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Il t., * ]u.^erial na/ 1 `ji >** an^rriKbH POLYCHLORINATED 131PHENYLS* 1. Chemical and Physical Data 1.1 'Synonyms and trade names diem. Abstr. No.: 13-36-36-3 Chlorinated biphenyl; chlorinated diphenyl; chlorinated diphenylcne; chloro biphenyl; chloro 1 ,1-biphenyl; polychlorinated polyphenyls; polychlorobiphenyl Aroclor; Clophen; Chlophen; Chlorextol; Dykanol; Fenclor; Inerteen; Kanechlor; Montar; Noflamol; Phenochlor; Phenoclor; Pyralene; Pyranol; Santotherm FR; Sovol; Therminol; Therminol FR-1 1.2 Cliemical formula In the above formula, X represents either a chlorine or a hydrogen atom. * Considered by the Working Group in Lyon, June 1974 261 NEV 036751 .1.3 Chemical and physical properties of the pure substance (see also Tables 1 & 2) (a) The melting- and boiling points of some chlorobiphenyls are given below*: MP C BP(760)C BP(mmHgJC 2-chlorobiphenyl 3-chlorobiphenyl 2,2*-dichlorobiphenyl 4,4'-dichlorobiphenyl 2,4,5-trichlorobiphenyl 3,5,4*-trichlorob iphenyl 3,4,3',4*-tetrachlorobiphenyl 2,4,2 ',4 *-tetrachlorobiphenyl 2,4,5,3',4*-pentachlorobiphenyl 3,4,5,3*,4*,5'-hexachlorobiphenyl 2,3,4,5,2',4*,5'-heptachlorobiphenyl 2,3,4,5,6,2*,31,4',5* 6'-decachlorobiphenyl 54 89 59, 61-62 148 78-79 88 172 83 179 198 310 267-268 284-285 154(12) 315-319 230(50) 195-220/10) 240-280(20) (b) Polychlorinated biphenyls are insoluble in water but soluble in most of the common organic solvents. 1.4 Technical products and impurities Products vary from mobile oily liquids to white crystalline solids and hard non-crystalline resins. Technical products vary in composition, in the degree of chlorination and possibly according to batch. For example: Kanechlor 500 has an average content of 55.01 pentachlorobiphenyl, 26.51 tetrachlorobiphenyl, 12.81 hexachlorobiphenyl and 5.01 trichlorobiphenyl (lot 360). Kanechlor 400 has an average content of 43.81 tetrachlorbiphenyl, 32.81 trichlorobiphenyl, 15.81 pentachlorobiphenyl, 4.61 hexachlorobiphenyl Data from Hubbard (1964) 262 TABLE 1 CHEMICAL AND PHYSICAL DATA CN KANECHLORS Appearance Kanechlor Specific gravity Viscosity Centistokes Refractive index Pour-point Acid value KOH Distillation temperature Tange (at 15C) (at 100C) (at 75C) (at 98C) (at 25C) (C) (mg/g) (C of 760 mm HG) 300 colourless, gunny oil 1.337-1.339 1.310-1.322 3.5-4.4 2.1 -2.6 1.6230-1.6260 (-19)-(-15) 0.005> 325-360 400 colourless, gunny oil 1.453-1.468 1.376-1.389 S.4-7.3 2.8-3.7 1.6295-1.6325 C-83-C-SJ o.oos> . 500 colourless, gummy oil 1.460-1.475 12-19 5.0-6.6 1.6370-1.6390 8-12 0.005> 340-375 365-390 ON' W NEV o Ul a Ul *. I r \ @ - 1 4ON>) TABLE 2 CHEMICAL AND PHYSICAL DATA ON ARCLRS Aroclor 1221 Appearance colourless, mobile oil* Density (at 20C) (at 90C) 1.18-1.19* Refractive index (at 20C) Pour-point m 1.617-1.618* +1* Aroclor 1242 almost colourless, mobile oil* 1.38-1.39** 1.625-1.627** -18 max** Aroclor 1248 yellow-green-tinted, mobile oil* 1.45-1.47** 1.6305-1.6325** -6 max** Aroclor 1254 light-yellow, viscous oil* 1.47-1.49** 1.638-1.640** +12 max** Prom Hubbard (1964) ** From Monsanto Co. (1973) ^ 6 9 e 0 A3N and 3.0% dichiorobiphenyl (lot 471). Kancchlor 300 has an average content of 59.81 trichlorobiphenyl, 23.0% tetrachlorobiphenyl, 16.6% dichlorobiphcnyl and 0.6% pentachloi-obiphenyl (lot 348). Monsanto, the only US manufacturer of these chemicals has produced a series of chlorinated biphenyls and chlori nated polyphenyls over the years which were numbered to identify eacli product. The first two digits indicated the type of material: 12 - chlori nated biphenyls; 25 - blend of chlorinated biphenyls and chlorinated triphenyls (75:25); 44 - blend of chlorinated biphenyls and chlorinated triphenyls (60:40); and 54 - chlorinated triphenyls. The last two digits indicated the approximate weight percentage of chlorine in the product. Thus, the product numbered Aroclor 1242 contains mainly trichlorobiphenyls, Aroclor 1248 contains mainly tetrachlorobiphenyls and Aroclor 1254 contains mainly pentachlorobiphenyls. Some of the physical and chemical properties of Japanese and US pro ducts are given in Tables 1 and 2. Specific data on the impurities in these products are not available, but colour is an indication of purity: the darker the product, the lower the purity (Monsanto Co., 1970). The raw materials used in the synthesis of polychlorinated biphenyls determine to a large degree the type of impurity or contaminant in the commercial product. Fractionated samples of some nonUS products have shown them to contain the tetra- and pentachlorodibenzofurans and the hexa- and heptachloronaphthalenes as contaminants (Interdepartmental Task Force on PCBs, 1972). 