Document g2bBagOa4Lpy050DOvG2zqB5a

UCC 108037 260 IARC MONOGRAPHS SUPPLEMENT 4 Prokaryotaa FungVOraan prana iMadi Mammaian oaM Mammili fri vtvof Humana fame} DNA damage Mutation - Chromosomal Other anomalies ?T 7 T{-> T cal VanatamMon RvImhcm ' IARC Monographs. 26,385-384,1961 1 Styles, j.a. (1973) Cytotoxic effects of various pesticides in mo and in vitro. Mutat. Res., 21,50-51 *Matheeon, D,, Bruslck, D. 6 Carrano, H. (1978) Comparison of the relative mutagenic activity for eight antineopiastic drugs m the Ames Saimcrwia/mtcrosome and TK*mouse lymphoma essays. Dnjg chem. Toxioai., 1,277-304 * Moser, D,, Ami, P.. Fritz, H., Langauer, M. & Strasser, F.F. (1978) Comparative studies of 14 mutagenic or carcinogenic substances In seven mutagenicity test systems (point mutation tests, cytogenetic test and the dominant lethai test) (Abstract). Mutat. Res., 53,235 1 Suter. W.. Bremand, J., McMiSan, S. & Fox, M. (1980) Relative mutagenicity of antineopiastic drugs and other alkylating agents in V79 Chinese hamster cete. Independence of cytotoxic and mutagenic responses. Mutat. Res., 73.171-181 * Langauer, M. & MQBer, D. (1980) Comparative studies with the nucleus anomaly test and the micronudeue test. Mutat. Res., 74.159-160 7 Morgan, W.F. & Crossen, P.E. (1980) Mitotic spincSe inhibitors and sister-chromatid exchange in human chromosomes. Muter. Res., 77,283-286 VINYL CHLORIDE (Group 1)* A. Evidence for carcinogenicity to humans (su/tlcient) Vinyl chloride causes angiosarcomas of the liver; it has also been associated with tumours of the brain and lung and of the haematopoietic and lymphatic systems in humans. Reports of increased incidences of tumours of the digestive system, urinary tract and breast (in women) are inadequate to evaluate the carcinogenicity of vinyl chloride for these sites'. ' Cawgwtad a* Group 1 Dy tha pravku Working Grcxp. and dab on hunana and on arena* ml rawUuotod by e rnHnt Qnxp VINYL CHLORIDE 261 B. Evidence lor carcinogenicity to animals (sufficient) Vinyl chloride is carcinogenic to mice, rats and hamsters after Its administration orally or by inhalation, producing tumours at several sites. Including angiosarcomas of the liver'. C. Evidence tor activity in short-term tests (sufficient) Vinyl chloride induced DNA damage In prokaryotes and in mammalian cells in vitro2. It was mutagenic to Satooneta typhtnuriurn in the absence of an exogenous metabolic activation system* and to Escherichia cot', Schtiosaccharomyces pombe* and Saccharomyees ceravtsiaa* but not to Neurospora crassa*. It was mutagenic to QroscpNftr melanogaster, inducing sex-linked recessive lethal mutations* end to hamster oeits in vitrcf. It Induced chromosomal aberrations and sister chromatid exchanges In Chinese hamsters exposed in vtvcfi. It dkf not inluce dominant lethal* or somatic mutations m mice7. Vinyl chloride alkylated the liver DNA of rats treated in vivo*. Chromosomal aberrations and sister chromatid exchange were induced in workers exposed to vinyl chlo^t^Je*,',^. Most such data ware obtained when exposure was to levels of 25 ppm. In follow-up studies, in which workers were exposed to levels that had been reduced to 15 ppm and lower, no aberration or sister chromatid exchange was reported1*'*. Sister chromatid exchange incidence dropped ti a normal level shortly after termination of exposure to higher levels; however, the ncxtence of chromosomal aberrations returned to normal only after two years'*. [Thus, itithough sister chromatid exchanges were not observed in some studies, sampling may havi occurred after the level returned to normal.) Prokaryote* Fungl/Qraan plants Insect* Mammalian cal* fln vftrp> Mammals 0n vtvo} Humana (in vivo} Di. - damfcrant tothal mutaUona DNA damage Mutation ++ + + + +a Chromosomal Other anomalies + DM-) + References 1 IARC Monographs, Suppl. 1,45,1979 7 Leifer, Z,, Kada, T., Mandel. M,, Zetger, E., Stafford, R. 6 Rosenkrani, RS. (1981) An evaluation ol tests usino DNA renalr deficient beoterin for orodlrtinn nnnntnvk-iru O O O 03 O Co CD 262 IARC MONOGRAPHS SUPPLEMENT 4 rd cardnoganlcrty. A report of the US EPA's Gene-Tox Program. Mutat. Rat., 87, 2t 1-297 * IARC Monographs, 18,377-436,1979 4Eckhardt, F., Mufiawan, H., de Rutter, N. & Kappus, H. (1981) Rat hepatic vinyl chloride metabolite* Induce gene conversion in the yeast strain D7RAD In vitro and it vim. Mutat. Rat., 91,381-390 * Dmon. C. & Kurokl, T. (1979) Mutagenicity of vinyl chloride, vkrytldene chloride and chtoroprene In V79 Chinee* hamster cefis. Mutat. Rat., 87,173-162 * Beeler, A. 6 Ro'hrbom, G. (1960) Vinyl chloride: An example for evaluating mutagenic effects in mammals in vivo after exposure to inhalation Arch. Toxicol., 43, t-7 * Peter, S. & Ungvary, G. (I960) Leek of mutagenic effect of vinyl chloride monomat In the mammalian spot test. Mutat. Rat., 77, f93-196 'Left, RJ,, Gwirmer, L.M. & Bolt H.M. (1961) DMA alkylating by vinyl chloride metBbalttea: Etheno derivative* or 7-elkyiirtfon of guanine? Chant-Hoi. interactions. 37.219-231 `Anderson, D., Richardson, C.R., Purchase, I.F.H., Evans, HJ. & ORiordan, ML (1981) Chromosomal analysis In vinyl chloride exposed workers: Comparison of the standard technique with the sistar-chromatid exchange technique. Mutat. Rea., 63, 137-144 * KucerovS, M., Pofivkov*. Z. A Bttora, J. (1979) Comparative evaluation of the frequency of chromosomal aberration* and the SCE numbers In peripheral lymphocytes of workers occupaUonatty exposed to vinyl chloride monomer. Mutat. Ras., 87,97-100 ' Purchase, I.F.H., Richardson, C.R., Anderson, 0., Paddle, G.M. 6 Adams. W.G.G. (1978) Chromosomal analyses In vinyl chlorideaxpoeed workers. Mutat. Ras., 37,325-334 " ROeaner, P., Srtm, RJ,, Novikov*. J. 6 Lambi, V. (1980) Cytogenetic analysis in workers oocupattonafy exposed to vSiyi chloride. Murat. Res., 73.425-427 **Hanstean, l.-L, HRestad, L, Thks-Evensen. E. 8 Heidaas. S.S. (1978) Effects at vinyl chloride In man. A cytoganetic folow-up study. Mutat. Res., 51.271-278 VtNYUDENE CHLORIDE (Group 3) A. Evidence tor carctnagealcity to humane (inadequate) In one epidemiological study of 138 workers exposed to vinyUdene chloride (with no concomitant exposure to vinyl chloride), no excess at cancer was found, but follow-up was incomplete and nearly 40% of the workers had less than 15 years' latency since first exposure1. A study of 447 German and 162 foreign workers exposed m wew VtNYUDENE CHLORIDE 263 reported seven deaths from cancer, which was not in excess of expected values. Two cases of bronchial carcinoma were found in workers both of whom were 37 years old, whereas 0.07 were expected tor persons aged 35-39 years. (The Working Group noted that this study has severe methodological weaknesses, eg., no allowance for latency, no information on smoking habits, 76% loss from foNow-up for the guest workers, young age structure of the cohort, and a reference category that can be considered valid only for the German workers.) a Evidence tor carcinogenicity to animals (knitted) Vinylidane chloride was tested by oral administration to female rats and mice and to their offspring. In rats, Hver and meningeal tumours, and In mice, liver and gastric tumours, were seen more frequently In treated than In control animals, although the differences were not statistically sign.ficanP. It was also tasted m one experiment by inhalation in mice, rats and hamsters, inducing adenocarcinomas of the kidney In male mice and an increased Incidence of mammary fibroadenomas and carcinomas in rats (although with no dose-response relationship). In hamsters exposed for 52 weeks, no tumour had occurred by 74 weeks, but the study was stW in progress at the time of reporting'. C. Evidence for activity In short-term tests {sufficient] Vlnytidene chloride was mutagenic to bacteria in the presence of an exogenous metabolic activation system' and to ysast'-4 but it was not mutagenic to V79 Chinese hamster calls in vftroA ir alkylated DNt In mammalian cells In vitrcA. and, at tumorigenic doses In mice. It produced minimal a.nounts of DMA alkylation and repair but massive amounts of tissue damage*, ft dkf not nduce dominant lethal mutations in mice4. No data on human* ware available. Prokaryote* Fungl/Grtan plants Insacta Mammalian cals vtooj Mammals {in vivo) Huqiana 0n vivo) DMA damage Mutation + + * +- Chromosomal Other anomalies DM-) OL - dormant Whal mutations References ' IARC Monographs, 19,439-459,1979 IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Risnans (2979), Volume 1$ 377 VINYL CHLORIDE, POLYVINYL CHLORIDE and VINYL CHLORIDE-VINYL ACETATE COPOLYMERS Vinyl chloride This substance was considered by a previous lAftC Working Group, In June 1974 (1AKC, 1974). Since that time new data have become available, and these have been Incorporated into the monograph and taken into account in the present evaluation. A literature compilation (Warren et at., 1978) and a review (Hilby, 1977) are available. 