frying of foods with the rice oil could have produced new compounds which may have altered the toxidty of the PCB's or the toxidty of possible contaminants. HONS 0106*2 23 6. Yusho oil was shown to contain high concentrations ol dibenzofurans. 5. Reported concentration of PCB's in the oil may not have been accurate enough to permit a rigorous quantitative analysis since the methods for estimating PCB's in foods were not fully developed at the time. Clinical features of the Yusho patients are listed in Table III. The Yusho incident is also important because it clearly documents the potential for reproductive and transplacental effects in humans: A study was made of the thirteen infants of 11 mothers affected by Yusho and of 2 unaffected wives of patients: Two of the Yusho mothers had stillbirths; ten of the babies had transient greyish or dark-brown pigmentation of the skin, and 3 had similar pigmentation of the gingiva and/or nails; increased ocular discharge was present in 9; and 12 of the 13 infants were small when compared with the national average (Funatsu et al., 1972; Kikuchi et alM 1969; Kuratsune, 1976; Taki et al.f 1969). Babies born to patients even 3 years after severe PCB exposure tended to show pigmentation of the skin on the back and the gingiva, although the degree of pigmentation was less than that of babies born to the same mothers up to one year after the poisoning (Kuratsune, 1976). Congenital abnormalities have also been observed in PCB-intoxicated infants. In the population of 13 offspring of Yusho mothers, premature eruption of teeth was observed in 2 cases, and larger than normal frontal and occipital fontanelles, exophthalmos and the persistence of an abnormally wide sagittal suture were observed in 3 others. No other gross maUormations were reported nor was any relationship between dose and outcome considered. (Funtasu et al., 1972). HONS 010663 26 Mothers' milk contaminated with PCB's also appears to be a source of exposure for infants: one baby showed signs of poisoning even though the mother had ingested the contaminated rice oil only after the baby was delivered. The infant began to show jigns of PCB intoxication after 3-4 months of breast feeding (Kuratsune, 1972; Yoshimura, 1974), Neurotoxicity Paresthesias were reported In over 30% of Yusho patients (see Table 111). In tha Yusho epidemic more detailed neurologic examinations were performed in 21 cases admitted to a University hospital in northern Tapan. Ten of the patients complained of numbness or pain in the distal extremities, and in five cases decreased pain, touch and temperature sensation was observed. Sensory conduction velocity in sural and radial nerves was below normal in 6 of 10 individuals with neuropathic symptoms (Murai and Kuroiwa, 1971). Headache and peripheral nervous system symptoms were alto reported in a poisoning episode which occurred in a Finnish paper company (Hakklnen et al., 1973), A decrease in amplitude of muscle action potential evoked by nerve stimulation, and a decrease in sciatic nerve conduction velocity has been reported in rats intoxicated with tetrachlorobiphenyl. Thus, PCB's can affect peripheral nerve function in both humans and experimental animals, but these have been reported only at doses which cause other systemic signs of poisoning. Cancer There is too little epidemiological evidence available yet to evaluate the potential of PCB's as human carcinogens (Bahn et aiM 1980; Brown and 3ones, 1980). A follow-up of the Yusho patients through 1977 has reported 31 deaths (31 with cause of death MON5 010604 27 confirmed) of the 1665 identified victims. There were 11 deaths from neoplasms, or 35.4% of the total. While this rate is higher than the 21.1% in the population of the same prefecture in 1977, these data were not age-adjusted. No particular site was elevated, and there were no deaths from malignant melanoma, a tumor previously suspected to be linked to PCB exposure (Bahn et al., 1976). Two liver