2. Production, Use, Occurrence and Analysis Several review articles on polychlorinated biphenyls have been pub lished (Fishbein, 1973; Hubbard, 1964; Interdepartmental Task Force on PCBs, 1972). 2.1 Production and use1 The polychlorinated biphenyls were first described in the chemical I Data from Chemical Information Services, Stanford Research.Institute, USA literature in 1881. Commercial manufacture of these chemicals in the US is believed to have begun in 1929; and although a number of US companies have registered trademarks for polychlorinated biphenyls, recent information indicates that there is only one US producer of polychlorinated biphenyls. If these chemicals are sold at present by other companies, they are either manufactured by this one US producer or imported. Polychlorinated bi-, ter- and polyphenyls are produced by chlorination of the appropriate aromatic hydrocarbon using either iron or ferric chloride as a catalyst. The composition of the end-product is determined by the quantity of chlorine present (Hubbard, 1964). It was estimated in 1970 that since the commercial introduction of polychlorinated biphenyls in 1929, 454 million kg of these chemicals had been sold in North America. Between 1960 and 1970, production of poly chlorinated biphenyls increased steadily from 17.3 million kg in 1960 to 85 million kg in 1970. In 1971 the US producer voluntarily agreed to restrict sale of polychlorinated biphenyls to those applications which minimize their introduction into the environment; thus, production dropped to 18.2 million kg, with an estimated output of 11.4-13.6 million kg for 1972. In general, the majority of these chemicals produced are the lower chlorinated grades (Interdepartmental Task Force on PCBs, 1972), US imports of polychlorinated biphenyls were 290,836 kg in 1971 (US Tariff Coronission, 1972) but only 160,985 kg in 1972 (US Tariff Commission, 1973). US exports of polychlorinated biphenyls increased steadily from 81 of production (1.6 million kg) in 1963 to 161 of production (6.2 million kg) in 1970. In 1971, 251 of total production was exported, but this amounted to only 4,4 million kg (Interdepartmental Task Force on PCBs, 1972). It has been estimated that US production in 1971 represented roughly one half of the total world production of polychlorinated biphenyls. The following countries have also been reported to produce these chemicals: Czechoslovakia, the Federal Republic of Germany, France, Italy, Japan, Poland, Spain, the United Kingdom and USSR (Anon., 1973; Interdepartmental Task Force on PCBs,*1972). Argentina, Brazil and India have been reported to be possible producers (Anon., 1972). 266 0 3t>'&fa Nfc' 1 Production began in Japan in 19S4, and by the end of 1971 approximately 55.4 million kg had been produced. Approximately 60% of Japan's total ex ports have gone to the US, with the remaining 40% going to Europe; between 1962 and 1971, exports of these chemicals totalled 4.5 million kg. Imports, solely from the US, totalled 0.6 million kg from 1967 to 1971. The produc tion of polychlorinated biphenyls is now prohibited in Japan. Prior to 1971, polychlorinated biphenyls were used in a variety of applications, primarily because of their excellent themil and chemical stability. However, in 1971, Monsanto, the sole US producer of these chemicals, voluntarily decided to limit their use to those closed electri cal applications from which possible release to the environment is minimized. Before that time about 40% of the polychlorinated biphenyls used in the US went into applications which led to loss into the environment, e.g., in plasticizers, hydraulic fluids and lubricants, surface coatings, inks, sealants, adhesives, pesticide extenders and microencapsulation of dyes for carbonless duplicating paper. The remaining 60% of US sales was used mainly in electrical transformers and capacitor applications; of all applications prior to 1971, the largest uses were in capacitors and transformers and in plasticizer applications, including carbonless duplicating paper. Today polychlorinated biphenyls are used in the US only in closed-system electri cal applications which minimize introduction into the environment (Hubbard, 1964; Interdepartmental Task Force on PCBs, 1972). 