1. Chemical and Physical Data 1.1 Synonyms and trade names Chen. Abstr. Services Reg. No.: 75-01-4 Chea. Abstr* Name: Chloroethene Chloroethylene; monochloroethylene; VC; VCM; Vinyl C monomer 1.2 Structural and molecular formulae and molecular weight C2H3C1 H >C=C< H Mol. vt: 62.3 1.3 Chemical and physical properties of the pure substance From Weast (1976), unless otherwise specified t (a) Description: Colourless gas (Wlndholz, 1976) (b) Boiling-point: -13.37C (c_) Melting-point: -153.8C (d) Penalty: dj 0.9106; vapour density, 2.2 (air = 1) (Anon., 1972) UCC 108039 378 IARC MONOGRAPHS VOLUME 19 (e) Refractive Index: n^ 1.3700 (f) Spectrosocpy data: Infra-red, nuclear magnetic resonance and mass spectral data have been tabulated (Grasaelll ft Ritchey, 1975). (ft) Solubility: Slightly soluble In water (0.11 g/XQO g at 25C) (Hsrdle, 1964); soluble in ethanol; very soluble in ether, carbon tetrachloride and benzene (h) Volatility: Vapour pressure is 2530 mm st 20C (Hardie, 1964) (1) Stability: Flash-point, -?8C (closed cup) (Hsrdle, 1964); polymerises In light or tn the presence of a catalyst (Wlndholz, 1976); on combustion it degrades to hydrogen chloride, carbon monoxide, carbon dioxide and traces of phosgene (O'Mara et at., 1971) <1) Reactivity: On treatment with strong alkalis at high tempera tures it loses hydrogen chloride (Miller, 1969). (k) Conversion factor: 1 ppm in air - 2.6 mg/m3 1.4 Technical products and impurities Vinyl chloride is generally supplied as a liquid under pressure. Usually no inhibitor Is added when it is to be shipped within the US. A typical analysis of a commercial US grade is as follows: water, 50 mg/kg (ppm); nonvolatile residue, 5 mg/kg (ppm); acetaldehyde, <1 mg/kg (ppm); acetylene, <1 mg/kg (ppm); iron, 0.1 mg/kg (ppm); hydrogen chloride, <0.1 mg/kg (ppm); and hydrogen peroxide, 0.01 mg/kg (ppm). In Japan, commercial vinyl chloride meets the following specifications purity, 99.91 min; water, 200 mg/kg (ppm) max; hydrogen chloride, 1 mg/kg (ppm) max; iron, 1 mg/kg (ppm) max; and evaporation residue, 50 mg/kg (ppm) max. Chlorinated hydrocarbons nay be present as impurities. 2. Production, Use, Occurrence and Analysis 2.1 Production and use (a) Production The first synthesis of vinyl chloride appears to have been made in 1835 (Regnault, 1835). Addition of hydrogen chloride to acetylene, VINYL CHLORIDE AND POLYMERS 379 formerly the most important route of synthesis, has been displaced by the halogenatlon of ethylene; over 95% of the vinyl chloride monomer produced In Che US and Japan in 1976 was made from ethylene. In this process, ethylene la reacted with hydrogen chloride and oxygen to give ethylene dichloride, which is subsequently cracked to produce vinyl chloride and hydrogen chloride. Vinyl chloride has been produced conmercially In the US for over fifty years (US Tariff Comnlssloa, 1928). In 1976, nine companies reported the production of 2580 million kg (US International Trade Commission, 1977). US Imports have been negligible' exports amounted to 291 million kg in 1976 (US Department of Cotmerce, 1977), and in 1977, exports were about 150 million kg to the following countries (I of total); Brazil (28), Canada (8), Colombia (11), Mexico (14), Norway (12) and Yugoslavia (14). Total western European production in 1976 amounted to 3925 million kg, In the following countries (millions of kg): Belgium (490), the Federal Republic of Germany (990), Finland (25), France (620), Greece (25), Italy (690), The Netherlands (340), Spain (190), Sweden (95), Switzerland (30) and the UK (430). Exports from western Europe in that year were 44 million kg. In Japan, commercial production of vinyl chloride began prior to 1946. In 1976, eighteen companies produced a total of 1281 million kg vinyl chloride; 115 million kg were exported. (b) Use About 96Z of the 2274 million kg vinyl chloride used in the US in 1976 was for the production of vinyl chloride homopolymer and copolymer resins. The remainder was used (essentially by one company internally) in the pro duction of methyl chloroform and as a comonomer with vlnylidene chloride in the production of resins. For a detailed description of the uses of vlnylidene chloride-vinyl chloride copolymers, see p. 450. The largest use for polyvinyl chloride resins is in the production of plastic piping and conduit. Other important uses are in floor coverings, in consumer goods, in electrical applications and in transport applications. For detailed descriptions of the uses of polyvinyl chloride and vinyl chloride-vinyl acetate copolymers, see pp. 406 and 414. Hardie (1964) reported that vinyl chloride has been used as a refri gerant, as an extraction solvent for heat-sensitive materials and in the production of chloroacetaldehyde (an intermediate in the synthesis of sulphonamldes); however no evidence was found that vinyl chloride Is presently being used for these purposes. Limited quantities of vinyl chloride were used in the US as an aerosol propellant, but in 1974 it was banned from use in pesticide aerosol products (US Environmental Protection Agency, 1974a), in self-pressurized household 380 IARC MONOGRAPHS VOLUME 19 containers, and as an Ingredient of drug and cosatetic products (US Cons user Product Safety Cn--lasIon, 1974a,b), Vinyl chloride vas used In western Europe In 1977 In the production of polyvinyl chloride X95X) and for other uses. Including the production of methyl chloroform (52). In Japan in 1976, vinyl chloride was used in the production of poly vinyl chloride (92-942) and for other uses, such as in copolymers (6-82). The US Occupational Safety and Health Administration's health standards for exposure to air contaminants require that an employees'a exposure to vinyl chloride not exceed an eight-hour time-weighted average of 2.6 mg/m1 (1 ppm) in the workplace air in any eight-hour work shift of a forty-hour work week. During any work shift an employee's exposure may not exceed s ceiling concentration limit of 13 mg/m3 (5 ppm), averaged over any period of 15 minutes or leas (US Occupational Safety and Health Admini stration, 1974). The work environment hygiene standards for exposure to vinyl chloride In various countries, in terms of time-weighted averages (S-hr) and celling concentrations (10- or 15-mln), were as follows in 1977: Canada, 10 ppm (B-hr) and 25 ppm (15-aln); Finland, 5 ppm (8-hr) and 10 ppm (10min); Italy, 50 ppm (8--hr), although this Is expected to change to 25 ppm (fr-hr); Japan, expected to be 10 ppm; The Netherlands, 10 ppm (8-hr); Norway, 1 ppm (8-hr) and 5 ppm (15-min); Sweden, 1 ppm (8-hr) and 5 ppm (15-min); USSR, 12 ppm (Bertram, 1977). In France, the standards were reported to be 5 ppm for 1 week, with a celling concentration of 15 ppm, In already existing factories, and 1 ppm and 5 ppm, respectively, for new factories; in Spain, no limits; In Denmark, 1 ppm (8-hr); in Belgium, 5 ppm (1 week), celling 15 ppm; in the Federal Republic of Germany, the same as for France in existing factories, and 2 ppm (1 year) and ceiling 15 ppm (1-hr) for new factories; In the UK, 10 ppm (8-hr), ceiling 30 ppm max; and in Switzerland, 10 ppm (1 week, 6-hr day for 5 days) (Thomas, 1977). In August 1977, the proposed European value was 3 ppm over one year for existing and future plants, with an 'alarm-value1 of 15 ppm (Connlssion of the European Communities, 1977a). The US Environmental Protection Agency has proposed new rules to reduce the national emission standard for vinyl chloride from 10 ppm to 5 ppm in order to reduce vinyl chloride emissions by one-half within 3 years of the actual rulemaking. This would result In hourly emissions (based on new average-sized plants) of 5.1 kg from an ethylene dichloridevinyl chloride plant (instead of 10.3 kg); 9 kg from a dispersion process polyvinyl chloride plant (instead of 17.5 kg); and 13.5 kg from a sus pension process polyvinyl chloride resin plant (Instead of 16 kg) (US Environmental Protection Agency, 1977). VINYL CHLORIDE AM) POLYMERS 381 In the Federal Republic of Germany, the emission in the environment is limited to 3 kg/hr/source or 150 mg/re3/source, with a ground level of 0.3 mg/m3 (992 confidence) in Inhabited areas (Thomas, 1977). The Commission of the European Communities has adopted a level of 1 mg/kg (1 ppm) as the amount of vinyl chloride which can be present in packaging and 0.01 mg/kg (ppm) in foodstuffs packed in polyvinyl chloride (Commission of the European Communities, 1977b, 1978). A maximum migration level of 0.05 mg/kg has been adopted in Belgium, Denmark, the Federal Republic of Germany, France, Italy, The Netherlands, Spain and Sweden (Thomas, 1977). 