cancers and two ling cancers were reported but smoking and drinking patterns were not available (Urabe et al., 1979). A retrospective cohort mortality study of 2,567 workers in two capacitor manufacturing plants was recently completed by NIOSH. The reports, still in draft form, did not find any statistically significant excess mortality for any cause of death among the exposed workers. Deaths from liver cancer, cirrhosis of the liver, and rectal cancer were slightly higher than expected, but no information was available on medical histories, drinking patterns, etc No correlation was observed between increased mortality and length of exposure, but the number of total deaths was small (165). NIOSH will continue to follow up the mortality experience of the cohort (Brown and Jones, I960). Ongoing Occupational Studies Two additional cohort mortality studies are currently underway. The first is a mortality survey of the entire workdorce employed between 1952-1957 at the largest U.5. facility that manufactired capacitors and transformers. There is detailed information available on exposure levels in the plant. While the duration from onset of exposure is shorter than optimal (only 25 years in some cases), the information will at least give data on the short-term mortality experience of a heavily exposed occupational group (Selikoff et al., in progress). HONS 010685 28 The second is a similar occupational mortality study, also of workers exposed in capacitor and transformer manufacturing. Over 2,000 workers have been identified for this study but no further details are yet available (Bertazzi et al., in progress). One case control study is currently being conducted to assess whether there is excess risk of malignant melanoma among PCB-exposed workers. This data will not be available until March, 1911 (Bahn et al* 1976). There is also one cross-sectional clinical field survey of 326 capacitor manufacturing wcrkers at two sites, encompassing a total workforce of 800 (Fischbein et al., 1979). Exposures were classified as none, low, medium, and high based on job description at the time of the survey (1975). Researchers were able to identify the PCB's used and had some data on environmental air levels in the plants. A number of parameters were measured, including complete history and physical exams, SMA panels and pulmonary function tests. Results have been published on respiratory function and general signs/symptoms, and results of serum lipids, endocrine function and dermatologic findings are forthcoming. To date, the only positive association involves dermatologic signs and symptoms. Further investigations of the effects of PCB exposure on serum lipids have been done in both occig>ationai and general environmental exposure settings. Smith et al., (1978), reported some statistically significant differences between exposed and non-exposed workers at two sites. They reported higher serum triglycerides and lower levels of high density lipo-protelns in the exposed group. Whether the magnitude of the difference is biologically significant is not dear from this study. For example, the ron-exposed group at site #1 compared to the ron-exposed group at site #2 showed a greater difference than the exposed and ron-exposed comparison at either site. In another MOMS 010686 29 study (Baker et al.f 1910) workers and community residents with exposvre to fertilizer made from sewage sludge contaminated with PCB's were studied. Plasma triglyceride levels were found to increase significantly with serum PCS concentration (both in drinkers and noivdrinkers), and the authors concluded that PCB's may alter lipid metabolism at levels of exposure and bio-accumulation insufficient to produce other identifiable signs of toxicity. Comments Although many problems have been identified in the studies evaluating the health effects of PCB's, it is clear that occupational exposure, at a minimum, can produce dermatologic effects. The long half-life of PCB's and