2.2 Occurrence (a) Occupational exposure Although polychlorinated biphenyls may have been used in pesticide formulations in conjunction with various pesticides, no information on human exposure during crop or forest spraying is available. The US Occupational Safety and Health Administration health standards for air contaminants require that an employee's skin exposure to chlorodiphenyl (42% chlorine) and chlorodiphenyl (54% chlorine) does not exceed eight-hour time-weighted averages of 1 mg/m* and 0.5 mg/mJ, respectively, in the workplace air during any eight-hour workshift for a forty-hour work week (US Code of Federal Regulations, 1974). Masuda et al. (1972) reported that polychlorinated biphenyls occurred in carbonless copying paper in Japan; average amounts of 30 pg were found remaining on the skin after handling such paper. Lister & Bennett (1972) reported that the major manufacturers of this paper in the UK did not use polychlorinated biphenyls. (b) Air and rain Polychlorinated biphenyls may enter the air during the destruction of manufactured articles containing polychlorinated biphenyls in waste-disposal burners, through th gradual wear and weathering of polychlorinated biphenylcontaining products or through leaks from sealed systems. It has been esti mated that some 400 thousand kg polychlorinated biphenyls were released into the atmosphere in 1970 in the US from waste-disposal burners (Nisbet & Sarofim, 1972) and that 1000-2000 thousand kg entered the atmosphere from the vaporization of plasticizers (Panel on Hazardous Trace Substances, 1972). In comparison, loss by evaporation or leakage from closed systems would appear to be insignificant. Carnes et al. (1973) have also demonstrated polychlorinated biphenyls in ash from industrial burners; in addition, some chlorinated dibenzofurans and dibenzodioxins may also be released through oxidation processes during incineration. Measurement of the monthly airborne fallout of polychlorinated biphenyls in 8 sites in Sweden during 1970-71 revealed levels of 550-10,500 ng/m2/ month (Sodergren, 1972). Air samples collected during February-April 1973 from a 20-metre high tower in Bermuda, or in June 1973 on the open sea off the island, contained polychlorinated biphenyl levels of 0,21-1.6 ng/m5 in the vapour phase. Higher levels (2.1-9.4 ng/m5) were found in Rhode Island where peaks resembled chromatograms of Arochlor 1242, which contains mainly tri-, tetra- and pentachlorobiphenyls (Bidleman & Olney, 1974), Bevenue et al. (1972) reported levels of 60 ng/1 polychlorinated biphenyls in rainwater in Hawaii during 1971-72. (c) Soil and water No data on polychlorinated biphenyl residues in various soils appear to be available. Holden (1970) reported concentrations of <0.1-14 ppm polychorinated biphenyls (wet weight) similar to Aroclor 1254 in 15 samples of 268 036758 sewage sludge intended for disposal in the sea off the Firth of Clyde in Scotland. Analyses by other laboratories of sewage sludge intended for disposal off the Thames and Mersey estuaries showed that 0.2 ppm and 0.1-5 ppm (wet weight) polychlorinated biphenyls were present, respectively * (Holden, 1970). These figures are equivalent to a total discharge of about 1 thousand kg polychlorinated biphenyls per year. Analyses at 9 sewage treatment plants in California in 1970 revealed that concentrations of 0.212 ppb occurred in sewage pumped into the Pacific Ocean (Sclimidt et al., 1971). In the US, polychlorinated biphenyl concentrations of about 0.02-2.5 jig/1 were reported in Milwaukee river water in 1969-70; the highest con centrations occurred near chemical plants (Veith & Lee, 1971). In Green Bay, Lake Michigan, Veith (1972) found concentrations of polychlorinated biphenyls (as Aroclor 1254) of <0.01-0.45 pg/1 in various river waters entering the bay. Measurements made during the summer of 1972 showed that the average concentrations of polychlorinated biphenyls in North Atlantic sea-water wore 35 ng/1 at the surface and 10 ng/1 at a depth of 200 metres; the polychlorinated biphenyl concentration in Sargasso Sea surface waters aver aged 27 ng/1 (Harvey et al., 1973). However, Bidleman & Olney (1974) found lower values, <1-19.3 ng/1, in Sargasso Sea surface waters; the peaks resembled chromatograms of Aroclor 1254 or 1260, which contain mainly penta-, hexa- and heptachlorobiphenyls. According to a review by the Panel on Hazardous Trace Substances (1972), polychlorinated biphenyls have been found at concentrations of 10-100 ng/1 in drinking-water in Japan. On July 3 1973, the US Environmental Protection Agency proposed a list of toxic pollutants which includes polychlorinated biphenyls (US Environmental Protection Agency, 1973). If this list is adopted, effluent standards restricting or prohibiting discharges of these chemicals into streams may come into effect. (d) Animals and plants A review of levels of polychlorinated biphenyls