2.2 Occurrence Vinyl chloride is not known to occur as a natural product. The occurrence of vinyl chloride in ambient air near vinyl chloride and polyvinyl chloride plants, in water, and in food has been reviewed (US Environmental Protection Agency, 1975a,b). (a) Occupational exposure The air concentration of vinyl chloride in a polymerization reactor prior to ventilation Is of the order of 7800 mg/m3 (3000 ppm); during the scraping procedure, 130-260 mg/m3 (50-100 ppm); and that close to the hands during scraping, 1560-2600 mg/m3 (600-1000 ppm) (Cook et al,, 1971). Between 1950 and 1959, concentrations up to 10.4 g/m3 (4000 ppm) were found in one factory near the polymerization reactors (Ott et al., 1975). Air concentrations of vinyl chloride in working places in polyvinyl chloride-producing factories have been reported variously to range from 100-800 mg/m3 (40-312 ppm), with p?sks up to 87.3 g/m3 (33 500 ppm) (Filatova & Gronsberg, 1957); free 112-556 mg/m3 (43-214 ppm) (Anghelescu et at,, 1969); and >195 mg/m3 (>75 ppm) in a Yugoslav plant (Orusev et al., 1976). In a Russian synthetic leather plant, <113.6 mg/m3 (44 ppm) (Bol'shakov, 1969) and in three UK cable factories, 0.4-0.9 mg/m* (0.150.35 ppm) (Murdoch A Hammond, 1977) were detected. In 1974, it was esti mated that 20 000 US workers, past and present, had been exposed to vinyl chloride in manufacturing plants (Heath et at1975). On a time-weighted average, the cqncentratlon of vinyl chloride mono mer to which coagulator operators are exposed ranges from 130-650 mg/m3 (50-250 ppm) (Baretta et al.t 1969). However, in a more recent survey for the US National Institute for Occupational Safety and Health of three vinyl chloride plants it was reported that the t: irae-weigh ted average exposure to vit^yl chloride ranged from 0,2-70 mg/m3 (0.07-27 ppra) (Hilby, 1977). Barnhart et al. (1975) found <0.03-15 mg/m3 (<0.01-5.89 ppm), 0.03-220 8/m3 (0.01-84.77 ppm) and 0.05-57 mg/m3 (0.02-21.8 ppm) in 3 vinyl chlo ride plants in the US. UCC 108042 3S2 1ARC MCMXRAPHS VOLUME T9 In 1974, It was reported that polyvinyl chloride leaving certain manufacturing plants nay have contained 200-400 mg/kg (ppm) vinyl chloride monomer; on delivery to the customer, this level was about 250 mg/kg (ppm); and after processing, levels of 0.5-20 mg/leg (ppm) were reached, depending on the method of fabrication (Anon., 1974). Wilkinson et al. (1964) found 100 mg/kg (ppm) residual vinyl chloride monomer In polyvinyl chloride dis persions. However, new processing methods leave as little as 1-2 mg/kg (ppm) residual vinyl chloride in vinyl chloride resins (US Food and Drug Administration, 1975). Residual vinyl chloride in commercial food grade resins has been reduced by processing and stripping techniques to 115 t>g/kg (ppb) for resin, less than 0.048 pg/lcg (ppb) for compound and less than 0.043 Ug/kg (ppb) for sheet polyvinyl chloride (Saggeae et al., 1976). Industrial grade polyvinyl chloride-coated films used for food packaging were found to contain 5-71 Ug/kg (ppb) of monomer (Gilbert et al., 1975) and plastic bottles up to 7.9 mg/kg (ppm) (Breder et al., 1975). <b) Air It has been estimated that prior to 1975 vinyl chloride emissions from US polyvinyl chloride plants amounted to 110 million kg/year (US Environmental Protection Agency, 1975b) and that the average concentration of vinyl chloride in air around these plants was 44 pg/mJ (17 ppb) (US Environmental Protection Agency, 1976). Vinyl chloride has been determined in the air in the Houston, Texas, area (where an estimated 40Z of the US production capacity is located) In concentrations of 6 Ug/m -3.2 mg/m3 (3.1-1250 ppb) (Gordon & Meeks, 1977) and in the ambient air near two vinyl chloride plants in the long Beach, California, area in concentrations of 0.26-8.8 mg/*3 (0.1-3.4 ppm) (National Field Investigations Center, 1974). It has also been detected in the air In Delaware City, Delaware, in maximum concentrations of 3.9 mg/m3 (1.5 ppm) with a mean of 2 mg/m3 (0.0 ppm) (Lillian et al., 1975). (c) Water Vinyl chloride has been detected In effluent discharged by chemical and latex manufacturing plants and in raw water in the US (Shackelford 6 Keith, 1976). The highest concentration of vinyl chloride detected in finished drinking-water in the US was 10.0 ug/1 (Safe Drinking Water Committee, 1977; US Environmental Protection Agency, 1975a). In 1974, it was estimated that about 12.3 kg/day vinyl chloride were discharged in the waste-water effluent from 2 vinyl chloride plants in the Long Beach, California, area (National Field Investigations Center, 1974). (d) Food In May 1973, a branch of the US Treasury Department banned the use of polyvinyl chloride for the packaging of alcoholic beverages (Anon., 1973a), as a result of studies reported by the US Food and Drug Administration indi cating that up to 20 mg/kg (ppm) vinyl chloride monomer were present in VINYL CHLOF IDE 'AND POLYMERS 383 alcoholic beverages packaged in this material (Anon., 1973b). Vinyl chloride has been found in a variety of alcoholic drinks at levels of 0-2.1 mg/kg (ppm) (Williams, 1976a,b; Williams A Miles, 1975) and In vinegars at levels of up to 9.4 mg/kg (ppm) (Williams A Miles, 1975). It has been found in edible oils, in concentrations of 0.05-14.6 mg/kg (ppm) (Roeall et al., 1975; Williams, 1976a; Williams A Miles, 1975), and In butter and margarine, in concentrations of 0.05 mg/kg (ppm) (Fuchs et al., 1975), when these products were packaged and stored In polyvinyl chloride containers. (e) Other Vinyl chloride has been found in 2/7 new automobile interiors in concentrations of 1-3 sg/m3 (0.4-1.2 ppm) (Hedley et al1976). In another study (Going, 1976), no concentrations above 10 ppb were found 16 new or used automobiles or In 4 new or old mobile homes. in Vinyl chloride has been detected in domestic and foreign cigarettes and little cigars, in concentrations of 5.6-27 ng/cigarette, and in a marijuana cigarette at a level of 5.4 ng/cigarette (Hoffmann et al., 1976). 2.3 Analysis A comprehensive critical review, containing over 100 references, of methods of sampling and analysis of vinyl chloride in the workplace atmo sphere, ambient air, water, food, cigarette smoke and polyvinyl chloride 1b available (Egan et al., 1979). Methods of collection and analysis of vinyl chloride have also been reviewed (US Environmental Protection Agency, 1975b). A review of methods used to determine vinyl chloride in air, water, and water piping Is available (Laramy, 1977). A gas chromatographic method of analysis has been accepted by the US National Institute for Occupational Safety and Health for determining vinyl chloride In the workplace atmosphere, in the range of 0.008-5.2 mg/a* in a 5-litre air sample (National Institute for Occupational Safety and Health, 1977). A gas chromatographic analytical method has been proposed by the Com mission of the European Communities for *determlnlng vinyl chloride in foodstuffs and In vinyl chloride polymers and copolymers Intended to come into contact with food (Comlssion of the European Comunitles, 1977b). An official analytical method has been drafted in the Federal Republic of Germany for determining residual vinyl chloride in polyvinyl chloride. It Is based on treatment of the polymer with AF, IP-dlmethylacetamlde, followed by gas chromatographic analysis of the solution with flame-ionisation detec tion and has a limit of detection of 0.5 mg/kg (ppm) (Deutsche Industrie Normen Ausschuss, 1977). UCC 108043 384 IARC MONOGRAPHS VOLUME 19 3. Biological Data Relevant to Che Evaluation of Carcinogenic Risk to Humans 3.1 Carcinogenicity studies in animala*'*2 (a) Oral administration Rat: Groups of 40 sale and 40 female 13-week-old Sprague-Davley rats received gastric Intubations of 0, 3.33, 16.65 or 50 mg/kg bw vinyl chloride dissolved In olive oil 4-5 times/week for 52 weeks. After 85 weeks from the initial treatment, 35, 39, 32 and 23 animals were still alive. At 120 weeks, 9 liver angiosarcomas, 2 Zymbal gland carcinomas and 3 nephroblastomas occurred In rats administered the 16.65 mg/kg bw dose; and 16 liver anglosarcomas, 2 nephroblastomas, 1 Zymbal gland carcinoma, and 1 thymic and 1 lntra-abdomlnal angiosarcoma were found in the 50 mg/kg bw group. One intra-abdominal angiosarcoma was seen in the low-dose group, and 1 Zymbal gland tumour occurred in the control group (Haltoni, 1977a; Hsltoni et al., 1975). tit) Inhalation and/or intratracheal administration House; Groups of 30 male and 30 female 11-week-old SwIbs mice were exposed to concentrations of 130-26 000 mg/m3 (50, 250, 500, 2500, 6000, or 10 000 ppm) vinyl chloride in air for 4 hours/day on 5 days/week for 30 weeks. A total of 344 alee (176 males and 168 females) died within 61 weeks. At 81 weeks (end of experiment), 176 animals (3.5, 57, 66, 57, 70 and 70X In the different groups, respectively) had adenomas and/or adeno carcinomas of the lung, 60 animals (33, 32, 24, 30, 28 and 47JC, respec tively) had mammary adenocarcinomas and 47 animals (2, 19, 19, 20, 5 and 16Z, respectively) had angiosarcomas of the liver. Except for lung tumours, which were not Increased In the group treated with 50 ppm, a significantly higher number of neoplasms occurred in all treated groups. In 80 male and 70 female untreated controls, 8 pulmonary tumours and 3 lymphomas were observed (Haltonl, 1977; Maltoni et al., 1974). *The Working Group was aware of studies in progress to assess the carcinogenicity of vinyl chloride In rats by administration In the dTinkingwater and by administration in the diet, and of complete but unpublished studies by inhalation in rats (1ARC, 1978a). 