their bio-accumulation in various human tissues leaves open the possibility of substantial chronic and delayed eflects analogous to those seen in animal bioassays. These effects have only recently begun to be studied in a rigorous manner, and although the epidemiological evidence is neither complete nor entirely consistent there can be no question of the necessity to protect the worker from exposure. HOMS 010687 30 VUL MEDICAL SURVEILLANCE AND BIOLOGIC MONITORING Medical surveillance and biologic monitoring are of limited usefulness in predicting health hazards if dose-response relationships are not known This certainly is the case with PCB's. Based on animal toxicology, there are many suspected adverse effects of PCB's which might result from exposure in occupational settings, but very few have been documented well enough to give even rough estimates of "no-effect" or "safe" levels. A large percentage of non-occupationally exposed people have detectable PCB levels in body fat, blood and milk. However, any attempt to estimate an adverse health effect associated with increases above this background level necessarily involves extrapolation from animal data and therefore is subject to considerable error, especially when the marked variation in sensitivity of various animal species is appreciated. Firthermore, not enough is known regarding the relative dose-response characteristics of the various documented effects (e.g., liver damage, sldn changes) to state that in the absence of a particular sign, symptom or laboratory abnormality, the risk of long-term effect (cancer, reproductive toxicity) will be negligible (see Table 1). For the clinician confronted with a worker who has a history of exposure to PCB's the approach to management cannot be easily outlined Given the current analytic methodology, residues can be measured in blood or tissue in the ppb range and compared to background; but assigning a health risk to a given level is virtually impossible, especially given the tack of pharmacokinetic data. Often patients are being evaluated after a considerable lag period (years) since last exposure occurred and extrapolation to peak blood levels is not possible. In fact, it may be that residue levels bear little relationship to the health risk. For example, the tower chlorinated compounds may be more toxic but they art more rapidly metabolized and excreted and therefore less MOWS 010068 31 likely to persist in blood or fat. Further, with the possible exception of chloracne, the presence of specific signs, symptoms or laboratory abnormalities is very difficult to definitely relate to PCB exposure in any given patient. ... Given these uncertainties and the potential for serious health effects, the approach to monitoring should emphasize environmental sampling and every attempt should be made to minimize exposure by engineering controls or personal protective measures in those settings where occupational exposure still occurs (e.g., utility repair workers). Biologic monitoring may be used to assess the effectiveness of environmental control, but it is really best utilized within a specific researdt protocol and probably has little value in the routine work-up ol individual patients. HONS 010689 32 SUMMARY AND CONCLUSIONS PCB's have low acute toxicity but are of public health concern because of their persistence in the environment and in human tissues and their demonstrated potential lor chronic or delayed toxicity. They are potent inhibitors of reproductive function in both rodents and non-human primates and are positive in animal cancer bioassays. As potent inducers of hepatic enzyme systems, PCB's may have additional unpredictable long-term health effects. Some of the conflicting reports in the toxicology literature are undoubtedly related to the variable composition and trace dtemical contamination of the tested mixtures. Occupational and environmental exposure is usually to those mixtures; but if we are to accurately