found in fish and birds 269 036759 in Japan has been published recently (Doguchi, 1973), The concentrations of polychlorinated biphenyls in vertebrate food chains increases in such a way that the top predators (e.g., birds of prey, sharks and seals) may have total concentrations of polychlorinated biphenyls 107-10 times that in the ambient environment. Studies of zooplankton from the North Atlantic shelf and slope areas revealed polychlorinated biphenyl concentrations in these organisms of 0.07-3 ppm (dry weight) and 0.02-0.64 ppm (wet weight) in the 2 areas, res pectively (Risebrough et al., 1972). In the Gulf of Mexico, concentrations of <3-1000 yg/kg (wet weight) have been found in zooplankton (Giam et al., 1973); and, in plankton in the Gulf of St. Lawrence, concentrations of 0.093 mg/kg (wet weight) have been found (Ware & Addison, 1973). In small predatory fish, polychlorinated biphenyl levels of 8 yg/kg were found in pike (fresh tissue) taken from an unpolluted lake in Finland, whereas 0.3 mg/kg were found in herring taken from the open sea (Hattula, 1972). Zitko (1971) found concentrations of 0.02-1 mg/kg polychlorinated biphenyls in eel, salmon, herring, mackerel, mussel, cod, hake and plaice, and traces in ocean perch, taken from the St John River system, New Brunswick, or from the Nova Scotia banks. Similar levels (0.36-1.S4 mg/kg) were found in tuna from the Atlantic coast of North America (Zitko & Choi, 1971). Much higher levels (up to 7 mg/kg Aroclor 1254) have been found in shrimp and crab caught in accidentally-polluted bays, e.g., Escambia Bay, Florida (Duke et al., 1970) and in fish from inland lakes: for example, 26 mg/kg were found in a 12-y.ear old trout caught in Cayuga Lake in Ithaca, New York (Bache et al., 1972) in which case the gas chromatogram lias similar to that of Aroclor 1254. Stalling & Mayer (1972) have also reported high levels of polychlorinated biphenyls (>20 mg/kg) in inland lake and river fisli in the US. Numerous reports concerning polychlorinated biphenyl residues in pre datory birds in Canada, Denmark, Finland, Sweden, the UK and the US have appeared, Jensen et al. (1969) ieported the presence of up to 190 mg/kg polychlorinated biphenyls (whole body-weight) in 4 white-tailed eagles found between March-June in 1965 and in 1966. Risebrough et al. (1968) 270 036760 identified up to 6S mg/kg polychlorinated biphenyls (wet weight) in the carcasses of 4 peregrine falcons which died after having been trapped for falconry. Residues of 30 and 900 mg/kg were found in the livers of 2 herons in the UK (Prestt et al., 1970). Levels of 1.3-272 mg/kg polychlorinated biphenyls (wet weight) (comparable to Clophen A 60) were found in the livers of terrestrial predatory birds in Denmark (Karlog et al., 1971), and' levels of 93-470 mg/kg (wet weight) were found in the livers of cormorants found dead in 1970 in the Netherlands (Koeman, 1973). Various concentrations of polychlorinated biphenyls have been recorded in birds1 eggs. Concentrations in the eggs of cormorants, gulls and ducks from the Bay of Fundy, Canada, ranged from 6-44 mg/kg (Zitko & Choi, 1972). Lower levels, about 1-5 mg/kg (wet weight), have been reported in the UK (Prestt et al., 1970) and in the US (Greichus et al., 1973). Polychlorinated biphenyl residues of up to 310 mg/kg have also been reported in the fat of seals living off the coast of Sweden (Jensen et al., 1969). (e) Food Sea-food or food packaged in grey cardboard packaging appear to have been the two main sources of dietary polychlorinated biphenyls. Small residues of polychlorinated biphenyls may also occur in milk and meat pro ducts, since silage stored in upright silos which have polychlorinated biphenyl wall sealants may contain about 0.1 mg/kg polychlorinated biphenyls (Savage et al., 1973). Fries (1972) detected 19 mg/kg in milk fat taken from cows at farms which had polychlorinated biphenyl-treated silos. Cereals packed in cardboard containing 10 mg/kg polychlorinated biphenyls have been shown to contain about 0.2-0.3 mg/kg polychlorinated biphenyls (Trout, 1972), One sample of cashew nuts packaged in cardboard drums was reported to have contained 10 mg/kg polychlorinated biphenyls (Bailey et al., 1970), and analysis of various types of food packed in paperboard with or without, a plastic barrier showed polychlorinated biphenyl levels of <0.1-4.3 mg/kg (Stanovick et al., 1973). Polychlorinated biphenyls have also been demonstrated in human milk in ,271 MEV 0 3 6 7 6 1 Japan at concentrations of 0.03 mg/kg (whole milk) and 1.1 mg/kg (fat basis) (Oura at al., 1972)*, and in the Federal Republic