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TOXICOLOGY AND APPLIED PHARMACOLOGY 49, 505-515 (1979) . /r?f 1/ Formation and Inactivation of a Chemically Reactive Metabolite of Vinyl Chloride1 D. Pessayre,2 J. C. Wandscheer, V. Descatojre, J. Y. Artigou, AND J. P. BENHAMOU Unite de Recherches de Physiopathologie Hepatique (1NSERM),, Hopital Beaujon, 92118 Clichy, France Received December 18,1978; accepted March 17,1979 Formation and Inactivation of a Chemically Reactive Metabolite of Vinyl Chloride. Pessayre, D., Wandscheer, J. C., Descatoise, V., Artigou, J. Y., and Benhamou, J. P. (1979). Toxicol, Appl. Pharmacol. 49, 505-515. The mechanisms responsible for, and pro* tecting against, metabolic activation of vinyl chloride were investigated in the rat. When ["CJvinyl chloride was incubated with hepatic microsomes, a ''C-labeled material became irreversibly bound to microsomal proteins; binding required NADPH, was decreased by CO, SKF 525-A, or glutathione, and was increased by l,l,l-trichIoropropene-2,3-oxide (TCPO). Inhalation of a 5% vinyl chloride atmosphere decreased hepatic cytochrome P-450 and glutathione. Pretreatment of the animals with DDT or phenobarbital (I) in* creased in vitro irreversible binding to microsomal proteins measured in the presence, but not in the absence, of TCPO and increased the in vivo loss of cytochrome P-450 during inhala* tion of vinyl chloride, but (2) decreased the in vitro irreversible binding to 10,000^ super natant protein; and the In vivo loss of glutathione during inhalation of vinyl chloride. These results are consistent with the views that (1) vinyl chloride is activated by cytochrome P-450 into its chemically reactive epoxide, (2) the epoxide may be inactivated by epoxide hydrase or by binding to glutathione, (3) pretreatment with DDT or phenobarbital in creases both the formation rate of the epoxide and its inactivation rate by epoxide hydrase, and (4) cytochrome P-450 destruction is related to the formation rate of the epoxide, whereas glutathione depletion seems related to only that fraction of the formed epoxide which has escaped inactivation by microsomal epoxide hydrase and has diffused in the cytosol. Vinyl chloride (chloroethylene) is massively used in the manufacture of plastics; Poly merization of this monomer leads to polyvinyl chloride, the most widely used synthetic plastic (Berk et at., 1976). In workers exposed to vinyl chloride, angiosarcomas of the liver and/or hepatic fibrosis have been ' This work was supported by Grant 021 R 07 from Faculte de Medecine Xavier-Blchat (Universite de Paris VII), and ATP 58-78-90 from Institut National de la Sante et de la Recherche Medicale (INSERM). 1 Recipient of a fellowship from the Fonds d'Etudes du Corps Medical Hospitalier. observed (Berk et at., 1976). Hepatic angiosarcomas and liver lesions have been reproduced in experimental animals chroni cally exposed to vinyl chloride (Torkelson et at., 1961; Lester et at., 1963; Viola et at., 1971; Maltoni and Lefemine, 1975; Prodan et at., 1975). Several carcinogenic and/or hepatotoxic compounds are transformed by the hepatic microsomal mixed-function oxidase system (MFOS) into chemically reactive metabolites that (l) covalently bind in vitro to micro somal proteins, (2) covalently bind in vivo OO4I-OO8X/79/O9O505-IIS0100/0 Copyright {5 1979 by Academic Press; Inc. All rights of reproduction in any form reserved. Printed in Great Uriiain SL 419i6 wmtuate Letters continued Book Review 7.7 A situation in which such a family with a latent, inherited disorder has suffered unexpected toxicity from an exposure, and in which the relationship of the af fected individuals has initially escaped notice, remains to be reported. This family demonstrates the potential for such a circumstance. Wynder7 has used the term "metabolic epidemiology" in propos ing integrated, interdisciplinary studies to define the extremes of risk for disease. The identification of sub populations within the community at elevated risk for exposure related illness is one aspect of this approach. Tee L. Guidotti, M.D. National Institute of Arthritis, * Metabolism and Digestive Diseases |oel M. Lamon National Cancer Institute Bethesda, MD 20014 References 1. Clayton DG: A model for association in bivariate life tables and its application in epidemiological studies of family tendency in chronic disease incidence. Biomctrika 65:141, 1978. 