assess the associated health hazards, further animal studies are needed which carefully define the toxicology of the individual agents. Epidemiologic studies of occupational exposures to PCB's to date have failed to detect serious adverse effects but are considered insufficient, and further studies are dearly needed. Of particular interest is the continued exposure among utility workers. Because of the potential ability to cause cancer and other long-term adverse eflects such as infertility and hepatic injury, human exposure to PCB's should be kept to the lowest level technically possible. The persistence of PCB's in the body and the irreversibility of some of Its effects make It necessary to act now, rather than to wait until more definitive data are available. MQNS 010090 33 REFERENCES A.C.G.l.H. Chlorodiphmyl - 42% chlorine. Documentation of the TLV's for substances in Workroom Air. 3rd ed., pp51-Z. Cincinnati, 1976. Albro, PW and Fishbein, L. Intestinal absorption of PCB's in Rats. Bull Environ Contam Toxicol 8:26, 1972. Allen, JR. and Abrahamson, L3. Morphologic and biochemical changes in the liver of rats fed PCB's. Arch Environ Contam Toxicol h265, 1973. Allen, JR Response of the non-human primate to PCB exposure. Fed Proc 34j 1675, 1975. Allen, JR and Barsottl, DA. The effects of transplacental and mammary movement of PCB's on infant rhesus monkeys. Toxicol 6:331, 1976. Allen, JR et al. Response of rats exposed to PCB's for 53 weeks. Arch Environ Toxicol 4:404, 1976. Allen, JR et al. Reproductive effects of halogenated aromatic hydrocarbons on non-human primates. Ann NYAS 320:419, 1979. Anderson, MW et al. The construction of a pharmacokinetic model for the disposition of PCB's in the rat. Clin Pharm Therap 22: 765, 1977. Bahn. AK et al. Melanoma after exposure to PCB's (letter to the editor) N Engl J Med 295: 435T1976. Baker, E et al. Metabolic consequences of exposure to polychlorinated biphenyls (PCB) in sewage sludge. Amer J Epidem 112: 553, I960. Barsotti, DA et al. Reproductive dysfunction in rhesus monkeys exposed to low levels of PCB's (Aroclor 1246) Food Cosmet Toxicol 2*: 99, 1976. Bertazzi, PA et al. Mortality experience among PCB workers. Univ di Milano, Inst Occ Health, Milan, Italy, In progress. Bitman, J and Ceal, HC. Estrogenic activity of DDT analogs and PCBs. J Ag Food Chem JJh 1108, 1970. Bowman, R et al. Correlation of PCB body burden with behavioral toxicology in monkeys. Pharmocoi Biochem Behav 9: 49-56, 1978. Brackner, JV et al. Biologic response of the rat to PCB's. Tox Appl Pharm 24: 434, 1973. Goldstein, JA et al. A cooperative study of two PCB mixtures on induction of hepatic porphyria and drug aetabollslng entynee. Tox Appl Fhana 32:461, 1975. HONS 010691 34 Brown, DP and 3ones, M. Mortality and industrial hygiene study ol workers exposed to polychlorinated biphenyls. Dralt report, NIOSH Division ol Surveillance, Hazard Evaluation and Field Studies 1980. Bumgarner. 3E et al. Polychlorinated biphenyl residues in reluse workers. National Institute of Environmental Health Sciences (as reported in NIOSH Criteria Document), i 973. Burse, VW et al. PCB's-storage, distribution, excretion and recovery: Liver morphology alter prolonged dietary ingestion. Arch Environ Health 29: 301, 197*. Curley, A et al. PCBs - Distribution and Storage in body fluids and tissues of Sherman rats. Environ Res 4s 481 1971. Curley, A et al. PCB's evidence of transplacental passage in the Sherman rat. Food Cosm Toxicol J_l: 471, 1973. DHEY: Subcommittee on health effects of PCB's and PBB's series of articles appearing in Env Health Persp 24: 146-198, 1978. Dougherty, RC et al. Sperm density and toxic substances: A potential key to environmental health hazard, submitted to Env Health Chem, 1980. EPA: Halogenated polyaromatics, in: L Fishbein, Potential industrial carcinogens and mutagens, pub #560/5-77-003, Office of Toxic Substances EPA, Washington, DC pp 173-197, 1977. Finklea, 3 et al. PCB residues in human plasma expose a major urban pollution problem. Amer 3 Public Health 62: 645,1972. Fishbein, A et al. Clinical findings among PCB-exposed capacitor manufacturing workers. AniTFiTAS 320: 203, 1979. Fries, GF. PCB residues in milk of environmentally and experimentally contaminated cows. Env Health Persp. U 55, April 1972. Funatsu, 1 et al. Polychlorobiphenyls (PCB) induced letopathy. 