of Germany concentrations of 0.1 mg/kg (whole milk) and 3.5 mg/kg (fat basis) (Tombcrgs, 197Z) have been found. However, none could be detected in the milk of women in Texas and New Guinea (Dyment et al., 1971), although the mean polychlorinated biphenyl level in samples of human milk in California was 60 pg/kg (Risebrough & Brodine, 1970). Thus, since the daily milk intake of breast fed infants is 150 g/kg bv, the amount of polychlorinated biphenyls ingested would be in the order of 9 pg/kg bw/day. This figure is slightly above the maximum daily intake which would occur in adults eating 150 g/week of fish containing 15 mg/kg polychlorinated biphenyls (e.g., coho salmon from Lake Michigan) or 8U g of fish per day in Japan, where values of up to 5 mg/kg may be present (Panel on Hazardous Trace Substances, 1972). The US Department of Agriculture has analyzed polychlorinated biphenyls in selected food commodities (US Department of Agriculture, 1972): fish contained from traces to 35.3 mg/kg (average, 1.87 with 541 positive samples); cheese contained from traces to 1.0 mg/kg (average, 0.25 and 61 positive samples); milk contained from traces to 27.8 mg/kg (average, 2.27 and 71 positive sauries); whereas eggs contained from traces to 3.74 mg/kg (average, 0.S5 and 29i positive samples). Of the total number of commodity samples examined, only 191 were positive with respect to contamination by polychlori nated biphenyls, reflecting an average concentration of 1.14 mg/kg of sample. Twenty-two of 720 composite samples from the US Food and Drug Administration's (FDA) market-basket surveys have been found to contain poly chlorinated biphenyls ranging in concentration from traces to 0.36 mg/kg. This maximum value was due to migration of polychlorinated biphenyls from greyboard containers and dividers for packaged shredded wheat. Estimates of the mean daily intake of polychlorinated biphenyls in the American diet range from S-10 pg per day (National Environmental Research Center, 1974). During the 'Yusho incident' in Japan, a poisoning accident caused by ingestion of rice oil contaminated with a commercial brand of polychlorinated biphenyl (Kanechlor 400), the minimum toxic intake for humans was estimated to be 200 pg/kg bw/day (Kuratsune et al., 1972), 272 MV 036762 L_ 'Hie PDA has established temporary tolerances for polychlorinated bi phenyls in foods animal feeds and food-packaging materials. These tolerances are as follows: 2.5 mg/kg (ppm) in milk (fat basis); 2.5 mg/kg (ppm) in manufactured dairy products (fat basis); 5 mg/kg (ppm) in poultry (fat basis); 0.5 mg/kg (ppm) in eggs; 0.2 mg/kg (ppm) in finished animal feed for food-producing animals (except in feed concentrates, feed supple ments and feed premixes); 2 mg/kg (ppm) in animal feed components of animal origin, including fishmeal and other by-products of marine origin and in finished animal feed concentrates, supplements and premixes intended for food-producing animals; 5 mg/kg (ppm) in fish and shellfish (edible portion); 0.2 mg/kg (ppm) in infant and junior foods; 10 mg/kg (ppm) in paper food-packaging material intended for or used with human food, finished animal feed and any components intended for animal feeds (US Federal Register, 1973). 2.3 Analysis This subject has been reviewed by Fishbein (1973) and by Jensen et al. (1973). One of the main problems in the analysis of polychlorinated biphenyls is that during their extraction from the media, other organochlorine pesti cides (which may have similar retention times on chromatographs) are also eluted. Sigler chromatograms can be obtained by using separation techniques prior to gas chromatography. Such clean-up methods include TLC, paper and column chromatography; and solvent partition or saponification and dechlori nation of other compounds with alcoholic KOH have also been used. p,p'-DDE can be oxidized to 4,4'-dichlorobenzophenone without affecting the poly chlorinated biphenyls (Collins et al., 1972). Some widely-used methods and their modifications are described in the Pesticide Analytical Manual (US Department of Health, Education and Welfare, 1968), by Armour & Burke (1970) and by Porter et al. (1970). Volume III of the Pesticide Analytical Manual (US Department of Health, Education and Welfare, 1970) and Biros et al. (1970) give a method for analyzing residues in human tissues. Quantitation of polychlorinated biphenyls from electron-capture 273 NEV 0 3 6 7 6 3 chromatograms has been discussed by Zitko et al. (1971), However, for a fast, simple determination, the polychlorinated biphenyl sample can be converted to decachlorobiphenyl and