Bioassay of tetrachloroethylene for possible carcinogenicity.
The bioassay of U.S.P.-grade tetrachloroethylene for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice. Tetrachloroethylene in corn oil was administered by gavage at either of two dosages to groups of 50 male and 50 female animals of each species, 5 days a week, over a period of 78 weeks followed by an observation period of 32 weeks for rats and 12 weeks for mice. Initial dosage levels for the chronic bioassay were selected on the basis of a preliminary subchronic toxicity test. Subsequent dosage adjustments were made during the course of the chronic bioassay. The high and low time-weighted average dosages of tetrachloroethylene in the chronic study were 941 and 471 mg/kg/day for the male rats, 949 and 474 mg/kg/day for the female rats, 1,072 and 536 mg/kg/day for the male mice, and 772 and 386 mg/kg/day for the female mice. For each species, 20 animals of each sex were placed on test as vehicle controls. These animals were gavaged with corn oil at the same time that dosed animals were gavaged with tetrachloroethylene mixtures. Twenty animals of each sex were placed on test as untreated controls for each species. These animals received no gavage treatments. No significant increased incidence of neoplastic lesions was observed in treated rats. In both dosed and control rats, respiratory disease was observed with increasing frequency for the latter part of the first year until termination of the bioassay. Lesions indicative of pneumonia were observed in nearly all rats at necropsy. A high incidence of toxic nephropathy was observed in treated rats. Toxic nephropathy was noted in rats that died early in the study (as early as week 20 for male rats and week 28 for female rats). Mortality of rats was dose-related. Fifty percent of the high dose males had died by week 44 and 50 percent of the high dose females had died by week 66. In both male and female mice, administration of tetrachloroethylene was associated with a significantly increased incidence of hepatocellular carcinoma. Hepatocellular carcinomas were observed in 2/17 (12 percent) untreated control males, 2/20 (10 percent) vehicle control males, 32/49 (65 percent) low dose males, 27/48 (56 percent) high dose males, 2/20 (10 percent) untreated control females, 0/20 vehicle control females, 19/48 (40 percent) low dose females, and 19/48 (40 percent) high dose females. Hepatocellular carcinomas metastasized to the kidney in one untreated control male and to the lung in three low dose males, one low dose female, and one high dose female. Toxic nephropathy, similar to that observed in rats, was also observed in treated but not control mice. Fisher exact tests indicated a highly significant increased incidence of hepatocellular carcinoma for each dosed group compared to each control group. Cochran-Armitage tests showed a highly significant positive association between increased dosage and elevated tumor incidence. Time-adjusted analyses, based on Kaplan and Meier survival curves, indicated that the estimated probability of observing hepatocellular carcinoma by week 91 was 1.00 in a dosed male mouse and 0.938 in a dosed female mouse. The results of the bioassay of tetrachloroethylene in Osborne-Mendel rats do not allow an evaluation of the carcinogenicity of this compound due to the high rate of early death among the treated animals. However, under the condition of this study, tetrachloroethylene is a liver carcinogen in B6C3F1 mice of both sexes.