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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
Toxicity of Selected Contaminants 75 by Schumann et al. (1982~. In both animals, the utility of estimating the kinetics following oral ingestion at the trace levels found in drinking water has yet to be proven. 1, 1,1-Trichloroethane is oxidized by the cytochrome P450 system to me- tabolites that bind covalently to cellular macromolecules, as evidenced by the dependence of the reaction on reduced nicotinamide adenine dinucleo- tide phosphate (NAPDPH) and the inhibition by carbon monoxide (Ivanetich and Van den Honert, 1981~. Metyrapone and SKF 525-A also inhibit the reaction. The activity is dependent on cytochrome P4SO rather than on cytochrome P448' since phenobarbital enhances both metabolism and binding, whereas ,B-naphthoflavone does not. 2,2,2-Trichloroethanol is the major metabolite found in in vitro studies by Ivanetich and Van den Honert (1981~. The identity of the reactive intermediate remains unknown. Fasting increases the metabolism of 1, 1,1-trichloroethane in the livers of rats without measurable effects on the cytochrome P450 or protein con- tent. Differences between the sexes are present after 1 day of fasting, but decline after 3 days of fasting (Nakajima and Sato, 1979~. The role of such nutritional effects on chronic low level ingestion is not known. HEALTH A SPE CTS Observations in Humans No new data were found by the committee. Observations in Other Species Acute Effects Cardiac arrhythmias observed in laboratory animals ex- posed to 1, 1,1-trichloroethane are similar to those seen in humans after self-intoxication. In rabbits, pretreatment with phenobarbital has reduced blood levels of 1, 1,1-trichloroethane and the incidence of cardiac arrhy- thmias, whereas pretreatment with the mixed-function oxidase inhibitors SKE 525-A and 2,4-dichloro-6-phenylphenoxyethyldiethylamine hydrogen bromide (Lilly, 18947) increased blood levels of 1, 1,1-trichloroethane and the incidence of arrhythmias (Carlson, 1981~. 1,1,1-Trichloroethane, rather than its metabolites, is responsible for the arrhythmias (Carlson, 1981~. Sprague-Dawley rats exposed by inhalation to 4,345 mg/m3 (800 ppm) 1, 1,1-trichloroethane for 4 weeks had increased liver weights, but no ap- preciable increases in cytochrome P450; however, androstenedione metab-
76 DRINKING WATER AND HEALTH olism in vitro was depressed (Toftgard et al., 1981~. Similar inhalation ex- posure of rats to 1, 1,1-trichloroethane did not appear to influence the hepatic metabolism of biphenyl or benzofa~pyrene (Nilsen and Toftgaard, 19801. The metabolism of aminopyrine is inhibited to a greater extent than aniline hydroxylation (Bolt et al., 1980~. This could be explained by the fact that 1, 1,1-trichloroethane binds readily to cytochrome P450, as evi- denced by its type I binding characteristics (National Research Council, 1980~. 1, 1,1-Trichloroethane is likely to interfere with monooxygenase ac- tivity, but the dose-response characteristics of this competitive inhibition have not been reported and it is not known if trace concentrations of 1,1,1- trichloroethane, such as those occurring in drinking water, have similar inhibitory effects. When 1, 1,1-trichloroethane is perfused into rat liver, a number of intra- cellular enzymes are released (Noviakovia et al., 1981), but similar effects have not been observed in vivo (National Research Council, 1980~. 1,1,1- Trichloroethane is not a potent hepatotoxicant. Chronic Effects No new data were found by the committee. Mutagenicity 1, 1,1-Trichloroethane was mutagenic in the Ames Sal- monella assay in strains TA1535 and TA100 when tested at concentrations of 0.1, 0.5, and 1.0 ml volumes in an open glass dish inside desiccators (Nestmann et al., 1980~. The investigators did not state whether the muta- genic response was obtained in the presence and/or absence of a metabolic activation system. Based on these data, 1, 1,1-trichloroethane is mutagenic in one bacterial test system. Carcinogenicity 1, 1,1-Trichloroethane was tested for carcinogenicity in both sexes of the B6C3F' mouse and the Fischer 344 rat (National Toxi- cology Program, 1982e). Doses of 3,000 or 1,500 mg/kg bw were adminis- tered by gavage to both sexes of mice. Rats were given doses of 750 or 375 mg/kg. The test material was administered in corn oil to groups of 50 rats and 50 mice of each sex 5 days/week for 2 years. There were also vehicle controls of 50 rats and 50 mice of each sex. Low doses were used to over- come the consequences of poor survival due to the toxicity previously en- countered in both Osborne-Mendel rats and B6C3F~ mice. The results in both sexes of rats confirmed the findings of an earlier study (National Can- cer Institute, 1977b) that the compound was not carcinogenic when ad- ministered by gavage to the Fischer 344 rat. ln the B6C3F' mouse, how- ever, the results indicate a possible compound-related increased incidence