compared with an Aroclor 1254 standard (National Environment Research Center, 1974). Some difficulties encountered with the use of standards in the quantification of polychlorinated biphenyls have been described by Beezhold & Stout (1973). Confirmation of identity can be made by combined gas chromatographymass spectrometry, which, in addition, yields the number of chlorine atoms per molecule (Bagley et al., 1970; Biros et al., 1970; Widmark, 1967). However, rearrangement of the chlorine atoms or phenyl groups occurring in the electron-impact-induced fragmentation limits the use of mass-spectro metry for structural studies. Nuclear-magnetic-resonance (NMR) spectroscopy has been used to resolve the structure of some polychlorinated biphenyl isomers (Sissons & Welti, 1971). Characterization of the components of technical polychlorinated biphenyl mixtures has been reported by Tas & Kleipool (1972) using pure standards, GLC retention times on 3 different columns, infra-red spectra and NMR spectroscopy. Methods for the determination of polychlorinated biphenyls in food, plant or animal tissue in Japan have been described by Wakimoto et al. (1973). 3. Biological Data Relevant to the Evaluation of Carcinogenic Risk to Man 3.1 Carcinogenicity and related studies in animals (a) Oral administration Mouse: Groups of 12 6-week old male dd mice were administered Kanechlor 300, 400 or 500 in the diet at concentrations of 100, 250 or 500 ppm for 32 weeks. Six control mice received the basal diet. Gross examina tion after 32 weeks of treatment showed that 7/12 mice given 500 ppm Kanechlor 500 developed liver nodules, and histopathological examination showed the presence of hepatocellular carcinomas in 5/12 mice. No metastases or tumours in other organs Were seen. Amyloid degeneration of the liver was seen in the other groups, especially in those at the 100 ppm dosage level. No changes occurred in the 6 controls (Ito et al., 1973; Nagasaki et al., 1972). [See also Table 3.] 274 03676** TABLE 3 HIST0PATH0L0GICAL FINDINGS IN THE LIVERS OF MALE dd-MICE TREATED WITH PCBs FOR 32 WEEKS PCBs in diet (ppm) Kanechlor 500 500 ZSO 100 Kanechlor 400 500 250 100 Kanechlor 300 500 250 100 Control Effective no. of mice 12 ' 12 12 12 12 12 12 12 12 6 Amyloid degeneration 0/12 2/12(16.71) 3/12(25.01) 0/12 3/12(25.01) 10/12(83.31) 1/12 (8.31) 4/12(33.31) 10/12(83.31) 0/6 Liver nodules Nodular hyperplasia Hepatocellular carcinoma 7/12(58.31) 0/12 0/12 - 0/12 0/12 0/12 - 0/12 0/12 0/12 - 0/6 - 5/12(41.71) 0/12 0/12 - 0/12 0/12 0/12 - 0/12 0/12 0/12 - 0/6 * NEV 036765 From Ito et al. (1973) cSni two groups of SO male BALB/cj mice were fed 300 ppm Aroclor 1254 in the diet for 11 months or for 6 months followed by the control diet for 5 months. Two additional groups of SO mice were fed the basal diet. At the end of 11 months 1/Z4 surviving mice treated for 6 months with Aroclor 1254 had a hepatoma, while of the mice surviving the continuous treatment 9/22 developed hepatomas. In addition, adenofibrosis was observed in all 22 mice fed Aroclor 1254 continuously for 11 months (Kimbrough & Linder, 1974). Rat: In groups of 10 male and 10 female Sherman rats fed 0, 20, 100, 500 or 1000 ppm Aroclor 1260* or 0, 20, 100 or 500 ppm Aroclor 1254, for 8 months, several rats died before 6 months at the 2 high-dose levels. Lesions described as adenofibrosis of the liver occurred in 2/10 males fed 1000 ppm Aroclor 1260 and in 1/10, 1/10 and 4/10 females fed 100, 500 and 1000 ppm Aroclor 1260, A higher incidence of this lesion occurred in rats fed Aroclor 1254, the incidences in males and females being 10/10 and 9/10 at 500 ppm,and 1/10 and 7/10 at 100 ppm, respectively (Kimbrough et al., 1972). A group of 10 male and 10 female Donryu rats was fed a diet containing 38.5-616 ppm Kanechlor 400 for 400 days. The initial concentration of 38.5 ppm was increased by factors of 2 in varying steps during the first 125 days until 616 ppm was reached. After 56 days at this level the concentration was reduced to 462 ppm for the remainder of the study except during two 28-day rest periods. A control group of 5 males and 5 females received a basal diet. In 6/10 treated females, multiple adenomatous nodules of the liver were ob served; such lesions did not occur in male rats nor in the controls. No hepatocellular carcinomas were seen (Kirnira & Baba, 1973). Groups of 30 male Wistar rats were fed for 52 weeks on diets containing 100, 500 or 1000. ppm Kanechlor 300, 400 or 500. One group received a control diet. Each Kanechlor produced cholangiofibrosis in a proportion of the rats Mien fed at 1000 Rim In the diet, while lower dosage levels were ineffective. Hepatic nodular hyperplasia was found with all compounds, the incidence increasing with the degree of chlorination and with concentration in the diet (Ito et al., 1974); ISee also Table 4.] 