2In all his experiments, Maltoni used vinyl chloride that contained the following Impurities (mg/kg): water, 100; acetic aldehyde, 5; ace tylene, 2; sllene, 5; butane, 8; 1,3-butadiene, 10; chloroprene (see also, p. 131), 10; diacetylene, 4; vinyl acetylene, 10; propine, 3; methyl chloride, 100. VINYL CHLORIDE AND POLYMERS 385 Groups of 100 male and 100 female CDl Swiss/ChR nice (age unspecified) were exposed to 130, 520 or 6500 ng/m3 (50, 200 or 2500 ppn) vinyl chloride In air (purity unspecified) foT 7 hours/day on 5 days/ueek for 9 nonths and were observed for an additional 9 nonths. After 8 souths' exposure, 49 treated animals died with tumours. A total of 42 pulmonary adenonas, 41 livex angiosarcomas and 11 mammary gland adenocarcinomas were observed (histological evaluation was carried out on grossly visible tumours only). A dose-related carcinogenic effect was evident (see Table I). At 8 months, no tumours were observed in 200 controls (100 fenales and 100 males). The study was still in progress at the time of reporting (Keplinger et al.. 1975). Table I Incidence of tumours in nice exposed to vinyl chloride (purity unspecified) for 8 months' Exposed groups 50 ppn 200 ppn 2500 ppn Control No. of nice with tumours at death Male Female Total i 34 3 12 li 6 24 3C 0 00 Type and location of tumour Adenomas Angiosar Adenocar comas cinomas lung liver mammary gland 22 12 11 28 28 00 2 3 6 0 'From Keplinger et al, (1975), preliminary results Two groups each of 12 male and 12 female 3-month-old NHRI outbred albino mice were exposed to either 130 or 1300 mg/m3 (50 or 500 ppm) vinyl Chloride in air for 6 hours/day on 5 days/week. The 500 ppm group was exposed for 26 weeks only (due to the poor condition of the mice) j the 50 ppm group wsb exposed for 52 weeks, at iwhich tine the experiment was ter minated. In the low-dose group, 18/24 animals had developed tumours, inclu ding pulmonary adenomas In 13/24, angiosarcomas at various sites In 15/24 and a mammary carcinoma in 1 mouse. Inhalation of 500 ppm vinyl chloride for 26 weeks induced pulmonary adenomas in all mice; in addition, 8 nice had 1 angiosarcomas, mammary adenocaicinomas were found in 4 animals, 1 mouse had an angiosarcoma of the liver, 1 an adenoma of the kidney and 1 an angiosarcoma of brown fat. In the control group, 3/48 had tumours: 1 adenocarcinoma of the mamnary gland, 1 dysgerminoma of the ovary and 1 reticulum-cell sarcoma of the spleen (Holmberg et al., 1976). UCC 108044 386 1AAC MONOGRAPHS VOLUME 19 Groups of 36 male and 36 female 2-month-old albino CD mice were exposed to 130, 650 and 2600 mg/m* (50, 250 and 1000 ppn) vinyl chloride (99.8X pure) In air for 6 hours/day on 5 days/week for 52 weeks; at that tine, 70, 52, 66 and 38 animals were still alive, respectively. A total of 12, 22 and 48 alee developed lung adenomas in the exposed groups, res pectively; 1 lung adenoma was found In untreated control animals. In addition, angiosarcomas of the liver developed in 3, 23 and 31 treated mice, respectively, and anglosarcomaa in other organs in 7, 5 and 9 mice. Maasaary gland tumours were found in 9, 3 and 13 mice, respectively; most of these tumours metastasized to the lungs (Lee et al., 1977, 1978). Rat: A group of 26 male 3-oonth-old Ar/IRJE Ulster rats were exposed to an atmospheric concentration of 32 v/v (equivalent to 78 g/m3 or 30 000 Ppe) commercial grade vinyl chloride (99X pure) for 4 hours/day on 5 days/ week for 12 months; the experiment was terminated at 54 weeks. Skin tumours developed In the submaxlllary parotid region In all 17 surviving rats (14 epidermoid carcinomas, 2 mucoepidermoid carcinomas, 1 papilloma); in addition, lung tumours developed in 7 rats and osteochondromas in 5. Ho tumours were observed In 25 untreated controls killed at an unstated time (Viola et at., 1971) [Haltonl 4 Lefemlne (1974) examined slides from this experiment and concluded that the skin tumours were Zymbal gland tumours and that the lung tumours were metestases from these]. Groups of 30 male and 30 female 21-week-old Sprague-Davley rats were exposed by inhalation to 130-26 000 mg/m5 (50, 250, 500, 2500, 6000 or 10 000 ppm) vinyl chloride In air for 4 hours/day on 5 days/week for 17 weeks. At 86 weeks, 18, IS, 37, 33, 16 and 9 animals were still alive In the 6 groups. At 155 weeks (end of experiment), carcinomas of the Zymbal gland were found In 0, 1, 1, 3, 6 and 7 animals, respectively (1 In un treated controls), nephroblastomas In 1, 2, 0, 2, 1 and 1 animals, liver angiosarcomas in 0, 0, 1, 1, 1 and 0 animals and angiosarcomas at other sites in 2, 0, 1, 2, 1 and 1 (1 In controls). Brain neuroblastomas were seen in 0, 0, 0, 2, 2 and 6 animals, respectively (Maltonl, 1977a; Haltonl et at., 1974). Groups of 64-96 13-week-old Sprague-Dawley rats were also treated for 52 weeks with the above concentrations of vinyl chloride in air. The following tumours developed in various organs by the end of the experiment, at 135 weeks: carcinomas of the Zymbal gland in 29/239 rats at the 4 highest dose levels, and nephroblastomas (26/257 rats) and angiosarcomas of the liver (47/357 rats) in all the treated groups (the numbers of rats given were those alive at 26 weeks); a total of 14 angiosarcomas was observed In organa other than the liver. The tumours of the liver and kidney metastasized to other organs. No such tumours were observed In 58 untreated controls alive at 26 weeks (see Table II). In a group of 60 17veek-old Sprague-Dawley rats treated with 78 g/m3 (30 000 ppm) vinyl chloride In air for 4 hours/day on 5 days/week for 43 veekB, 30 (501) developed Zymbal gland carcinomas, 13, liver angiosarcomas and 1, a lung angiosarcoma within the 61 weeks of observation (Maltonl et al., 1974). No. o f o th e r tum ours 11 10 7 8 7 10 10 VINYL CHLORIDE AND POLYMERS JX 3? jHoa ot'i h I 2$ i O 9 03 9 *i 8 J3 frS * 3* 4I1 u o 5* u't 3 m <M0 "O 0a u-v 1g JJ X `S-S VM N No. o f Zymbal g la n d tum ours .i O 'fCH O MRJ ss ja W90 aII *(*J0 Hx* 0M O J O Tf 4 g 0 O J4S u O V O> tCo M *j t*JH z i 4n en u-% o o o o cn m cn cv rj rH o n 1 f O * o OH 0a0 ouO * JJ3J u tl > 2 3 4OH m 1i 4-1 o uO uO .c n O. 4 O 4 -f a ca on <Hn fHi rs. o in Sj- vD >3- cO H O p*H r- S3 O O 61 60 59 59 59 59 58 * as IMH J J * *3$ H du u4 O H 4 *M o 4 Ua 1h wa a M H <8 d 8 u -trsi > *UH o 0O pH UOO <J> , N r* r- 03 ' Cn rs 4 O 4 \0 10 000 6000 2500 500 250 50 C o n tro ls From M a lto n l e t a l. (1974) "t: 387 9^080V0 0 0 388 1ARC MONOGRAPHS VOLUME 19 Wlstsr rats were also exposed by inhalation to 130-26 000 mg/m3 (50, 250, 500, 2500, 6000 and 10 000 ppm) vinyl chloride in air for 52 weeks. After 136 weeks of observation, 1 Zymbal gland carcinoma was found, whereas at a comparable time the Sprague-Dawley rats had developed 29 such tumours. In the Ulster rats, 1 nephroblastoma, 8 liver angiosarcomas and 1 brain neuroblastoma were found In the 10 000 ppm group; 3 nephroblastomas, 2 liver angiosarcomas and 1 brain neuroblastoma In the 6000 ppm group; 3 liver angiosarcomas la the 2500 ppm group; and 1 nephroblastoma and 4 liver angiosarcomas in the 500 ppm group (Maltoni, 19?7a; Maltoni et al., 1974). The effect of length of treatment by inhalation of vinyl chloride on the incidence of liver angiosarcoma* was investigated. Croups of 60-120 Sprague-Dawley rats wets given either 15.6 or 26 g/s* (6000 or 10 000 ppm) vinyl chloride In air for 4 hours/day on 5 days/week for 5, 17 or 52 weeks. The experiment was terminated at 155 weeks. Liver angiosarcomas developed In 13 (222) and 9 (151) of the 6000 and 10 000 ppm groups exposed for 52 weeks; 1 (0.6Z) liver angiosarcoma was found in s rat exposed to 6000 ppm for 17 weeks and none in the 10 000 ppm group. Wo such tumours were Induced in rats treated for 5 weeks (Maltoni, 1977b) [Ho Information was given about tumours occurring at other sites]* The influence of age on the incidence of liver tumours was examined in Sprague-Dawley rata exposed to 15.6 or 26 g/m3 (6000 or 10 000 ppm) vinyl chloride in air for 4 hours/day on 5 days/week for 5 weeks, starting at the age of 13 weeks (120 rats/group) or 1 day <43 and 46 rats). The animals were observed for 135 weeks. One hepatoma was reported in the older rata treated with 10 000 ppm. In the newborn rats, 10 angiosarcomas and 13 hepatomas were observed in the 6000 ppm group, and 10 angiosarcomas and 15 hepatomas were