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70 DRINKING WATER AND HEALTH CONCLUSIONS AND RECOMMENDATIONS Suggested No-Adverse-Response Level (SNARL) Chronic Exposure Until the unconfirmed report of mammary tumors in female rats can be resolved, results of the 6-month study by Ellis et al. (1980) can be used to calculate a chronic SNARL. Using the lowest appar- ent no-effect level in dogs (2 mg/kg) and an uncertainty factor of 1,000 (because this is less than a lifetime study), and assuming that a 70-kg hu- man consumes 2 liters of water daily and that 20% of intake is provided by the water, one may calculate the SNARL as: 2 mg/kg X 70 kg X 0.2 14 /li 2 liters X 1,000 Because results of acute toxicity studies have been variable, additional studies with the purified chemical, with several animal species, and with several routes of administration appear warranted. Additional teratologi- cal evaluation should also be considered, assuming that humans may be exposed to the chemical through drinking water. In addition, pharmaco- kinetic metabolism studies are needed, since rates of absorption and routes and rates of excretion would undoubtedly assist in the evaluation of toxic responses. Since rotenone enters surface waters through direct appli- cation in fishery management, definitive studies should be conducted to determine the fate (rates and routes of degradation) of the chemical in wa- ter under various environmental conditions. Since rotenone is quite sensi- tive to degradation following exposure to air and sunlight, it is necessary to determine the extent of these reactions and the ultimate products to which humans would be exposed. Of greatest concern is the uncertainty of the chemical nature of the ro- tenone being tested. The compound's potential carcinogenicity must then be resolved. Carcinogenesis bioassays have produced equivocal results that cannot be resolved on the basis of current information. More recent studies have been negative. TETRACHLOROETHYLENE ethene, tetrachIor~ CAS No. 127-18~ Cl2C = CC12 Tetrachloroethylene was evaluated in the first and third volumes of Drink- ing Water and Health (National Research Council, 1977, pp. 769-770;
Toxicity of Selected Contaminants 71 1980, pp. 134-1423. The following material, which became available after the 1980 report was prepared, updates and, in some instances, reevaluates the information contained in the previous reviews. Also included are some references that were not assessed in the earlier reports. TetrachloroethyJ- ene has also been the subject of a monograph by the International Agency for Research on Cancer (1979b), in which toxicology data on animals and humans are evaluated. METAB OLI S M Recent metabolism studies have been prompted by an interest in the rela- tive reactivity of the metabolites of chlorinated ethylenes. The symmetrical chlorinated ethylenes, including tetrachloroethylene, are postulated to be more resistant to metabolism and to the formation of reactive intermedi- ates than are the unsymmetrical members of the series (Politzer et al., 1981~. Tetrachloroethylene epoxide has been synthesized and the mecha- nism of rearrangement that was studied in vitro was consistent with the in vivo metabolism of tetrachloroethylene through an epoxide intermediate to trichloroacetic acid (Henschler and Bonse, 1978~. As noted in the third volume of Drinking Water and Health, only a small portion of systemic tetrachloroethylene is metabolized. Data from balance studies that permit good quantification of the disposition of tetra- chloroethylene are generally lacking. In a study of mice given a single oral 500 mg/kg dose of ~4C-tetrachloroethylene, Schumann et al. (1980) re- ported that approximately 755to of the dose was expired as unchanged tetrachloroethylene. Water-soluble metabolites in the urine accounted for the other major portion of the dose. There were two additional facets of this study that deserve attention: (1) a lower dose in mice 10 ppm (69 mg/m3) administered for 6 hoursresulted in a much larger proportion of the dose being metabolized and (2) observations of relative hepatic mac- romolecular binding of tetrachloroethylene metabolites indicated that the metabolism of tetrachloroethylene proceeds at a more rapid rate and to a greater extent in mice than in rats. In vitro studies with rat hepatic micro- somes conducted by Costa and lvanetich (1980) have shown that the maxi- mum rate of metabolism for tetrachloroethylene is approximately 30-fold lower than the corresponding rate for trichloroethylene. This observation and those of Schumann and colleagues are all in keeping with the hypothe- sis that the hepatotoxicity of the chlorinated ethylenes is inversely related to the stability of the compound to biotransformation. If this is so, then it is of fundamental importance that the relative rates of metabolism for lab- oratory animals and humans be established before data from animals can be extrapolated with any confidence to humans.