1 Clinical observation (Abstract No. 72-2360). Kurume Med 3 J9t 43-51. Gardner, AM et al. PCB's Hydroxylated trlnary metabolites of 2,5,2',5'-tetrachlorobipheny) identified in rabbits. Biochem Biophys Res Comm 35: 1377, 1973. Grant, DL et ai. Metabolism of a PCB (Aroclor 1254) mixture in the rat. Bull Environ Contam Tox 6:102, 1971. *(Gold*tln, JA et *1. bottow p. 34) Hakkinen, 3 et al. Diphenyl poisoning in fruit paper production. Arch Environ Health 26: 70, 1973. Hara, 1 et al. Follow-up study of condenser factory after use of PCB discontinued. (As reported NIOSH Criteria Document) 3pn 3 Ind Health ^7: 371-372, 1973. Hasegawa, H et al. Report on survey of work area stvironment where PCB is handled and of the health ol workers handling PCB, in Special research report on prevention of environmental pollution by PCB-like. substances. (As reported in NIOSH Criteria Document) 3apan, Research Coordination Bureau, Science and Technology Agency, pp. 141-99, 1972. MOWS 010692 33 Heddle, 3A and Bruce, WR. Comparison of tests lor mutagenicity or carcinogenicity using assays for sperm abnormalities, formation of micronuclei and mutations in Salmonella. In, Origins of Human Cancer, Cold Spring Harbor Lab., pp 15*9, 1975. Higuchi, K ed. PCB poisoning and pollution. Academic Press, NY 1976. Hirokdru, O and Ota, H. Transfer of PCBs to infants from their mothers. Arch Environ Health 35: (2) 95, 19S0. Hsu, IC et al. Metabolic fate if ^H2,5,2\5'-tetrachlcrobiphenyl in infant non-human primates. Bull Environ Contam Toxicol Ni:233, 1975. IARC: Working Group on the evaluation of the carcinogenic risk of chemicals to humans - Poly<hl<xinated Biphmyls, Vol IS, 1978. [noue, Y et al. Discovery of PCB pollution in textile factory--1. PCB level in blood serum of laborers and results of physical examination (As reported in NIOSH Criteria Document) 3pn. 3 Public Health 22s 1637, 1973. Ito, N et al. Histopathological studies on liver tumarigenesis In rats treated with PCB's Gann 6TT345, 1974. 3ensen, S and Sundstrom, G. Structure and levels of most chloroblphenyls in two technical PCB products and in human adipose tissue. Ambio 3: 70, 1974. 3erina, DM and Daly, 3W. Arene Oxides: A New Aspect of *ug metabolism. Science 183: 573 1974. Karppanen, E and Kolho, L. The concentration of PCB in human blood and adipose tissue in three different research groigrs. In, PCB Conference R, Stockholm 1972. (As reported in NIOSH Criteria Document) 5olna, Sweden National Swedish Environment Protection/Publications, 4E, pp 124-28, 1973. Katzenellmbogen, 3 and Ames, BN. Personal Communication 1980. mrKeplinger, M et ai. Toxicologic Studies with PCBs (abstract) Tox Appl Pharmocol I?* 402-403, i Kihlstrom, 3E et al. Sexual function of mice neon*tally exposed to DDT or PCB. Environ Phys Biochem 5: 54, 1975. Kikuchi, M et al. An autopsy case of stillborn of chlorobiphenyls poisoning. Fukuoka Acta Med dSTSH 1969. Kimbrough, RD et al. Morphologic changes in liver of rats fed PCB's. Arch lnd Health 25: 354, ff75T Kimbrough, RD. The toxicity of polychlorinated polycyclic compounds and related chemicals. Crlt Rev Toxicol 2: 445, 1974. Kimbrough, RD and Linder, RE. Induction of adenofibrosis and hepatomas of the liver in BALB/C3 mice by PCB's (Aroclor 1254). 3 Natl Cancer Inst 53: 547, 1974. Kimbrough, RD et al. Induction of liver tumors in Sherman strain female rats by PCB (Aroclor 1260). 