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Toxicity of Selected Contaminants 85 Rather limited data indicate that trichloroethylene does not have signifi- cant teratogenic potential in mice and rats. CONCLUSIONS AND RECOMIdENDATIONS Information that became available since the last review of trichloroethyl- ene in Drinking Water and Health (National Research Council, 1980) is not sufficient to permit any more realistic assessment of suggested no- adverse-response levels than those made in Volume 3. Moreover, the addi- tional studies recommended in the last review identify needs that are still present. A greater understanding of the differences among various species will be necessary before data obtained in studies in animals can be extrapo- lated to humans with more confidence. The current risk estimation for exposure to trichloroethylene is very sim- ilar to that calculated in Volume 1 of Drinking Water and Health. Fur- thermore, this reconfirmation is important when and if limits for trichlo- roethylene in drinking water are established. It is also important that the uncertainties surrounding the carcinogenicity bioassay be resolved prior to reaching any decision on the potential for adverse health effects in humans following exposure to trichloroethylene. A chronic SNARL for trichlo- roethylene is not calculated because of its carcinogenicity in animals, but acute SNARL's were presented in Volume 3. VINYL CHLORIDE (MONOCHLOROETHYLENE) ethene, chIor~ CAS No. 75 014 H2C = CHCl Vinyl chloride was evaluated in the first volume of Dunking Water and Health (National Research Council, 1977, pp. 783-787~. The following ma- terial, which became available after the 1977 report was prepared, updates and, in some instances, reevaluates the information contained in the pre- vious review. Also included are some references that were not assessed in the earlier report. METAB OLISM After oral and inhalation exposures, vinyl chloride is rapidly absorbed, and its uptake can be saturated by either route (Bolt, 1978; Watanabe et al., 1976a,b). Phannacokinetics data indicate a dose-dependent metabo-

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86 DRINKING WATER AND HEALTH lism of vinyl chloride resulting in exhalation of the monomer at saturation (Gehring and Blau, 1977; Radwan and Henschler, 1977) and excretion of the sulfur-containing products thioglycolic and N-acetyl-S-~2-hydroxy- ethyl)-cysteine in the urine (Watanabe et al., 1976a,b). Nonlinear (pseudo zero-order) kinetics apply at inhalation exposures to 250 ppm (640 mg/m3) or greater, and the lungs provide the most rapid route of elimination. However, when saturation has been reached, vinyl chloride is eliminated by metabolism and urinary excretion (Bolt, 1978~. Oral doses less than 250 mg/kg result in 70% to 75% of the vinyl chloride being excreted as a urinary metabolite and 4% to 5% in the expired air, whereas equivalent intravenous doses (which simulate inhalation expo- sure) result in 99% elimination of the compound in the expired air and less than loo in the urine (Green and Hathway, 1975; Watanabe et al., 1976a,b). Vinyl chloride is metabolized through the reactive epoxide (oxirane) in- termediate, which binds macromolecules (Bergman, 1982) and depletes glutathione reserves (Du et al., 1982; Hefner et al., 1975~. This reactive intermediate is the product of cytochrome P450 activation and can be en- hanced by preexposure to inducers of mixed-function oxidases (Pessayre et al., 1979a). HEALTH ASPECTS Observations in Humans No new data were found by the committee. Observations in Other Species Acute Effects No new data were found by the committee. Chronic Effects Several long-term inhalation toxicity and carcinoge- nicity studies have been reported. The chronic toxicity of vinyl chloride in the diet and in soy oil has recently been studied by Feron et al. (19811. In this experiment, the levels of exposure ranged from 1.7 to 300 mg/kg/day. These authors reported a decreased blood-clotting time, enlargement of liver and spleen, and a shift from angiosarcoma at 300 mg/kg to angiosar- coma and hepatocellular carcinoma at 14.1 and 5 mg/kg to the exclusive development of adenocarcinomas at 1.7 mg/kg. The no-observed-effect le~rel is less than 1.7 mg/kg. Mutagenicity The following investigators reported nnyl chloride to be mutagenic in the Ames Salmonella assay: Hallstrom et al. (1981), Bartsch