276 NV 036766 TABLE 4 HISTQPATHOLIGXCAL FINDINGS IN THE LIVERS OF MALE WISTAR RATS TREATED WITH PCBs PCBs in diet (ppm) Kanechlor 500 Kanechlor 400 1000 500 100 1000 500 10O Kanechlor 300 1000 500 100 Control Experi mental period (weeks) 49.3 52 52 40 27.8 39.6 52 52 52 52 Effective no. of rats 13/30 16/30 25/30 10/30 8/30 16/30 15/30 19/30 22/30 18/20 Fibrosis ++ - Cholangiofibrosis 4/13(30.8;) 0/16 0/25 2/10(20.01) 0/8 0/16 - 2/15(13.31) 0/19 0/22 - 0/18 - Nodular hyper plasia Amyloidosis 5/13(38.51) 5/16(31.31) 3/25(12.01) ' 0/13 0/16 0/25 - - 3/10(30.01) 0/8 2/16(12.51) 0/10 0/8 - 2/16(12.51) 0/15(6.71) 0/19 1/22(4.51) 0/15 0/19 0/22 - 0/18 - 0/18 - tsj ; From Ito et al. (1974) NEV Q36767 3.2 Other relevant biological data (S) Animals The LD5Q's of orally administered Aroclor 1254 and 1260 in Sherman rats are 4-10 g/kg bw (Kimbrough et al., 1972) and that of Aroclor 1242 4.25 g/kg bw in male Wistar rats (Bruckner et al., 1973). In DDD mice, the various components of a single oral dose of Kanechlor 400 were equally absorbed and distributed, mainly in the skin, liver and kidney. The tetrachlorobiphenyls, the major components of Kanechlor 400, were almost completely eliminated after 3-4 weeks; but the penta- and hexachlorobiphenyls, the minor components, were still retained after 9-10 weeks (Yoshimura & Oshima, 1971). In male Wistar King rats, 3 days after a single oral dose of 25 mg 3H-Kanechlor 400, radioactivity was' distributed mainly in the liver, skin and adipose tissue. During the first 4 weeks, 701 of the radioactivity was excreted in the faeces and 21 in the urine (Yoshimura et al., 1971). Fifty male Sherman rats were fed 500 ppm Aroclor 1254 in the diet for 6 months, and 5 rats were killed 0, 1, 2, 3, 4, 6, 8 and 10 months after exposure to Aroclor 1254 had ceased. In the rats killed 10 months after the end of exposure, about 1200 ppm and 22 ppm polychlorinated biphenyls (PCBs) were present in the adipose tissue and liver, respectively. The compounds found were those containing mainly 5, 6 or 7 chlorine atoms (Kimbrough et al., 1973). Preliminary work by Goto et al. (1973) on the metabolism of orally administered 2,2'-, 2,4-, 2,3-, 3,4-, 3,3f- and 4,4*-dichlorobiphenyls in male rats indicates that the main metabolites are dichlorodihydroxyhiphenyls, which are excreted via the urine and faeces as such and not as conjugates. In male Wistar rats 641. of a single oral dose of 25 mg 3,4,3*,4-tetrachlorobiphenyl (TCB) was excreted unchanged in the faeces during the first 14 days after dosing, and a metabolite thought to be the 2- or 5-hydroxy3,4,3*,4*-TCB was also found in small quantities (31) (Yoshimura & Yamamoto, 1973). Similarly, the metabolites of 2,4,3*4,'-TCB were identified in the 278 NEV 0 3 6 7 6 6 faeces of rats as free 5- or 3-hydroxy-2,4,3*,4'-TCB (Yoshimura et al., 1973). Gardner et al. (1973) showed that in rabbits oral administration of 2,5,2',5'-TCB resulted in 3 urinary metabolites (3- and 4-hydroxy-2,5,2,5'TCB and trans-3,4-dihydro-3,4-dihydroxy-2,5,2',5'-TCB), possibly fonned through an arene oxide (epoxide). Low levels of PCBs in the diet, or i.p. injections of PCBs, increase the microsomal mixed-function oxidase activity of the liver in rats (Bruckner et al., 1973; Norbach & Allen, 1972). PCBs can also be absorbed through the skin in rabbits (Vos & Beems, 1971). In Sherman rats given doses of 10 or 50 mg/kg bw/day Aroclor 1254 on days 7-15 of pregnancy, the average PCB concentrations in foetuses taken by Caesarean section on day 20 of pregnancy were 0.63 and 1.38 mg/kg, respec tively, compared with <0.12 mg/kg in controls (Curley et al., 1973a). Transplacental transfer was also demonstrated in rabbits (Grant et al,, 1971). Vos & de Roij (1972) demonstrated immunosuppressive activity of PCBs on both the humoral and cellular response of the immune system. Mien Aroclor 1254 was fed to pheasants either as a single dose of 50 mg or as 17 weekly doses of 12.5 or 50 mg, up to 821 was absorbed from the gastrointestinal tract and up to 50 mg/kg (wet weight) were found in their eggs (Dahlgren et al., 1971). In cows fed 200 mg/day Aroclor 1254 for 60 days, the average concentration in milk fat was 60 mg/kg (measured between the 40th and 60th days of feeding) (Fries et al., 1973). PCBs are also excreted in human milk (see section 2,2 (e)). Two-day old cockerels were given a diet containing 400 mg/kg Phenoclor