found in rats treated with 10 000 ppm. No liver tumours were reported in the 249 untreated rats (Maltoni, 1977b). Croups of 36 male and 36 female 2-month-old CD rats were exposed to 0, 130, 650 and 2600 mg/m3 <0, 50, 250 and 1000 ppm) vinyl chloride In air (99.8X pure) for 6 hours/day on 5 days/week for 12 months, at which time the surviving animals (72, 70, 58 and 51) were killed. In rats treated with 250 and 1000 ppm, liver angiosarcomas occurred in 12 and 22 and lung angloaarcomas developed In 3 and 13 (Lee et at., 1977). In a report of a study in progress, 4 groups of 60 Sprague-Dawley male rata received either 5Z ethanol In the drinking-water or drinking-water only for 4 weeks prior to beginning inhalation of 1560 mg/m3 (600 ppm) vinyl chloride for 4 hours/day on 5 days/week for 12 months or air; ethanol-water was given until death or sacrifice. After 60 weeks from the first exposure to vinyl chloride, 55 rats had died or had been sacrificed; liver tumours were found in 21/28 (751) in the vinyl chloride-ethanol group and 5/13 (382) in the vinyl chloride only group (Radike et at., 1977), Hamster: Croups of 32-35 male 11-week-old golden hamsters were exposed by inhalation to 130-26 000 mg/m3 (50, 250, 500, 2500, 60G0 and 10 000 ppm) VINYL CHLORIDE AND POLYMERS 389 vinyl chloride in air for 4 hours/day on 5 days/week for 30 weeks. At 48 weeks from the initial treatment, 60/198 treated animals were still alive. At 109 weeks (end of treatment), 2 liver angiosarcomas were seen in hamsters treated with 500 ppm and 1 in those treated with 6000 ppm. Skin tricho epitheliomas developed In 22 treated hamsters (in 1-6 animals /group) and in 2/70 controls. Two animals treated with 6000 ppm and 1 each treated with 50, 2500 and 10 000 ppm developed melanomas. In addition, 6 lymphomas and 35 forestomach papillomas and acanthomas were found in treated animals, and 2 and 2, respectively, in controls (Maltoni, 1977a; Maltoni et al., 1974). Rabbit: A group of 40 rabbits were exposed for 4 hours/day on 5 days/ week for 12 months to air containing 26 g/m3 (10 000 ppm) vinyl chloride. Between 9-15 months of exposure, 12 skin acanthomas and 6 lung adenocar cinomas were seen. No similar tumours occurred in 20 controls after 15 months of observation (Caputo et al., 1974) [The Working Group noted the Inadequacy of reporting]. <c) Subcutaneous and/or intramuscular administration A group of 75 male and female 21-week-old Sprague-Dawley rats were given single s.c. injections of 4.25 mg/animal vinyl chloride in 1 al olive oil. One nephroblastoma occurred :n the treated animals (Maltoni, 1977a) [The Working Group noted that survival times and period of observation were not given]. (d) Intraperitoneal administration Groups of 30 male and 30 female 13-week-old Sprague-Dawley rats received single injections of 4.25 mg/animal vinyl chloride In 1 ml olive oil, 2, 3 or 4 times In 2 months. One nephroblastoma and 1 s.c. angiosar coma were found (Maltoni, 1977s) [The Working Group noted that survival times and period of observation were not given]. (e) Other experimental systems Prenatal exposure: Two groups of 30 female Sprague-Dawley rats were given 15.-26 g/m1 (6000 or 10 000 ppm) vinyl chloride in air for 4 hours/ day by lnnalatlon from the 12-18th day of pregnancy. Of the offspring, 17/32 and 23/54 had died by the 95th we^k after birth. After 143 weeks (end of experiment), 1 s.c. angiosarcoma was observed In each group of offspring; 1 animal exposed in utevo to 6000 ppm had a Zymbal gland car cinoma; and 3 animals exposed to ""O 000 ppm had Zymbal gland carcinomas, and 1, a nephroblastoma. One female rat treated with 10 000 ppm developed a Zypbal gland carcinoma (Maltoni, .974; Maltoni, 1977a). 390 IARC MONOGRAPHS VOLUME 19 3.2 Other relevant biological data (a) Experimental systems toxic effects The 2-hour LCji of vinyl chloride for nice was 294 g/m3 (113 000 ppm); for rats, 390 g/m3 (150 000 ppm); for guinea-pigs, 595 g/m3 (230 000 ppm); and for rabbits, 295 g/t* (113 000 ppa). Vinyl chloride gas had a narcotic effect on experimental animals, the most sensitive species being alee, followed by rats, guinea-pigs and rabbits. The death of animals was prece ded by excitement, contractions and convulsions, accelerated respiration, followed by respiratory failure. Rabbits and guinea-pigs had more accen tuated muscular contractions and convulsions than mice and rats. Micro scopically, congestion of the Internal organs with more intense damage to the lunga, liver and kidneys were found (Prodan et al., 1975a). The hepatotoxiclty of vinyl chloride has been shown to be Increased after administration of cytochrome P-450 inducers such as phenobarbltal, Aroclor 1254 and hexachlorobenzene (Ivanetlch et al., 1977; Reynolds et al., 1975a,h). The extent of liver damage has been measured by the release of alanine a-ketoglutarate, glutamic oxalacetic and glutamic pyruvic transaminases (Reynolds et si., 1975b, 1976) and of sorbitol dehydrogenase (Gonolly 4 Jaeger, 1977) into the serum. A single 6-hour Inhalation exposure to 130 g/m3 vinyl chloride (50 D00 ppm) produced acute liver Injury In male Sprague-Davley rats pretreated with phenobarbltal or Aroclor 1254. The degree of injury, as Indicated by elevation of serum levels of enzymes derived from the liver, correlated with the magnitude of Induction of cytochrome P-450 and morphological changes in the endoplasmic reticulum (Reynolds et at., 1975a,b, 1976). Similar find ings were reported in phenobarbltal-pretreated male Holtzman rats (Jaeger et at., 1974) and in phenobarbltal-treated male Charles River CD-I rats that received 10 daily exposures for 6 hours/day to 35 g/m3 (13 500 ppm) vinyl chloride In air (Drew et at., 1975). Cytochrome P-450 concentration decreased during in vivo exposure or during in vitro incubation of liver homogenate from phenobarbltal or 3methylcholaathtene-lnduced rata (Ivanetlch et at., 1977; Reynolds et al., 1975c). In an abstract. It was reported that male rats pretreated by gavage with Aroclor 1254 for 3 consecutive days and exposed on day 4 by inhalation to 62.5 g/m3 (24 000 ppm) vinyl chloride for 4 hours shoved significant elevations of serum alanlne-o-ketoglutarate transaminase and severe degener ation and necrosis of the liver (Conolly et al., 1977). Overnight fasting, which depletes hepatic glutathione, of Aroclor-pretrested male Holtzman rats before exposure to 26 g/m3 (10 000 ppm) for 4 hours significantly Increased the hepatotoxlc effects, as measured by sorbitol dehydrogenase levels in the serum (Conolly 4 Jaeger, 1977). VINYL CHLORIDE AND POLYMERS 391 Simultaneous exposure to 1.75 g/m3 (671 ppm) vinyl chloride with 200 ppm vinylidene chloride prevented vinylidene chloride-induced hepatic injury in fasted male rats. However, pre-exposure to concentrations of vinyl chloride which depleted hepatic glutathione concentrations signifi cantly enhanced early acute hepatotoxlc response to vinylidene chloride in fed rats (Jaeger et al., 1975a,b). Exposure of guinea-pigs to 260 g/m3 (100 000 ppm) vinyl chloride for 2 hours/day for 3 months resulted In marked growth disturbances and Intense hlstopathologlcal and hlstochemlcal lesions in the liver, kidneys, spleen, and lungs. Interruption of the exposure resulted in a regenerative effect, denoting a certain degree of reversibility of the hepatorenal lesions. Large quantities of vitamin C reduced the gravity of the leslonB caused by vinyl chloride (Prodan et al., 1975b). Mice were exposed to 13Q, 650 or 2600 mg/m3 (50, 250 or 1000 ppm) vinyl chloride for 6 hours/day on 5 days/week. The highest dose caused some acute deaths with toxic hepatitis and marked tubular necrosis in the renal cortex* From the 6th month of treatment, all mice became lethargic, lost weight quickly and died. Only a few mice exposed to 50 ppm survived for 12 months (Lee et al., 1977). The non-protein, free SU-groups of the liver are depleted in tats exposed to 390-5200 mg/m3 (150-2000 ppm) vinyl chloride for 1-7 hours, as a function both of concentration and duration of exposure (Uatanabe et al.. 1976a). Vinyl chloride and two of Its presumed metabolites, chloroethylene oxide and chloroacetaldehyde, depressed DNA synthesis in rat liver in vivo (Border & Webster, 1977). Embryotoxlclty and teratogenicity Pregnant CF-1 mice were exposed by inhalation to 130 and 1300 mg/m3 (50 and 500 ppm) vinyl chloride on days 6-15 of gestation, Sprague-Davley rats to 1300 and 6500 mg/m3 (500 and 2500 ppm) on days 6-15 of gestation, and New Zealand rabbits to 1300 and 6500 mg/m3 (500 and 2500 ppm) on days 6-18 of gestation, for 7 hours/day, with or without simultaneous exposure to 152 ethanol In the drinking-water. A significantly Increased Incidence of several skeletal anomalies was bbeerved In offspring of mice that received vinyl chloride plus ethanol (John et al., 1977; Schwetz et al., 1975). Absorption, distribution, excretion