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Toxicity of Selected Contaminants 87 et al. (1975, 1979), and Simmon et al. (1977~. The assays were performed in desiccators. Metabolic activation was not required to elicit the muta- genic response, but inclusion of liver S9 fraction from humans, rats, or mice, in addition to S9 derived from Drosophila Karsnas and Hikone lar- vae, enhanced the mutagenic response. Greim et al. (1975) reported vinyl chloride to be mutagenic in an E. cold suspension assay. A positive response was obtained in a micronucleus test with male mice exposed by inhalation to Do vinyl chloride for 4 hours (Jenssen and Remel, 1980~. Negative results were obtained in a dominant lethal study with male mice exposed to 3,000, 10,000, and 30,000 ppm (7,670, 25,566, and 76,700 mg/m3) for 6 hours/day for 5 days (Anderson et al., 1977~. The frequency of sister chromatic exchanges and induced chromosome aberra- tions was increased in bone marrow cells of Chinese hamsters exposed to vinyl chloride at 1.25%, 2.5~o, or 5~0 (v/v) for 6, 12, or 24 hours (Basler and Rohrborn, 1980~. Chinese hamster V79 cells showed an increase in resistance to 8-azaguanine and ouabain after exposure for 5, 10, or 15 hours at 37C to vinyl chloride at 5%, 10%, 20%, and 30% (v/v). The mutagenic response was observed only in the presence of a liver S15 frac- tion derived from phenobarbital-pretreated male rats (Drevon and Kuroki, 19791. No detectable mutation induction in two strains of Neuro- spora crassa was observed after their conidia were treated with vinyl chlo- ride in an ethanol solution or in its gaseous form in the presence and ab- sence of uninduced rat liver S9 fraction (Drozdowicz and Huang, 1977~. Mutagenesis or gene conversion were observed in several yeast assays: Sac- charomyces pombe and S. cerevisiae D4 (Loprieno et al., 1976) and S. cerevisiae D7 (Eckardt et al., 1981~. No chromosome aberrations were observed in peripheral Iymphocytes from workers exposed for 2 years to maximum vinyl chloride levels of 4 ppm (19.2 mg/m3) (Rossner et al., 1980~. Peripheral Iymphocytes ob- tained from workers occupationally exposed to levels of vinyl chloride greater than 5 ppm (12.8 mg/m3) were found to have a higher incidence of chromosome aberrations than those obtained from a control group (An- derson et al., 1981~. When concentrations of vinyl chloride were reduced to levels less than 5 ppm, chromosome aberrations in peripheral Iymphocytes returned to control values in workers occupationally exposed to the chemi- cal (D. Anderson et al., 1980~. ln summary, vinyl chloride was mutagenic in several microbial muta- genicity test systems and in one in vitro mammalian mutagenesis assay. Positive results were also obtained in a mouse micronucleus test. increases in the incidence of chromosome aberrations were observed in Iymphocytes of occupationally exposed workers. Chromosome abe~Tations and sister chromatic exchange were seen in one animal species exposed to vinyl chlo- ride.

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88 DRINKING WATER AND HEALTH Carcinogenicity Vinyl chloride is a proven carcinogen in mice, ham- sters, and rats. In most experiments, the animals were exposed to vinyl chloride by the inhalation route, in concentrations ranging from 1 to 30,000 ppm (2.6-76,687 mg/m3) in air. Exposures were usually adminis- tered 4 hours/day 5 days/week for 17 to 52 weeks. In some studies, vinyl chloride in olive oil was administered by gavage S times a week during 1 year. In comparatively few studies did investigators examine the effects of vinyl chloride given by intraperitoneal subcutaneous injection (Maltoni et al., 1981~. Vinyl chloride produced tumors in mice, hamsters, and rats, regardless of the route of administration selected. Angiosarcomas of the liver were found in all animals examined. Some types of tumors were observed in one type of animal only, e.g., brain tumors, hepatomas, nephroblastomas, or sebaceous cutaneous carcinomas were found in rats only, whereas lung tu- mors (adenomas and adenocarcinomas) were found in mice only. In most experiments there was an indication of a dose response. Important deter- minants of the tumor response were duration and schedule of treatments. Newborn animals appeared to be especially sensitive to the carcinogenic effect of vinyl chloride, and there was evidence for transplacental carcino- genesis. The lowest dose of vinyl chloride to have a carcinogenic effect was claimed to be 50 ppm (130 mg/m3) in air for an unspecified exposure time in Sprague-Dawley rats (Maltoni et al., 19811. A review of all other carci- nogenicity studies on vinyl chloride largely confirmed these conclusions (International Agency for Research on Cancer, 1979a). Adult Sprague-Dawley rats were exposed to 940 ppm (2,403 mg/m3) concentrations of vinyl chloride by inhalation for 7 hours/day, 5 days/ week for 24 weeks. Exposure was begun when the animals were 6, 18, 32, or 52 weeks old (Groth et al., 19811. The investigators found that older adult animals and females were more likely to develop angiosarcomas than were young or male animals. If confirmed, this observation would indicate that older animals are more susceptible to the carcinogenicity of vinyl chlo- ride and that the latency period for the development of angiosarcoma could be shorter than in young animals. In another study, animals exposed to vinyl chloride by inhalation [600 ppm (1,534 mg/m3), 4 hours/day, 5 days/week for 1 year] and to 5~o ethanol in drinking water had an inci- dence of hepatic tumors (angiosarcoma and hepatocellular carcinoma) that was twice the incidence in animals exposed to vinyl chloride alone. Exposure to vinyl chloride and ethanol together also produced more hepa- tocellular carcinomas than exposure to vinyl chloride alone (Radike et al., 1981~. Hehir et al. (1981) examined single 1-hour exposures to various concen- trations of vinyl chloride in air [50 to 50,000 ppm (128 to 127,812 mg/m3~] to determine if they would elicit a carcinogenic response. In Fischer 344