DP 6, Clophen A60 or Aroclor 1260 for 60 days, and concentrations of 120-- 2900 mg/kg and 40-700 mg/kg PCBs were found in the liver and brain, respec tively, between the 12th and 58th days (Vos & Koeman, 1970). A maximum of 50 mg/kg Aroclor 1254 was found in eggs of white Leghorn hens fed for 12 weeks on a diet containing 50 mg/kg PCBs (Platonow & Reinhart, 1973). In a series of papers describing an outbreak of poisoning involving 2 million chickens in Northern Japan, Kohanawa et al. (1969a,b) first reported that a 'dark oil', a by-product of a rice bran, may have been involved. -279 NEV 0 3 6 7 6 9 'Hit; pathological changes seen in the poisoned chickens included oedema of the subcutaneous tiv-uo and l-irjgs, hydropericardium, peritoneal ascites and yellowish wottling of the li^'.-r. Histologically, oedema of skeletal muscle, opicardium and Jon;;'' ;nd focal necrosis of the liver were observed. Similar pathological change-', could 1^.- induced in 20 experimental chickens fed on a commercial diet made op by the manufacturer with the dark oil, which was shown to contain Kanochlor 40'# (Koga et al., 1970, 1971; Shoya et al., 196y), (b) Man Storage in human adipose tissue of the general population Two samples of Ifumrifi adipose tissue were found to contain 200 and 600 mg/kg J'Clis, but the source of these samples was not reported (Biros et al., J970J. Price K Welch f1-972) estimated that 361 of the general population had levels of 1-2 mg/k;j (wet weight) PCBs, ranging from penta- to decachiorobiphonyl:;, in their adipose tissue. In a Human Monitoring Survey of the exposure to pesticides experienced by the general population, Yobs (1972) found measurable amounts of l*CBs (1-2 mg/kg) in 261 and >2 mg/kg in SI of 637 samples of human adipose tissue taken from tlie general population of 18 states in the Uh and of Colombia. Bjerk (1972) reported average levels of 0.9 mg/kg (1.6 mg/kg lat basis) in adipose tissue taken from 40 humans dying in the Oslo area. n Japan, mean PCB concentrations in 25 samples were found to ho 0.5 and 0.8 ing/kg, using 2 different separation techniques (hurley et al., 1973b). Slightly higher concentrations (averages, 2.6 mg/kg in males and 1.8 mg/iii in females) were reported in 98 adipose tissue samples taken from humans living in Tokyo. Maximums of 5.1 mg/kg occurred In 70-79-year old men and 2.4 mg/kg in 60-69-year old women (Ooguchi, 1973). 3.3 Observations in man Kuratsunc et at. (J972) reported an incident of accidental poisoning by PCB involving 1057 persons in Japan who ingested rice-oil which had been contaminated by Kanechior 400 during the manufacturing process. From that group, 4 autopsy reports, 3 in adults and 1 in a stillborn, are available. The autopsy of one 48-year old Japanese female, who was diagnosed as 280 NEV 0 3 6 7 7 0 having liver cirrhosis, showed multilobular cirrhotic changes in the liver und many nodules of hepatic-cell carcinoma (Kikuchi, 1972). In the other 3 cases, there were various skin lesions associated with exposure to PCB, and chromatographic analysis showed PCB to be present in the mesenteric fatty tissue and skin in all 4 cases (Kikuchi et al., 1969, 1971). The skin of the stillborn child from an exposed mother showed disturbances of pigmenta tion; histologically, the changes were the same as those of PCB poisoning. The presence ofjPCB in the tissues of this stillborn child demonstrates transplacental passage (Kikuchi et al., 1969), and further evidence of such passage was provided by Miller (1971) and by Kuratsune et al. (1972) who reported on several infants b o m to mothers included in these cases of poisoning. 4. Comments on Data Reported and Evaluation1 4.1 Animal data A limited number of PCBs have been tested. Kanechlor 500 and Aroclor 12S4 are carcinogenic in mice inducing benign and malignant liver-cell tumours following oral administration, the only route tested. In rats, Kanechlor 500, 400 and 300 induced multiple hyperplastic liver nodules following oral administration. 4.2 Human data In the absence of epidemiological studies the available case report does not allow an evaluation to be made. See also the section, "Animal Data in Relation to the Evaluation o f . Risk to Man" in the introduction to this volume (p. 15). 281 NEV 0 3 6 7 7 1 5, References Anon. (1972) FCB family of chemicals found presenting a threat to man; law proposed to limit use, import. Commerce Today, May IS, pp. 29-30 Anon. (1973) OECD recoirmends restricted use of polychlorinated biphenyls. European Chemical News, March 2, p. 21 Armour, J.A. & Burke, J.A. 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