and metabolism The in vivo and in vitro metabolism of vinyl chloride has been studied and reviewed (Antweiler, 1976; Bartsch 4 Montesano, 1975; Bonse & Henschler, 1976; Green 4 Hathway, 1975, 1977; Haley, 1975; Hefner et al., 1975; Malavellle et al., 1975; Mttller 6 Norpoth, 1975; HUlleT et al., 1976; Plugge 4 Safe, 1977; Watanabe & Gehrlng, 1976; Watanabe et al., 1976b,c). UCC 108047 392 IARC MONOGRAPHS VOLUME 19 Low concentrations (130 mg/*, 50 ppm, for 65 Bin) of vinyl chloride ere readily Metabolized In rats exposed by Inhalation and are converted Into polar Metabolites, which are predominantly excreted in the urine; a very small amount la expired in air aa unchanged vinyl chloride (Hefner at at., 1975). Following exposure of male rata by Inhalation to 26 mg/m3 (10 ppm) *11C-vinyl chloride for 6 hours, urinary 1 "C-activlty and expired vinyl chloride comprised 68 and 21, respectively, of the recovered radioactivity; after exposure to 2600 ng/m* (1000 ppm) '"C-vinyl chloride, the proportion of the radioactivity in the urine was lower and that expired as vinyl chloride higher, representing 56 and 12X, respectively. The pattern of pulmonary elimination of 10 and 1000 ppm vinyl chloride per ae was descri bed by apparently similar first-order kinetics, with half-lives of 20.6 and 22.4 min, respectively; the half-lives for the initial phase of excretion of 1'C-radioactivlty in the urine were 4,6 and 4.1 hours, respectively. 13C-Badinactivity recovered from the carcass after 72 hours was 14 and 152, respectively; no vinyl chloride per ae waa found in tissues. The propor tions of 3 urinary metabolites, W-acetyl-S-(2-hydroxyethyl)cysteine, thiodlglycolic acid (thiodlacetic acid) and an unidentified metabolite, were not markedly influenced by the level of exposure (Watanabe et at., 1976b). Following single oral administration of 0.05, 1 or 100 mg/kg bw l*Cvinyl chloride to male rats, excretion in the urine was 59, 68 and 111, respectively; the 1 * CO? in expired air accounted for 9, 13 and 3X, respec tively; pulmonary elimination of unchanged vinyl chloride represented only 1-3X of the lower dose levels and 67X of the higher level. The pulmonary clearance of 0.05 and 1 mg/kg bw doses of vinyl chloride was monophaslc, with half-lives of 53.3 and 57.8 min, respectively; it waa biphasic after administration of 100 mg/kg bw, with half-lives of 14.4 and 40.8 min for the fast and slow phases, respectively. The percentages of the doses left in the carcass after 72 hours were 10, 11 and 2X of the 0.05, 1 and 100 mg/kg doses, respectively. Two of 3 urinary metabolites were identified as tf-acety1-S-(2-hydroxyethyl)cysteine and thiodiglycolic acid; their propor tions were not Influenced by dose (Watanabe et at., 1976c). It has been suggested that the metabolism of vinyl chloride in rats following oral and inhalation exposure is a saturable process (Watanabe et at., 1976b,c). The kinetic parameters and half-lives for the elimination of vinyl chloride from rats after Inhalation and i.v. administration have elso been reported by Withey (1976). When rats were exposed to Initial concentrations of less than 260 mg/m3 (100 ppm) (1.2-1'cl-vlnyl chloride, about 40X of that inspired was absorbed by the lung. Highest radioactivity levels were observed in the liver and kidney immediately after exposure. Host of the radioactive metabolites were excreted rapidly, largely by the kidneys: the radioactivity In the urine amounted to 70X within 24 hours. Some metabolites, however, remained in tissues (mostly in spleen, liver, kidneys) even 48 hours after exposure (Bolt et al., 1976). Metabolites that were not excreted in urine were pertly VINYL CHLORIDE AND POLYMERS 393 excreted via faeces and partly via expiration of 1*C0? (Bolt et at., 1976; Green & Hathway, 1975). Vinyl chloride is metabolized by microsomal mixed-function oxidases to chloroethylene oxide, which can rearrange spontaneously to chloroacetaldehyde (Fig. 1). Although there is no direct evidence for this pathway in vivo, the following data ate consistent with this hypothesis. Vinyl chloride in the presence of a mouse liver microsomal fraction, rat liver homogenate, an NADPH generating system and oxygen yielded an alkylating intermediate which reacted with either 3,4-dichlorobenzenethiol (Gdthe et al., 1974) or with 4-(4-nitrobenzyl)pyridine. The absorption spectra of the latter adduct was identical to those obtained with the product formed with synthetic chloroethylene oxide (Barbln et al., 1975; Bartsch et at., 1976). These studies Indicate that the primary in vitro metabolite of vinyl chloride la chloroethylene oxide, which can rearrange to chloroacetaldehyde. Metabolism of vinyl chloride occurs predominantly through the cyto chrome P-450 system (Ivanetich et al., 1977; Reynolds et al., 1975c; Salmon, 1976). Inhibitors of microsomal mixed-function oxidases, such as 3-bromophenyl-4(5)-imidazoie or 6-nitTo-l,2,3-benzothiadiazole, reduced vinyl chloride metabolism in vivo (Bolt et al., 1976). Chloroethylene oxide, with a half-life of 1,6 min in aqueous solution at neutrality (Barbin et al., 1975), rearranges to chloroacetaldehyde (Bonse et al., 1975) . Chloroacetaldehyde combines directly or enzymatically via gluta thione S-transferase with glutathione to form S-formylmethy1glutathione, which is excreted as AI-acetyI-S-(2-hydroxyethyl)cysteine (Green 4 Hathway, 1977) (Fig. 1). Chloroacetaldehyde can be oxidized to chloroacetic acid, which ia either excreted as such -t bound to glutathione to form S-carboxyraethyl glutathione, which upon further enzymic degradation is excreted as thiodiglycolic acid (thiodlacetic acid) (Plugge 4 Safe, 1977). Chloroacetic acid was metabolized in rats to two major urinary meta bolites, S-carboxymethylcysteine and thiodlacetic acid (Tllner, 1971). tf-Acetyl-S-(2-hydroxyethyl)cysteine (a major metabolite) (Green 4 Hathway, 1977; Watanabe et al., 1976b,c), S-(carboxymethyl)cysteine and tf-acetyl-Svinylcystelne have been shown to be metabolites of vinyl chloride In rats after oral administration (Green 4 Hathway, 1977) and IV-acetyl-S-(2-hydroxyethyl)cysteine after inhalation (Watanabe et al., 1976b); 3-{2-chioroethy1)cysteine waa also identified after oral administration of vinyl chloride to rats (Green 4 Hathway, 1975). As thiodiglycolic acid was obtained as a common metabolite In rats dosed separately with chloroace taldehyde, chloroacetic acid or S-(carboxymethyl)cysteine, the identifica tion of the same S-containlng metabolite from vinyl chloride-treated animals gives further support to the hypothesis that chloroethylene oxide or chloroacetaldehyde are formed and react with glutathione (Green 4 Hathway, 1977). Following oral administration of lllC-vinyl chloride, 1 "co2 (Green 4 Hathway, 1975; Watanabe et al., 1976c), 1"c-labelled urea and glutamic acid were identified as minor metabolites (Green 6 Hathway, 1975). UCC 108048 594 IARC MONOGRAPHS VOLLME 19 VINYL CHLORIDE AND POLYMERS 395 In vitro binding of l*C-vinyl chloride was shown to be dependent on the thiol content of proteins (Bolt & Fllser, 1977), and binding was dependent on the presence of NADPH, oxygen and microsomal enzymes (Kappua et at,, 1976)* It has been suggested that an epoxide of vinyl chloride la involved In the covalent binding reaction (Kappus et al., 1975). In the presence of a rat liver microsomal system, vinyl chloride binds to RNA _ in vitro (Kappus et al., 1975) and to RNA and DNA in vivo (Laib A Bolt, 1977). Chloroacetaldehyde reacts with adenosine to give l,tfs-ethenoadenosine (Barrio et at., 1972). Chloroethylene oxide and vinyl chloride, incubated in the presence of a nouse liver-microsomal preparation with adenosine in vitro, produced the same product (Barbin et al., 1975). Reaction of chloroacetaldehyde with cytldine gives 3l/fi*'-ethenocytldine (Barrio et at*, 1972). l,//*-Ethenoadenoslne was isolated after hydrolysis of polyadenosine that had been incubated with rat liver nlcroaomes and ^C-vinyl chloride or with liver RNA of rata treated with ^C-vinyl chloride (Laib 4 Bolt, 1977). The corresponding etheno-derlvatives of deoxyadenosine and deoxycytidlne were Identified in hydrolysis products obtained from calf thymus DNA treated with chloroacetaldehyde in vitro and from liver DNA of rats fed 250 ng/1 vinyl chloride in their drinking-water (Creen & Hathway, 1978) The 2-hydroxyethyl derivatives of guanine, cysteine and histidine were identified after chemical reduction of the hydrolysis products of DNA and proteins isolated from the livers of mice treated with '^C-vloyl chloride (Osterman-Golkar et at,, 1977). Mutagenicity and other abort-tern tests The mutagenicity of vinyl chloride has been reviewed by Bartsch & Montesano (1975), Bartsch et al. (1976) and Flshbeln (1976). Vinyl chloride vapour irduced reverse mutations of the base-pair substitution type in Salmonella typhimurivsm