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Toxicity of Selected Contaminants 15 (10 mg/kg) did not result in elevated micronuclei counts in the bone mar- row cells of mice (Seller, 1977~. Negative results were obtained in the Ames Salmonella assay, yeast Saccharomyces cerevisiae D3 mitotic recombina- tion assay, E. cold WP2 assay, and relative toxicity assay with Escherichia cold and Bacillus subtilis (Poole et al., 1977, abstract). Germinating onion bulbs (Allium cepa) were treated with O.l~o carbo- furan for 2 to 4 hours (Sathaiah et al., 1974~. The investigators observed an irregular scattering of chromosomes during the metaphase stage as well as chromosome abnormalities such as fragments, clumping, scattered ana- phases, and contractions. In summary, carbofuran was found to be nonmutagenic in several short- term assays. Although chromosome abnormalities were observed in one plant assay, there is no evidence to suggest that DNA damage was directly involved in producing these effects. Carcinogenicity No data were found by the committee. Teratogenicity McCarthy et al. (1971, abstract) reported that al- though no increase in defects occurred in the offspring of treated rats, rab- bits, and dogs, there was a reduced survival rate in rat offspring exposed to diets containing 100 ppm. Wolfe and Esher (1980) administered the same dietary dose level to mice and found a reduced survival rate, but the differ- ence from controls was not significant, and fetal weights were not reduced. After reviewing these limited data, the committee concluded that carbo- furan does not appear to be teratogenic to mice, rats, rabbits, or dogs. CONCLUSIONS AND RECOMMENDATIONS The published information is not sufficient to permit a calculation of a suggested no-adverse-response level (SNARL) or otherwise to assess the potential hazard of chronic exposure to carbofuran. There is a need for more data on the chronic toxicity, carcinogenicity, and teratogenicity of carbofuran. CARBON TETRACHLORIDE methane, tetrachIorm CAS No. 5~23-5 CCl4 Carbon tetrachloride was evaluated in the first and third volumes of Drink- ing Water and Health (National Research Council, 1977, pp. 703-706;
16 DRINKING WATER AND HEALTH 1980, pp. 96-98~. The following material, which became available after the 1980 report was prepared, updates and, in some instances, reevaluates the information contained in the previous review. Also included are some ref- erences that were not assessed in the earlier reports. METAB OLI SM Carbon tetrachloride is believed to be metabolized by cytochrome P450 enzymes contained in the membranes of the endoplasmic reticulum (mi- crosomes) and in the nuclear membrane (Diaz Gomez and Castro, 1980; Recknagel and Glende, 1973~. Low doses of the compound induce lipid peroxidation (LPO), whereas higher doses (>0.5 ml/kg administered orally) inhibit the mixed-function oxidase system and further induce lipid peroxidation (Harris et al., 1982; Recknagel and Glende, 19731. The hy- pothesis that the metabolic pathway of carbon tetrachloride proceeds from the trichloromethyl radical ~ CCl3) to phosgene (COCA) to carbon monox- ide (CO) (Recknagel, 1967) has withstood the test of time. Recent evidence has suggested that chloroform (CHCl3) may also forte under anaerobic conditions in hepatic microsomes (Ahr et al., 1980~. Inhibitors of cyto- chrome P450 decrease carbon tetrachloride toxicity, whereas Type I induc- ers of cytochrome P450 enhance the hepatotoxicity (National Research Council, 19801. HEALTlI A SPE CTS Observations in Humans No new data were found by the committee. Observations in Other Species Acute Effects Carbon tetrachloride toxicity is manifested by a rapid rise in LPO in ~e target organ (Recknagel, 1967~. The reactive metabolite inducing LPO is belie~red to be the trichloromethyl radical, which alters membrane function by blocking ion pumps within the cell (Bernacchi et al., 1980; Lowrey et al., 1981; Moore, 1980~. These effects ha~re been ob- senred in rats that were given acute oral doses ranging from 0.5 to 1 ml/kg. Recently published e~ndence indicates that there is an age difference in susceptibility to carbon tetrachloride-induced hepatotoxicity. At intraperi- toneal doses of 1 ml/kg, the increase in serum aspartate aminotransferase and triglyceride accumulation in the neonatal (1- to 14-day-old) rat was