Toxicity of Selected Contaminants 77 of hepatocellular carcinomas in both sexes. The incidence and types of tu- mors are presented in the following section. Carcinogenic Risk Estimate In a study by the National Toxicology Program (1982e), there was an increased incidence of hepatocellular carci- nomas in the exposed mice of both sexes. An NTP review committee con- cluded that 1, 1,1-trichloroethane was carcinogenic for female B6C3F' mice, causing an increase in hepatocelluJar carcinoma. The association in male B6C3F~ mice was considered equivocal. The tumor incidences are summarized in Table II-6. Each set of data showing a statistically significant increase was used to estimate a lifetime risk and an upper 95% confidence estimate of lifetime risk in humans following a daily consumption of 1 liter of water containing the compound in a concentration of 1 ~g/liter. The estimates of lifetime risk are based on the multistage model for carcinogenesis described earlier in this chapter for chlorobenzene. The conversion of animal doses to human doses is again based on body surface area, assuming the following weights: humans, 70 kg; rats, 400 g; and mice, 33 g. The conversion formula is: animal consumption = human consumption X (human weight/animal weight)3'3. The human dose esti- mates were also reduced by a factor of 5/~ to take into account the fact that the test animals were only gavaged 5 days per week. Using the data from the study by the National Toxicology Program (1982e), the committee estimated the lifetime risk and upper 95870 confi- dence estimate of lifetime risk in humans after a daily consumption of 1 liter of water containing the compound in a concentration of 1 ~g/liter (Table II-7. In previous volumes of Drinking Water and Health, the risk estimates from male and female rats and mice were averaged to yield one composite number. If one averages the data in Table II-7, the estimated upper 9S~o confidence estimate of lifetime risk per ~g/liter is 2.98 X 10-8. Using the criteria for interpreting animal carcino.genicity data as out- TABLE II-6 Tumor incidence in 1, 1,1-Trichloroethane-Exposed Micea Tumor Dose Levels, Animal Sex Site mg/kg/day Tumor Rates B6C3F~ mouse Male Liver 0, 1,500, 3,000 16/50, 24/50, 20/50 B6C3F' mouse Female Liver 0, 1,500, 3,000 3/49, 5/49, 10/49 a Based on data from the National Toxicology Program, 1982e.
78 DRINKING WATER AND HEALTH TABLE II-7 Carcinogenic Risk Estimates for 1, 1,1-Trichloroethanea Upper 9S% Confidence Esti- Estimated Human mate of Lifetime Cancer Animal Sex Lifetime Risky Risk per ~g/liter B6C3Fl mouse Male 1.27 x 10-8 3.70 x 10-8 B6C3FI mouse Female 1.09 X 10-8 2.26 X 10-8 a Based on data from the National Toxicology Program. 1982e. bAssuming a daily consumption of I liter of water containing the compound in a concentration of I fig/ liter. lined in Chapter I, the committee based all the above calculations on lim- ited evidence. Teratogenicity Schwetz et al. ( 1975) exposed pregnant mice and rats to 1,1,1-trichloroethane vapor at concentrations of 875 ppm (4,827 mg/m3~. Both groups of animals were exposed for 7 hours/day on days 6 through 15 of gestation. No fetal toxicity or teratogenicity was found. Lane et al. (1982) exposed mice to 1,000 mg/kg concentrations of 1,1,1-trichloro- ethane in drinking water and found no adverse effects on reproduction. The limited data indicate that 1, 1,1-trichloroethane is not teratogenic in mice or rats. CONCLUSIONS AND RECOMMENDATIONS Because virtually all of the studies of 1, 1,1-trichloroethane have been con- ducted with inhalation exposures, it is difficult to make judgments con- cerning the effects following oral exposure. Data on the metabolism and pharmacokinetics of 1, 1,1-trichloroethane in laboratory animals and hu- mans are still needed. When 1, 1,1-trichloroethane was reviewed in the third volume of Drink- ing Water and Health, the only available carcinogenicity study was nega- tive. Therefore, the committee calculated a chronic SNARL based on the lowest dose used in the negative cancer bioassay. Subsequent retesting has produced limited evidence that 1, 1,1-trichloroethane is carcinogenic to mice but not to rats. Until such time as data are available to differentiate the effects of the doses in mice, rats, and humans, it must be assumed that 1, 1,1-trichloroethane is carcinogenic in humans. Therefore, the carcino- genic risk estimate given above, even though based on limited evidence, should supercede the chronic SNARL published in the 1980 review.