3 Natl Cancer Inst 55: 1453, 1975. MQhS 010693 56 Kimbrough, R et *1. Animal toxicology, in DHE9 Subcommittee on Health Effects of PCB's and PBB's. Env Health Persp 24; T>3, 197*. Kimbrough, R Chronic toxicity of halogenated biphenyls and related compounds in animals and health effects in humans. CDC report, 1910. Kimira, NT and Baba, T. Neoplastic changes in the rat liver induced by PCB. Gann 64; 105, 1973. Kitamira, M et al. PCB in blood of workers employed in an electrical parts manufacturing plant. (As reported in NIOSH Criteria Document) 3pn 3 Ind Health 15; 539, 1973 (3ap). " Kuratsune, M et al. Epidmeiologic study on Yusho, A poisoning caused by ingestion of rice oil contaminated with a commercial brand of PCB's. Environ Health Persp It 119, 1972. " Kutz, FW and Strassman, SC Residues of PCB's in the general population of the US. In; Proceedings of the natural conference on PCB, Chicago, EPA - 560/6*75-004, Washington DC, pp 139. Linder, R et al. The effect of PCB's on rat reproduction. Food Cosmet Toxicol J2t 63, 1974. --- Lutz, R3 et al. Preliminary pharmacokinetic model for several chlorinated biphenyls in the rat. brug Metab Dis 5: 386, 1977. Mathews, HB and Anderson, NW. Effect of chlorination on the distribution and excretion of PCB's. Drug Metab Dis 3: 371, 1973. Meigs, 39 et al. Chloracne from and vnusual exposure to Aroclor. 3AMA 154; 1417, 1954. Miller, 39. Pathologic changes in animals exposed to a commercial chlorinated biphenyl. Public Health Rep 39; 1085, 1944. Moore, 3A et al. Comparative toxicity of three halogenated dibenzofurant in guinea pigs, mice and rhesus monkeys. Ann NYAS 320: 131, 1979. Murai, Y and Yoshigoro, K, Peripheral neuropathy in chloroblphenyl poisoning. Neurol 2U 1173, 1971. NCI: Carcinogenesis technical report series #38, DHEW publication (KN1H) 78-838, 1978. Nelson, N et al. PCB's - environmental impact. Environ Res 5; 249, 1972. NIOSH: Criteria for a recommended standard - Occupational exposure to PCB's NIOSH, Cincinnati, 1977. Norback, DH and Weltman, R. Personal communication 1980. New York State Health Planning Commission. Report of the ad hoc committee on the health implications of PCB's In mothers' milk. Albany Health "Advisory Council, 1977. Oishi, S et al. Comparative toxicity of PCB's and dibenzofurans in rats, Tox Appl Pharm 43TTT, 1978. HONS 010694 37 Oberg, 3 and Klhlstrom, 3E. Effects of long-term feeding of PCB, Clophen A-60 on length of estrus 'cycle and frequency of implanted ova in the mouse. Environ Res 6: 176, 1973. ~ Ouw, HK et al. The use and health effects of Aroclor 1292, a polychlorinated biphenyl, in an electrical industry. Arch Environ Health M.t 1*9, 1976. Sato, M and Hasegawa, H. Amount of PCB In blood of laborers. (As reported in NIOSH Criteria Document) 3pn 3 Ind Health 363, 1979 (3pn). Safe, S et al. The metabolism of 9-chlorobiphenyl In the pig. Can 3 Phya Pharmacol 33: 392,T9T3. Schwartz, L. Dermatitis from synthetic resins and waxes. Dermatitis 26: 3*6, 1936. Selikoff, 13 et aU Mortality experience of factory workers exposed to PCB's in the manufacture of transformers and capacitors. Mt. Sinai School of Med, Env Sciences Lab, New York, NY, in progress, 19*0. Shiote Postnatal behavioral effects of prenatal treatment with PCB's in rats. (As reported in 1ARC, 197S). Okajlmas Pol Anat 3pn 33: 103, 1976. Smith, AB et al. Lipid and Lipoprotein alteration: Occupational exposures to PCB. Clinical ResTST 399, 1978. Stalling, DL et al. An expanded approach to the study and measurement of PCB's and selected planar halogenated aromatic environmental pollutants. Ann NY AS 320; 9*. 