C46, TA1530, TA1535 and TA100 in the presence of a 9000 x g supernatant from rat liver (Andrews et al., 1976; Bartsch et al., 1975; Garro et al,, 1976; Halaveille et al1975; McCann et at., 1975; Rannug et al., 1974), mouse liver (Bartsch et al., 1975; Garro et al., 1976; Mplaveille et al., 1975) and human liver biopsy specimens (Bartsch et al., 1975, 1979; Halaveille et al., 1975). Although vinyl chloride also induced ablations in the absence of a metabolic activa tion system, a much higher mutagenic response was observed when a 9000 x g supernatant from liver was ac led (Andrews et al., 1976; Bartsch et al., 1975; McCann et al., 1975), Vinyl chloride in aqueou* or methanollc solution was not mutagenic in the Salmonella test system (Bartsch et aZ., 1975; Rannug et al., 1974) Vi but produced reverse mutations in Escherichia coli K12 (Grela et al., 1975), O forward mutations In Schizosaccharcmyces pombe and mitotic gene conversions in Saccharomgces cerevieiae in the presence of a 9000 x g supernatant from mouse liver. Forward mutations in S. pombe were also induced in the host- mediated assay in mice (Loprieno et at., 1976, 1977). UCC 108049 396 IARC MONOGRAPHS VOLUME 19 Vinyl chloride as vapour or as ethanol solution was not mutagenic In Neuroapora araasa in the presence or absence of a metabolic activation system (Drozdowlct & Huang, 1977). In inhalation experiment* in Drosophila melanogaster, vinyl chloride vaa mutagenic in the recessive lethal test (Magnusson & Kamel, 1976; Verburgt A Vogel, 1977} but not mutagenic In tests for dominant lethals, translocations and sex-chromosome loss (Verburgt A Vogel, 1977). No dominant lethals were observed in male CD-I alee after exposure by inhalation to 7.8, 26, or 78 g/m* (3000, 10 000 or 30 000 ppm) vinyl chlo ride in air for 6 hours/day for 5 days (Anderson et al., 1976, 1977). Exposure to vinyl chloride vapour in the presence of a 15 000 x g supernatant from phenobarbital-pretreated rat liver Induced forward muta tions in V79 Chinese hamster cells in terms of 8-azaguanlne and ouabain resistance (Orevon et ol., 1977). The mutagenicity of several possible metabolites of vinyl chloride has also been examined. Chloroethylene oxide was the strongest mutagen among those tested in S, typkimurium TA1530 and TA153S (Bartsch et al., 1975; Malavellle et al., 1975; Rannug et al., 1976), E. aoli (Hussain A Oeterman-Golkar, 1976), S. pombe (Loprieno et al., 1977), S. eerevisiae (Loprleno et at., 1977) and V79 Chinese hamster cells (Huberman et al., 1975). Chloroacetaldehyde was mutagenic in S. typhimurium TA1535, TAI530 and TA100 (Bartsch et al., 1975; Malavellle et al., 1975; McCann et al., 1975; Bannug et al., 1976) and V79 Chinese hamster cells (Huberman et al., 1975). Chloroethanol was a weak mutagen in S. typhimuriwn TA1530, TA1535 and TA100 (Bartsch et al., 1976; Malavellle et al., 1975; McCann et al., 1975; Bannug et al., 1976; Rosenkranx et al., 1974). Chloroecetic acid was not mutagenic in S. typhimurtum TA1530, TA100 or TA1535 (Bartsch et al., 1975; Malavellle et al., 1975; McCann et al1975; Rannug et al., 1976). 1,2-Oichlomethane, a possible by-product of vinyl chloride production and a main component of waste products from vinyl chloride industries (EDC-tar), was mutagenic in S. typhisnurim TA1535 (Rannug A Ramel, 1977) and in S. typHmuHum TA100 (McCann et al., 1975) in the presence or absence of a liver microsomal metabolic activation system. (b) Humana Toxic effects Exposure to vinyl chloride is associated with multiple systemic dis orders, Including a sclerotic syndrome, acro-osteolysis (sometimes associa ted with a Raynaud-like symptomatology), thrombocytopenia and liver damage, consisting of parenchymal damage, fibrosis of the liver capsule, periportal fibrosis associated with hepatomegaly, and splenomegaly (Lange et al.. 1974a; Thomas et al., 1975). VINYL CHLORIDE AND POLYMERS 397 Examination of 70 workers from a single polyvinyl chloride-producing factory showed a high frequency of signs and symptoms of vinyl chloride disease. Although skin and bone changes may disappear when the patient la removed from contact with vinyl chloride, the thrombocytopenia persists after termination of exposure (Veltman et al., 1975). Non-cirrhotic portal fibrosis with associated portal hypertension was found In 7 patients who had been Involved in the production of vinyl chloride monomer for 4-15 years. An angiosarcoma developed In one patient, but flbrosia waa a more comon lesion and vaa considered to be probably not premalignant (Smith et al., 1976a). Of 487 workers involved in polyvinyl chloride production, two cases presenting with thrombocytopenia were found to have portal hypertension due to periportal fibrosis, with oesophageal varices and splenomegaly (Williams et at., 1975, 1976). Exposure to vinyl chloride was not only associated with circulatory and liver dysfunction and skin and bone disorders, but also deafness, vision failure and giddiness (Jtihe A Lange, 1972). Elevated carclno-embryoalc antigen levels have been found In 48% of 200 polyvinyl chloride workers, as compared with 91 of a normal healthy population (Pag6 et al.t 1976). Ho evidence of an auto-immune disorder waa found In 13 patients employed In polyvinyl chloride production who had symptoms of rvlnyl chloride disease* (Lange et al., 1974a); however, Immunological data from 19/28 patients with vinyl chloride disease and in 2/30 workers exposed to vinyl chloride suggested an immune complex dis order (Ward et al1976). A group of 168 workers (114 from one factory and 54 from another) were examined medically at various times during 1962-1969* Manifestations of disorders of the nervous system were recorded commonly; hepatomegaly and splenomegaly occurred in 30% and 6% of workers; and some cases of anaemia and leucopenla were also observed. The incidence of Raynaud's syndrome fell from 6% in 1962 to 2.9% In 1966; this phenomenon cleared spontaneously upon removal of the subjects from exposure: these different incidence figures were associated with a 22-fold decrease in vinyl chloride levels during the period of the study. A much higher percentage of vaso spastic changes was found in the two groups (66 and 55%, respectively), suggesting that vinyl chloride acts as an Irritant in the reticuloendothe lial system to produce reactive splenic enlargement (Suclu et al., 1975). , Reduced pulmonary function has been observed in workers exposed to vinyl chloride (Gamble et al., 1976; Miller et at., 1975). The preva lence of this impairment waa similar in smokers and nonsmokers, sugges ting that occupational or other environmental factors were operative (Miller et al1975). 398 I ARC MONOGRAPHS VOLUME 19 Embryotoxicity and teratogenicity A significant excess of foetal deaths vas reported in women whose husbands were exposed to vinyl chloride* 15.8Z, or 23, foetal deaths in 139 pregnancies, as compared with 8.8X (24/273) in the age-adjusted control group. This excess of foetal deaths was shown not to be a function of chronic abortions, i.e., the association was maintained after excluding pregnancies of women who had had more chan 2 abortions (Infante at al., 1976a). The significance of this study was questioned because data col lection methods were not specified and there was no statistical treatment of the data (Paddle, 1976). Subsequently, the data collection nethods were described, showing that there had been no interviewer-respondent bias, and details of statistical analyses were specified (Infante et al., 1976b). In a registry-based study. Infante (1976) reported that an excess of central nervous system defects, of deformities of the upper alimentary and genital tracts, and of clubfoot has been observed in stillborn and live children in 3 cities in Ohio in which vinyl chloride polymerization plants are located. In hospital-baaed studies la newborns in Painesville (Ohio), where there are two polyvinyl chloride plants, and in Kanawha county (Heat Virginia), where there is one plant, excesses of anencephaly and spina bifida were reported, but no association was made with vinyl chloride (Edmonds, 1977; Edmonds et at., 1975, 1978). Mutagenicity and other short-term teats Chromosome aberrations were found in workers occupationally exposed to vinyl chloride in the US (Ducatman et at., 1975; Heath et at., 1977), Sweden (Funea-Cravioto et at., 1975), the UK (Purchase et at., 1975), Eelglum (Leonard et at., 1977), Hungary (Szentesl et at., 1976) and Norway (Hansteen et at., 1976). These aberrations were in most cases fragments, dicentrics and rings, and breaks and gaps. 3.3 Case reports and epidemiological studies1 In 1974, more than 40 years after the introduction of vinyl chloride into industry, Creech A Johnson (1974) first reported an association of exposure to this chemical with cancer in man. ThTee cases of liver angio sarcoma were reported in men who were employed in the manufacture of poly vinyl chloride resins (one had cleaned reactor vessels) in a single vinyl chloride polymerization plant in the US. 