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Toxicity of Selected Contaminants 89 rats, there was no evidence for a chemically induced tumor response. In ICR mice, only the 50,000-ppm doses produced an unequivocal increase in bronchial alveolar adenomas and carcinomas, whereas the A/J mice had pulmonary neoplasia following multiple inhalation exposure to 50 ppm. It was not clear whether dose fractionation had a significant influence on tu- mor incidence. Since the two experiments (single dose exposure and dose fractionation) were conducted in two different mouse strains (ICR and A/J), which are not equally susceptible to the development of Jung tumors (Shimkin and Stoner, 1975), and since no data on tumor multiplicity were reported, the results are difficult to interpret. However, from this and some other experiments (Maltoni et al., 1981; Suzuki, 1981), it can be con- cluded that vinyl chloride inhalation produces lung tumors in ICR, A/J, CDI, CD, and NMRI mice. Analysis of all available data on humans led the International Agency for Research on Cancer (1979a) to conclude that exposure to vinyl chloride results in an increased carcinogenic risk to humans. Organs most likely to be affected were the liver, brain, lung, and hemato- and lymphopoietic systems. In a more recent review of epidemiological studies of workers ex- posed to vinyl chloride, essentially the same conclusion was reached (In- fante, 1981; Vianna et al., 1981~. Thus, there is convincing evidence that exposure of animals or of hu- mans to high doses of vinyl chloride produces cancer. However, for many chemicals, vinyl chloride among them, the toxicitr and carcinogenicity are mediated through a metabolic intermediate rather than through the par- ent compound. This could necessitate an estimate of how much of a chem'- cal would indeed undergo biotransformation during exposure of animals before meaningful dose-effect relationships could be obtained or cross- species comparisons could be made. I:or vinyl chloride in particular it was shown that the incidence of angiosarcoma in rats was related to the amount of vinyl chloride metabolized rather than to the concentration of exposure (Gehring et al., 1978; Watanabe et al., 1977~. Pharmacokinetic considerations should thus apply in extrapolating results from animal studies to humans. This has been done in several attempts to estimate risks from vinyl chloride exposure (M. W. Anderson et al., 1980; Gehring et al., 1978; Van Ryzin and Rai, 1980~. It must be remembered, however, that in the final analysis the scientific rationale behind this approach relates only to a possible initial event in carcinogenesis, the interaction of a chemical with DNA. Carcinogenesis is more likely a multistage process rather than a one-hit event (Farber and Cameron, 1980), and pharmacokinetic consid- erations may not necessarily apply to all stages. Teratogenicity John et al. (1981) exposed rodents and rabbits by inha- lation to vinyl chloride ranging from doses of 50 to 2,500 ppm (128 to 6,390

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90 DRINKING WATER AND HEALTH mg/m3) during major organogenesis and found no adverse fetal effects. Ungvary et al. (1978) exposed rats to 1,500 ppm (3,840 mg/m3) during pregnancy and observed that there was increased fetal mortality but no malformations. Although Infante et al. (1976a,b) reported increased rates of malforma- tions in one city where a vinyl chloride plant was located, subsequent stud- ies by Edmonds et al. (1978) revealed that the parents of these children had not been workers in the plant nor had they been living closer to the manu- facturing source than had the controls. Infante et al. (1976b) reported a significant increase in fetal loss among the wives whose husbands had been exposed. As a "control" group, they used workers in rubber plants. Sanotskii et al. (1980) did not find an increase in spontaneous abortions among the wives of vinyl chloride workers. In summary, vinyl chloride does not appear to be teratogenic in rats or rabbits. The data on humans are not adequate for judgment to be made. CONCLUSIONS AND RECOMMENDATIONS A SNARL for chronic exposure was not calculated because orally adminis- tered vinyl chloride is an established carcinogen in humans. It is also car- cinogenic in mice, hamsters, and rats, in which angiosarcomas were found, regardless of route. The older animals and females appeared to be more susceptible. The cancer risk estimate for vinyl chloride can be found in Volume 1 of Drinking Water and Health. URANIUM (U) Uranium was evaluated in the third volume of Drinking Water and Health (National Research Council, 1980, pp. 173-178~. That review was devoted exclusively to the element's chemical toxicity. In the following review, the committee also considers its radiological effects and provides updates and, in some instances, reevaluations of the information on chemical toxicity contained in the previous volume. Included are some references that were not assessed in the earlier report. Uranium is ubiquitously distributed throughout the earth's crust. It has a complex radioactive decay scheme resulting in the emission of different radiations and the production of several radioactive daughter products. Because its abundance in the crust varies geographically, uranium is a highly variable source of contamination of drinking waters that may be directly consumed by humans and incorporated into their diet. In this brief review, the committee discusses the potential for radiation and chemical toxicity from the ingestion of natural uranium and clarifies the difference