1979. Taki, 1 et al. Report on Yusho (chloroblphenyls poisoning): Pregnant women and their fetuses. Fukuoka Acta Med 60: 971, 1969. Treon, 3F et al. The toxicity of the vapors of Aroclor 1292 and Aroclor 1259. Am Ind Hyg Q 17:159, 1956. Urabe, H et al. Present state of Yusho patients. Ann NYAS 320: 273, 1979. Vodicnik, M3 and Lech, 33. The transfer of 2,9,5,2',9\5,,-hexachlorobiphenyl to fetuses and nursing offspring. Tox Appl Fharm -39: 293, 1910. -- Van Miller, 3P et al. Distribution and metabolism of ^H-2,3,2,,3',-tetrachlorobiphenyl in rats. Proc Soc Exp Biol Med 198: 682, 1975. Vos, 3G and Beems, RB. Dermal toxicity studies of technical PCB's and fractions thereof in rabbits. Tox Appl Pharm Jjh 617, 1971. Warshaw, R et al. Decrease in vital capacity in PCB-exposed workers in a capacitor manufacturing lac ility. Ann NY AS 320: 277, 1979. Vyndham, C et al. The In vitro metabolism, maeromolecular binding and bacterial mutagenicity of 9-chlorobipfienyl, a model PCB substrate. Res Commun Chem Pathol Pharmacol l*t 363, 1976. Yoshimura, T. Epidemiological study on Yusho babies born to mothers who had consumed oil Contaminated by PCB. Fukuoka Acta Med 65: 79, 1979. HONS 010695 38 TABLE 1 ni jjiinal. mieoLDct Ipaclaa Ut **vl t bi Untln bt AOalt lit v**aHh| bt iah 1*1 Mill bt Unit bt 14*U DUl Ulll nu ibntaf >to*ar Mtktf tMif Uvlt Malt Halt Hull bt* CflM* flf A4*U 44*U Mitt Ullt 1*9 . Nm*I . A4wl 1 C*|M* fl|. Ml cal N|aa 1 **! hie* 1*1* J mb 4 *4kf l*t* lltl ml* 1 ***fc b*t 4r**l*r l?94. i:to *r*tlar 115*, 1119 Ar*<lr IbS* i:t. i:ii Araalat ll4l, 1011 Uh1*V 4rMl*f HM HmUt UH tanadar J00 -FO*'*- Cl*lw* t*0 KU( UM tml IHI UMUl 11*1 UHlft 11*1 llMllfl 4m l*r* 4tbr Uio AracL*t 111! **la* 900 AtnIw 1194 irHlat 1110 ItmIm 1110 Ma*cKlr*M ph*Tl l*t Oral Oral Or#i 0k*1 Ofil Oral Oval 01 Oral Oral Oral Oval Oral Oral banal banal Nrval lahal. a Oral Oral Oval Oral Oral bat "/*|/4af Bvratl-- Tatal Oaja tlfMt tafafanaar * io,or* 1,1cw * MOO 90 S.9.4.4 too l.o 9.0 1.0 7.0 1.0 llhl1* ftaala ti|*ar* 1 Ml 4 *atha ........... * 1100 )oe*im Umc bfirtifrir, fattp l*f Uuattaa Taicf |lp 7.19 *T faaiatl** 2 omtha pcla* t* atla 1 MtlW pc tar m Wb Oaf 0*14 #r 15,11 iMialir* 4 a tartly t hut. thn.lt* TOO IK# MM 4.0 200 Bail non firrrltil . affaprlM m frati* 4 Hum aiaa 4mvlfil *[fapfl<H tpfUl|T * i(lMfl"l +*atlnt bbl*r affiprlnt 4 wrrlaua laar*l*f aaaaft a/fapri*f dadnutlafia* llUir aUa-affaprlat; th**t*a la artraa* cfda-af faprlnt ImitbaH itfwi cpdaa ^tlflriUtliaa tlMravftfc at al 14 74 ki*arairtfi *t *i 197| Allan 4 ftwfa at al,, 1974 1974 19)4 INm a| al, 19U fhtata, 1974 JUHlatra at al 197J 94arf 4 liar* itm, 197] 10 4 mtba 40 valffit laaa, alapaaia, laalal Allan. 1979 adana, if* |lMhtT|* 1.9 1 wat* 100 livar ibai -- UUM (attal*vla*l) Allan. 1979 0.1*10 4 Wtb TT-JTOO facial *4aaw tlpU atrvpfcf *u*.. itti 0.04-0.IT 1 ymt 14.41 facial rtfN, alapaaia mm, 4favtllltf, LrrapuUr rmii. f*arl? abtUMit affaprtnt: Oaalflit, *<! tlt*l*ti"i UfMlUll* Mk* tn ilaaual Alla*, 1973 W10O *20 4tr* Until Kapaaara 1W0 ill|lt A', llrar hlatalagf Oaacfc blffll f ca 71 4*pa rtth livar atrpphf 1144 Miliar, 1944 *10 1,9 * 11 4*fa IT m. 740 490 Itraaaaptc llv*r A'l Traaa* t94 0,1 * 90 Jl mil ]i... m rmnlkla livar A * 4 hapaiaart tular tirtlham (tanird 0/4: latil 9/12) + r**aia*tic n**l* (aanttal 0/a; 4aa4 7/t2) Tr*H| 1994 Ha at al, * I97J 90 44 wafca i*.i ** fniffiMtli naOvlar lta4r#v(h 4 (cantfal 0/21; 4aaa4 4/11) Llndan, 1974 10 II --.th. *.3 4hariacatlulaf areln*na tl^ravftM at al Uadral i/171, *aia< U4/144) 1979 4n##pi**tic a4wlv <aa*tt#l O/lJJ; J*aa4 14/144) 10 104 ink* T.l O fbMtKillflir cirtlMMI Kartac* at al., <ftpub||ah4l 1910) 1910 10 104 h<Ii 7,7 * Ib^tMtUvUr uriihM*! (wpadla***, 1940) 1900 i* >' ' *f' ' "ts-.iar ii (ir / nogtl'iT, > 4a?a/*ep* lor if vmii, ^ t 4^t in a/4a/4hV, (h| Ullv|n| tirnctlWi *at* aptUttf: 0.1 if air hfatthaO ^ w ^ a^tarl par 4if); 0*9 (*alant af M*a| u kg); 14/? UirrMttiP tut 14 KMr/4if t*p#*ara); 7/9 (catradian far 7 Ujfwh aps*ta>, favaltlni film aafeaaat \QQ\ oMr|tit, Acr>*. 39 HONS 010696 Cu -A^g WUV ?:\si:!-c n_ ^ n ssi I Si 1i 1s S % B z_c T~poaJ30. 55;- aoass *0 9 w 5 na i a9 J ** hxc _ | Ti3 -- = g;fl:*lEl I,*25 =v Q 5 g H! m i u E: Sf* -o# 8C iph2* 3 "it i--3i-* *scO^ih"a3 9 |SSI 11 * s S, !:-8 H:s fl it i 3o C5 V - TM o MS SlSrf 43 S3 Ji sr*i H ls o<M > 8M pi *1 |4* 2.5 iii nf 1! 2l|pE E Q 2 u 5? E 6 sill I > i'?g 5i*i ..8 -.5 I3s* M< 3l Finding* $ lu 4 r Amputation I ?fig li> -- 5 ~ 8 "o '1 I c 4 Ef E 2 . S b IS1 3 ? 3 *5 C * ?5 |J'6< 5 -- j5 u a -5 IE 1 S_s n ? IVlI .