2 Calabrese |; Will elevated levels of lead ex posure precipitate clinical symptoms of por phyria in individuals svith the latent condition! Med Hypotheses 4:282. 1978. 3. MagnusSen CR, Levine JB, Doherty )M. et at: A red cell enzyme method for the diagnosis of acute intermittent porphyria. Blood 44-857, 1974. 4. Fagius ) and Cr'dnqvist B: Function of peripheral nerves and signs of polyneuropathy in solvent-exposed workers at a Swedish Steelworks. Acta hlctirol Sound 57:305, 1978. 5. Tschudy DP. Valsamis M, and Magnussen CR: Acute intermittent porphyria: Clinical and selected research aspects. Ann Intern Med 83:851, 1975. 6. Anderson DE: Familial susceptibility, in Per sons at High Risk of Cancer. |. F. Fraumeni, |r. (Ed). New York: Academic Press, 1975. pp 3954. 7. Wynder EL: Metabolic epidemiology. Lancet 1:260, 1978. Log Normal Distribution of the In cubation Period of Liver Angio sarcoma in Vinyl Chloride Poly merization Workers To-the-fc/itor. -- In the June 1978 issue of the Inurnal of Occupational Medicine (9:427-429), NIOSH pre sented data on 64 cases of liver angio sarcoma among vinyl chloride polymeri7ation workers. fig 1 is a log-probit representation of the cumulative percent of the in- incubation period (log) Fig 1. -- Log normal distribution of in cubation period of 63 liver angiosarcoma cases in vinyl chloride exposed workers. Estimated median (19.3 years) and dispersion factor (1.40) closely resemble those for occupational bladder tumors in the dyestuff industry. cubation periods of the vinyl chloride induced liver angiosarcomas. The in cubation period is defined as the num ber of years from first exposure to diagnosis. A straight line was fitted to the data. The median of the incubation period for occupational angiosarcoma is 19.3 years with a dispersion factor of 1.40. The dispersion factor is de fined as. the anti-logarithm of the logarithmic standard deviation. Thus, Sartwell's model1 of the distribution of incubation periods of infectious diseases applies equally to the distribution of incubation periods in occupational liver angiosarcoma. Armenian and Lilienfeld7 demon strated earlier that this was also true for the incubation periods of other neoplasms in humans. The median of the incubation period and the disper sion factor for vinyl chloride induced angiosarcoma of the liver strikingly resemble those calculated by these authors for occupational bladder tumors in the dyestuff industry. Jean P. Tassignon, MD. Head, Department of Occupational Health and Toxicology Sovay & Cie, SA 33 Rue du Prince Albert B-1050 Brussels. Belgium References 1 Sartwell PE. the distribution of incubation periods of infectious disease Am / Hyg 51:310318. 1950, 2 Armenian UK and Lilienfeld AM- The distribution of incuhation periods of neoplastic diseases. Am I Ipidemml 99:92-110, 1074. Patricia Yarvote, M.D. . Department Editor Chloroform, Carbon Tetrachloride, and Other Halomethanes: An Environmental Assessment. Prepared by the Environ mental Studies Board, Commission on Natural Resources of the National Research Council, 294 pp, $8.95 1978. Report avail able in paperback from the Printing and Publishing Office, National Academy of Science, 2101 Constitution Avenue, Washington. DC 20418. The study assesses the scientific and technical information available on a class of potential multimedia environ mental pollutants, the nonflubrinated halomethanes. This class of com pounds