Toxicity of Selected Contaminants 17 equivalent to that observed in the adult rat; however, there was much less macromolecular binding and lipid peroxidation in the young rats, whereas blood acetoacetate levels were 3 to 5 times higher (Cagen and Klaassen, 1979~. Ethanol toxicity in mice has been enhanced by oral pretreatment with 0.5 ml/kg doses of carbon tetrachloride, which resulted in a concomi- tant 3- to 5-fold increase in acetaldehyde production (Hjelle and Petersen, 1981~. These authors concluded that carbon tetrachloride inhibits acetal- dehyde oxidation and hepatic aldehyde dehydrogenase. In young rats, this inhibition may be the result of the exquisite sensitivity of these enzymes to carbon tetrachloride and may account for the enhanced toxicity of carbon tetrachloride in diabetic rats (Cagen and Klaassen, 1979; Hanasono et al., 1975). Chronic Effects No new data were found by the committee. Mutagenicity Callen et al. (1980) reported that carbon tetrachloride induced recombinations and mitotic gene conversions as well as point mu- tations when 21, 28, and 34 mM concentrations were incubated with Sac- charomyces cerevisiae D7 cells growing in log phase for 1 hour at 37°C. No exogenous mammalian metabolic activation system was required to induce the genetic effects. The yeast D7 cytochrome P450 system apparently me- diates the metabolic conversion. In summary, carbon tetrachloride was mutagenic in one microbial mu- tagenicity assay. Carcinogenicity The carcinogenicity of this compound was evaluated in the first volume of Drinking Water and Health (National Research Council, 1977, pp. 703-707) and more recently in a publication by the In- ternational Agency for Research on Cancer (1979a). In a study not re- viewed in these two reports, Altpert et al. (1972) gave 30 female rats subcu- taneous injections of carbon tetrachloride twice weekly for 2 years. Eight of the dosed animals developed mammary adenocarcinomas. No mammary tumors developed in a control group of 15 female rats. Teratogenicity Wilson (19S4) gave oral (0.3 ml) or subcutaneous (0.8 ml) doses of carbon tetrachloride to rats on days 2 or 3 of gestation. No congenital defects were observed in the offspring. Adams et al. (1961) noted some degeneration of embryonic discs in the blastocysts of rabbits exposed in viva to 1.0 ml/kg. Schwetz et al. (1974) subjected pregnant rats to inhalation exposures of carbon tetrachloride in concentrations ranging from 300 to 1,000 ppm
18 DRINKING WATER AND HEALTH (1,890 to 6,300 mg/m3) for 7 hours/day on days 6 through 15 of gestation. Fetal size was reduced, but neither resorptions nor malformations oc- curred more frequently than in the controls. Transplacental passage has been shown in pregnant mice (Roschlau and Rodenkirchen, 1969), rats (Tsirel'nikov and Dobrovol'skaya, 1973), and humans (Dowty et al., 1976~. The amounts were not quantified. The car- bon tetrachloride was identified by the use of gas chromatography and mass spectrometry. The data indicate that carbon tetrachloride is not teratogenic to rats. CONCLUSIONS AND RECOMMENDATIONS Carbon tetrachloride is apparently metabolized by mixed-function oxi- dases, which generate a reactive trichloromethyl radical. It is believed that the reactive intermediate induces lipid peroxidation, which leads to hepa- totoxicity. The compound is mutagenic in yeast without metabolic activa- tion, since yeast has an active mixed-function oxidase system. Carbon tetrachloride is not teratogenic to rats exposed orally, subcuta- neously, or via inhalation, but it has been shown to reduce fetal weight after maternally toxic inhalation exposures. The carcinogenicity of carbon tetrachloride was discussed in previous reviews. CHLOROBENZENE monochlorobenzene; benzene' chlorine CAS No. 108-90 7 Cl Chlorobenzene was reviewed in the first volume of Drinking Water and Health (National Research Council, 1977, pp. 709-7101. 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 OLI SM No significant data on the metabolism of chlorobenzene have been re- ported since the initial review. However, there have been reports providing -