*N* ^ ,,-- Aotc c } i 9 S lX-llvSi. paS- '<Sgs^i*^ 8iL 1 i^x I ills* S 2 HONS 010697 IS Vs-5 S ill " s Iu M MSI. Lose 2 S2Sk 5 i -1 i: > ? a*-* CP T<i. 4o)* l. c iite.sSj *8 Sii -- rj g.*8Sji2a* ; i2'Ss*8g I .- * S u Sl ov-f^iOCSfcguSw o1 . 3 st* II j 3 Q.| J Jj fe 2 - a * f - cr hirsiii lli"Sit5 I E 2 I Sts * 1 i f 2 t, E|**|z2.3-|. 2 - 2 *I , e Study Pofxdatlon I ?"& 2E lii ss - SL. i T* iC * J If-sfisi?-" fc * 8s c " IJ S *K , 9 f a 2S 11 aa o3> , ..S' r> ^ -T' ,,zs,,i S11S dl^risCLjgM HONS 010698 a ty 'Z * 2 & Sf I >s g to* i'f g <j ,*,J o c C5 c -o SU J S Ms Mi! t 1 fl g tCt Uco iwt Cg I=r i u SiS S,,5g 5ri fBK Itf*|" ,^ Hit l Study Population aration of a ita e l H * B > od p. o 2 HOMS 010699 2 o ^ 3 S I a xC - * ng * till gsf RS ? r! *= - * c - -S=. lsS = `si,A -" 3 a -s 2 3 a || s? s s e J 5 2-occ t loaj ua -. Iffi - 4-/1 5_ - Qy. 8 w 1 So a is ! Ss e e li n o e jt >. ,,2 6j S. **i 133 i t/1 mm it, w 8 Study Population I u t \ -i * i K Hi - i -isl !. OHhMi a; s I MONS 010700 table ni percent distribution of symptoms of yusho reported BY 189 PATIENTS EXAMINED BEFORE OCTOBER 31, 1968. Symptoms Dark brown pigmentation of nails Distinctive hair follicles Increased sweating at palms Acnelike skin eruptions Red plaques an limbs Itching Pigmentation of skin Swelling ol limbs . .................. Stiffened soles in feet and palms of hands Pigmented mucous membrane Increased eye discharge Hyperemia of conjunctiva Transient visual disturbance Jaundice Swelling of upper eyelids Feeling ol weakness Numbness in limbs Fever Hearing difficulties Spasm of limbs Headache Vomiting Diarrhea Males (N-89) Females (N- 100) 83-1 64.0 30.6 87.6 20.2 42.7 73.3 20.2 24.7 J6.2 SS.S 70.8 36.2 11.2 71.9 58.4 32.6 16.9 18.0 7.9 30.3 23.6 19.1 73.0 36.0 33.0 82.0 16.0 32.0 72.0 41.0 29.0 47.0 83.0 71.0 33.0 11.0 74.0 32.0 39.0 19.0 19.0 8.0 39.0 28.0 17.0 Source: Kuratsune et al, 1972 MONS 010701 49 ricunz i biphentl molecule and ring numbering ststzh 3-chlotobiphanyl 2,2',3,4 ,5-pntachlorobiphenyI EXAMPLES OP NOMENCLATURE STSTEM OP CHLOROBIPHENTL COMPOUNDS NUMBER OF ISOMERS AND PERCENT CHLORINE FOR THE 10 CHLOROMPHENYL (PCB) CLASSES Chlorobiphenyl Empirical Formula No. of Isomers Weight % Cl mono di tri tetra Penta hexa hepta octa nona deca C H,C1 C H,Cl 2 C HtC1 3 C HC1 4 C H.CI 3 C H.C1 6 C HiCl 7 C HiCl 8 C HC1 9 c Cl 10 Source: NIOSH, 1977 3 12 24 42 46 42 24 12 3 t 43 18.79 31.77 41.30 48.54 54.30 58.93 62.77 69.98 68.73 71.18 MONS 010702 FIGUM II Source: Riebrouih, 1974 FIGURE III CHLORODBENZOFURAN TYPES AND CONCENTRATIONS (yg g) IN COMMERCIAL PCB PREPARATIONS Chi orodibenzofur era Mixture* di tri tetra panta hexa hepta Total (1) 1016 Cl) 1016 (1) 1241 (1) 125* (1) 1254 (1) 1260 (l) 1260 (2) A-60 C3) DP-6 (4) K300 (4) K400 (4) K500 (4) K600 0.5 Cc)*** (e) . __ <0.0001 0.5 0.1 0.2 0.1 0.2 1.4 0.7 (a) (e) (a) <0.0001 1.2 0.2 0.4 0.4 0.3 5.0 10.0 U) (c) (a) (a) -- <0.0001 0.3 1.4 0.9 0.5 0.3 2.2 2.9 (c) (b) 0.5 2.0 1.7 1.5 1.0 0.8 8.4 13.6 1-1.5 17-18 (a) 2,5-4 (b) 3-5 *(1) Aroclor, (2) Qophen. (3) Phenoclor , (4) Kanechlor **(), (b), (c), (d), (e) represent relative amounts in increasing order Source NI-SH, 1977 HONS 46 010703 FIGURE IV Responses ol primates and rats to PCIVs* Response Susceptibility to toxicity Acne Hyperpigmentation of skin Alopecia Hyperactive Meibomian glands Conjunctivitis Oedema of eyelids Subcutaneous oedema Keratin cysts in hair follicles Hyperplasia of hair follicle epithelium Gastric hyperplasia ` Thymic atrophy Hepatic hypertrophy Liver enzyme change Decreased no. of red-blood cells Decreased haemoglobin Serum hyperlipidaemia Leucocytes is Man ' Monkey Rat High Yes Yes NA Yes Yes . Yes Yes Yes Yes NA NA Yes NA Yes Yes Yes Yes High Yes Only Infants Yes Yes Yes Yes Yes Yes Yes Yes NA Yes Yes Yes Yes Hypolipidaemia Yes Moderate No No No No No No No No No No" Yes Yes Yes No No Yes No Sources IARC, 1971 * This table summarizes acute and subacute clinical effects but does not Include chronic or delayed effects such as reproductive effects or cancer. MOMS 010704