includes the chlorinated, brominated and iodinated methanes. Chloroform and carbon tetrachloride have been considered in greatest de tail because there is more extensive data available on these, and they have been demonstrated to be carcinogenic in high doses in test animals. A quantitative assessment of human and ecosystem exposures and effects is explored in depth as well as sources, concentrations and global mass bal ances. Various control options are out lined such as changes in water dis infection practices which would reduce locally elevated concentrations of chloroform and other halomethanes at waste-water treatment plants. The economic analysis of benefits and costs associated with control practices is reviewed. The participants conclude that fur ther studies are needed to evaluate carcinogenesis, mutagenesis and teratogenesis dose-response effects from low-level environmental ex posure to halomethanes. Better pri mary and secondary calibration Stan dards are essential to assure valid and reproducible lab results. More in formation is also needed on the world wide distribution of halomethanes in the environment, including the oceans and glaciers. Although this is a highly technical document of limited interest, it is an important source of information for those involved with this class of com pounds. -- Patricia M. Yarvote, M.D. 10 SL 041917 I. Cancer Res. Clin. Oncol. 94, 139-147 (1979) Cancer Research Clinical Oncology () Springcr-Verkij; 1979 Vinyl Chloride and Trichloroethylene: Comparison of Alkylating Effects of Metabolites and Induction of Preneoplastic Enzyme Deficiencies in Rat Liver R.J. LaibJ,G. Stockle1, H.M. Bolt `,and W. Kunz2 1 Inslitut fiir Toxikologie der Universitiit Tubingen, Wilhelmstr. 74, D-7400 Tiibingen, Federal Re public of Germany 3 Deutsches Krebsforschungszentrum, D-6900 Heidelberg, Federal Republic of Germany Summary. [1,2-14C] Vinyl chloride and [1,2-14C] trichloroethylene were in cubated with rat liver microsomes, NADPH and RNA (rrom yeast). Whereas trichloroethylene metabolites were irreversibly bound to proteins in micro somal incubations to a higher extent than vinyl chloride metabolites, irreversible binding to RNA was lower for trichloroethylene metabolites. Hydrolysis of the RNA which was reisolated from microsomal incubations with 14C-vinyl chloride or 14C-trich!oroethylcne and separation of the nucleo sides showed different alkylation products arising from vinyl chloride and from trichloroethylene, characteristic for vinyl chloride being formation of l,N6-ethcnoadenosine and 3,N4-ethcnocytidine. The different reactivities of metabolites of vinyl chloride and of trichloroethylene prompted a comparison of the oncogenic effects of both compounds against the rat liver cell. Newborn rats were exposed for 10 weeks to 2000 ppm vinyl chloride or trichloro ethylene (8h/day; 5 days/week). After this period livers of the animals were stained for nudeoside-5-triphosphatase. Whereas the vinyl chloride exposed rats showed focal hepatocellular deficiencies in this enzyme, which are sup posed to represent an early sign of malignancy, no such changes were induced by trichloroethylene exposure. The data therefore suggest differences between the hcpatocarcinogenic activity of vinyl chloride and possible effects of tri chloroethylene on the liver. Key words: Vinyl chloride-Trichloroethylene - Rat liver - Liver carcinogene sis-Alkylation Possible carcinogenicity of trichloroethylene is subject of recent discussion. The close structural relation to the proven hepatocarcinogen vinyl chloride prompted the argument that trichloroethylene, via similar routes of metabolic activation as vinyl chloride, might be canccrogenic (Van Duuren, 1975). Mutagenicity of tri chloroethylene metabolites in bacterial test systems (Greim et al., 1975) and cova- Ojfprint requests to: Hermann M Bolt (address see above) 0171-5216/79/0094/0139/S 1.80 SL 041918