72 DRINKING WATER AND HEALTH HEALTH ASPECTS Observations in Humans Two fatalities resulting from acute inhalation exposures to tetrachlo- roethylene have recently been reported. In each case, a male employee in a dry-cleaning establishment was overcome by tetrachloroethylene vapors. Postmortem blood levels of 4.5 mg/liter (Levine et al., 1981) and 44 ma/ liter (Lukaszewski, 1979) were reported. The lower value is not far above the maximum blood level of approximately 2.S mg/liter reported by Ste- wart et al. (1961) in humans exposed for 3 hours to a tetrachloroethylene concentration of approximately 200 ppm (1,374 mg/m3) in air. This lends further credence to previous observations that sustained atmospheric con- centrations exceeding 200 ppm can lead to narcosis and death. The committee found no reports that extended or amplified the findings in earlier Drinking Water and Health reports on the effects of graded doses of tetrachloroethylene in humans. Observations in Other Species Acute Effects In a study of the toxicity of several solvents in mice pre- treated with polybrominated biphenyls or Aroclor 1254, Kluwe et al. (1979) were unable to produce functional lesions of the liver or kidneys by administering a single maximal sublethal dose of tetrachloroethylene. This observation is consistent with earlier reports that tetrachloroethylene has a low potential for producing acute organ damage in animals. Chronic Effects Schumann et al. (1980) gave 11 consecutive daily oral doses of tetrachloroethylene at levels of 100, 250, or 1,000 mg/kg to B6C3~ mice and Sprague-Dawley rats. Although body weight was not af- fected by treatment, relative liver weight was significantly increased in mice at all except the lowest doses and in rats at 1,000 mg/kg. Histological examination revealed hepatic changes only in the rats receiving 1,000 ma/ kg/day, and these were considered minimal. In mice, however, hepatocel- lular swelling in the centrilobular region and an accentuated lobular pat- tern were observed at all dose levels. Mutagenicity Negative results were obtained with strain TA100 in the standard plate Salmonella assay when tested with tetrachloroethylene up to 4 X 10 -3 M concentration in the presence and absence of liver S9 frac-
Toxicity of Selected Contaminants 73 tion derived from phenobarbital-induced mice (Bartsch et al., 1979~. When incubated with log phase Saccharomyces cerevisiae D7 cells for 1 hour at 37°C at concentrations of 4.9 and 6.6 mM, recombinations, mi- totic gene conversions, and gene reversions were observed. A concentration of 8.2 mM was toxic to 99.9~o of the cells. No exogenous mammalian acti- vation system was needed to induce the genetic end points (Caller et al., 1980). No chromosome aberrations, increases in sister chromatic exchange (SCE), or changes in cell-cycle kinetics were found in peripheral blood lymphocytes obtained from six workers exposed to tetrachloroethylene lev- els as high as 92 ppm (632 mg/m3 ~ from 2 months to 18 years or from four workers exposed to 10 to 40 ppm (69-276 mg/m3) from 2 months to 18 years (Ikeda et al., 19801. In summary, tetrachloroethylene was mutagenic in one of two microbial mutagenicity assays. Negative results were obtained in one in vivo cytoge- netics study in humans. Carcinogenicity As described in the third volume of Drinking Water and Health, a study by the National Cancer Institute (1977a) yielded posi- tive findings of carcinogenicity in both sexes of B6C3F ~ mice. Only a pre- liminary report of a recent study by the National Toxicology Program (1982d) is now available. It is premature to make further judgments on this compound before the NTP study has undergone peer review and analysis. Thus, a risk estimate is not possible at present. Teratogenicity Schwetz et al. (1975) exposed pregnant mice and rats to concentrations of 300 ppm (2,040 mg/m3) for 7 hours/day during days 6 through 15 of gestation. No fetal toxicity or teratogenicity was found. Nel- son et al. (1979) performed behavorial tests on the offspring of rats ex- posed to 100 ppm (680 mg/m3) for 7 hours/day on days 14 to 20 of gesta- tion and found no changes from the control pups. At exposure levels of 900 ppm (6,120 mg/m3), the maternal animals gained less weight and the off- spring performed less well on neuromotor tests and had lower levels of brain acetylcholine and dopamine. Pair-fed controls were not used. The limited data indicate that tetrachloroethylene is not teratogenic in mice and rats. CONCLUSIONS AND RECOMMENDATIONS Information made available since the last review of tetrachloroethylene in Drinking Water and Health (National Research Council, 1980) is not suffi-
74 DRINKING WATER AND HEALTH cient to enable the committee to make a more realistic assessment of no- adverse-response levels than that developed in 1980. The earlier recom- mendations for additional studies are also still valid. There also continues to be a need for further research to elucidate mechanisms of tetrachlo- roethylene toxicity and species differences in response to this compound. Data from carefully designed subchronic studies to determine effect and no-effect doses would permit much better estimation of the risk associated with low-level exposure of humans. The question of carcinogenicity remains unresolved pending the com- plete analysis of the ongoing study by the National Toxicology Program. 1, 1, 1-TRICHLOROETHANE ethane, 1,1,1-trichloro CAS No. 71-55-6 Cl3 C-CH3 1, 1,1-Trichloroethane (methyl chloroform) was evaluated in the third vol- ume of Drinking Water and Health (National Research Council, 1980, pp. 144-1551. The following material, which became available after the 1980 report was prepared, updates and, in some instances, reevaluates the in- formation contained in the previous review. Also included are some refer- ences that were not assessed in the earlier report. METAB O LI S M There have been no studies of the metabolism of 1, 1,1-trichloroethane fol- lowing ingestion. Most reports continue to focus on the metabolic products of inhaled 1,1,1-trichloroethane, since occupational exposures to the com- pound occur by this route. The major metabolites of 1, 1,1-trichloroethane are 2,2,2-trichloroethanol and 2,2,2-trichloroacetic acid. In humans, the appearance of trichloroethanol in the urine has been estimated to be a more accurate measure of intermittent exposure and metabolism than 1, 1,1-trichloroethane exhaled in the breath (Caperos et al., 1982~. The low partition coefficent of 1, 1,1-trichloroethane in blood and the low rate of metabolism (3.5~o) in humans combine to result in a rapid, but small up- take upon inhalation and a consequently rapid rate of excretion (Monster. 1979~. A detailed pharmacokinetic model of 1, 1,1-trichloroethane uptake and metabolism following inhalation by mice and rats has been suggested