'The Working Croup was aware of a study in progress on the occupational and community carcinogenic risk of vinyl chloride (IARC, 1978b). VINYL CHLORIDE AND POLYMERS 399 By reviewing medical records and pathological material and by syste matic medical screening, the association between exposure to vinyl chloride and angiosarcoma of the liver has been reported from a number of other countries; Canada (Delorme A Theriault, 1978; Norla et at., 1976); Czechoslovakia (Lloyd, 1975); the Federal Republic of Germany (Lange et at,, 1974b, 1975); France (Couderc et at., 1976; Ravler et at., 1975; Roche et al., 1978); Italy (Haltonl, 1974); Norway (Lloyd, 1975); Romania (Lloyd, 1975); Sweden (Byren A Holmberg, 1975); the UK (Lee A Harry, 1974; Smith et al., 1976b); the US (Block, 1974; Falk et at., 1974a; Hakk et at., 1974); and Yugoslavia (Sari? et al., 1976). A review of 64 reported cases in various countries as of October 1977 is available (Splrtaa A Kaminski, 1978). No history of acro-osteolysls and no evidence of exposure to hepatotoxic materials other than vinyl chloride was reported in a clinical review of 7 cases of liver angiosarcoma among US vinyl chloride polymeri zation workers (Heath et at., 1975). In a pathological evaluation of cases of liver augloaarcona among exposed US vinyl chloride workers, it was con cluded that these tumours were often multicentrlc: angiosarcomas were bIbo detected in the wall of the duodenum, in the heart and kidney, and in other organs (Thomas A Popper, 1"5). The cancer risk among a -ohort of hales in the US who had at least one year of occupational exposure to vinyl chloride was studied. When compared with the US male population, an excess of cancer of the digestive system, of the liver (primarily angiosarcoma), of the respiratory system, of the brain and of unknown sites, aa well as lymphomas was observed in those members of the study cohort with the greatest estimated exposure to vinyl chloride (Tabershaw A Oaffey, 1974) [Vital status was undetermined for 15X of the study cohort, and only 50Z had 15 or more years since onset of exposure to vinyl chloride]. In a proportional-mortality analysis of 161 deceased workers In two US plants producing and polymerizing vinyl chloride, a 50Z excess of deaths due to all cancers was reported. Sites of cancer with the greatest excess were liver and biliary tract, brain, digestive tract and lung (Monaco et at., 1974). Falk et al. (1974b) questioned the authors' conclusion, on the grounds that not all deaths studied were among workers in activities directly related to vinyl chloride production or polymerization and that the study failed to include deaths among workers who had terminated employment prior to retirement or death. The cancer mortality experience of 257 US workers (255 were traced), each of whom had been occupationally exposed to vinyl chloride for at least 5 years and observed after 10 years from onset was studied using union seniority and company employment records. Among 24 deaths from all causes, a 2.3-fold excess was observed in deaths from cancer; of the 24 deaths, 3 were due to haemangioaarcoma of the liver (Nicholson et al., 1975). UCC 108051 400 IARC MONOGRAPHS VOLUME 19 Ho excess of tots! or cause-specific mortality vas reported in a study of 2100 male workers in the UK exposed to vinyl chloride for periods of up to 27 years; In addition, the authors reported a decreasing risk of morta lity with increasing duration of exposure to vinyl chloride (Duck et al*, 1975)* Wagoner et al. (1976) challenged the conclusions of the study on the grounds of analytical shortcomings. After reanalysing the data, the authors (thick 6 Carter, 1976) reported an increased risk of cancer of the digestive system 15 years after initial exposure to vinyl chloride. The cancer mortality of 594 US workers exposed occupationally to vinyl chloride end to lesser amounts of vlnylldene chloride (see p. 439) and other compounds (such as methyl methacrylate, see p. 167, and acrylonitrile, see p. 73) wsa studied* Although no angiosarcomas were found (no deaths due to any liver cancer), an excess of ail malignancies combined was reported among those workers classified ss having been highly exposed to vinyl chloride when compared with all other exposure categories. However, the number of workers in the lower expoeure categories who were exposed for more than 10 years was email, resulting In part from the feet that workers first took Jobs in the dry end of the polymerization process where exposures to vinyl chloride were low; many employees who remained with the units and established seniority would subsequently have moved to the higher exposure areas <0tt et at., 1975). The incidence of abnormal sputum cytology among workers in the vinyl chloride-polyvinyl chloride industry in Italy was much higher than expected, even when compared with a population of heavy smokers who did not work in chemical Industries (Haltoni, 1976). Waxwelller et al* (1976) studied the cancer mortality experience of 1294 individuals with 5 or more years of employment and 10 years since onset of employment in departments or jobs with direct exposure to vinyl chloride at 1 of 4 vinyl chloride-polyvinyl chloride production plants in the US. When compared with the US white male population, an excess of cancer waa found in four organ systems: brain and central nervous system, respiratory system, hepatic system, and lymphatic and haematopoietic systems. This excess of organ-specific cancer was restricted to those workers with 15 or more years since onset of vinyl chloride exposure. For all malignant neoplasms combined, the standard mortality ratio was 184; for the brain and central nervous system, 498; for the respiratory system, 194; for the hepatic system, 1606; and for the lymphatic and haematopoietic system, 176. Of 14 histologically confirmed cases of biliary and liver cancer among workers from these 4 plants, 11 were angiosarcoma of the liver. Of 10 cases of brain cancer, 9 were classified histologically as glioblastoma multiforme, a cell type of brain cancer reported to be unusual In the US. Of the 14 cases of primary lung cancer, 5 were large-cell undifferentiated and 3 were adenocarcinoma. In 771 workers employed in a Swedish vinyl chloride-polyvinyl chloride plant since its start in the early 1940's, a 4- to 5-fold excess of cancer of the liver and pancreas was found. Although the risks of cancer of the VINYL CHLORIDE AND POLYMERS 401 brain and of the lung were also increased, they were not statistically significant (Byren et al,, 1976). Whereas no excess mortality from lung cancer was demonstrated among currently employed individuals 15 years after Initial occupational expo sure to vinyl chloride, a 562 excess of lung cancer vas observed among those individuals who had termIDated employment less than 15 years since initial exposure; this excess vas found for each duration of exposure (Fox & Collier, 1976). Fox & Collier (1977) investigated the cancer mortality among 7561 males who were exposed to vinyl chloride in the manufacture of polyvinyl chloride in the UK at some time between 1940 and 1974. An excess mortality from liver cancer was reported for each group of workers, whether exposure was thought to be high, medium or low; however, the authors reported no evidence of an excess mortality from cancers other than of the liver. Relatively few subjects had long-term exposure to vinyl chloride, and even In cases In which men had completed 20 years of employment, the follow-up period was judged to be too short to evaluate the carcinogenic effect of vinyl chloride. A study vas reported of cancer mortality among 7021 males employed in the production and polymerisation of vinyl chloride In the Federal Republic of Germany. When compared with the national male population, an excess of cancers was found for 4 organa: liver, brain, lung and lym phatic organs. This excess of organ-specific cancer was shown to Increase with duration of exposure (von Reini et al1977). The risk of cancer mortality was investigated among residents 45-years of age and older in three US coauunlties with vinyl chloride polymerization facilities. Among males, the death rate from central nervous system cancer waa higher than that for the state as a whole. Ho excess mortality from leukaemia and aleukaemlc leukaemia or from lymphoma was found (Infante, The incidence of liver and lung cancer was studied for a 4-year period in a city in Yugoslavia with a factory in which vinyl chloride was polymerized and polyvinyl chloride processed. Polyvinyl chloride workers were included in the study. Except for liver angiosarcoma, no association was found between cancer incidence and place of work or residence (>ari st al*, 1976). ^