Bioassay of toxaphene for possible carcinogenicity.

Abstract

A bioassay of technical-grade toxaphene for possible carcinogenicity was conducted by administering the test chemical in feed to Osborne-Mendel rats and B6C3F1 mice. Groups of 50 rats of each sex were administered toxaphene at one of two doses for 80 weeks, then observed for 28 or 30 weeks. Time-weighted average doses for males were 556 or 1,112 ppm; for females they were 540 or 1,080 ppm. Matched controls consisted of groups of 10 untreated rats of each sex; pooled controls consisted of the matched-control groups for toxaphene combined with 45 untreated male and 45 untreated female rats from similar bioassays of five other test chemicals. All surviving rats were killed at 108-110 weeks. Groups of 50 mice of each sex were administered toxaphene at one of two doses for 80 weeks, then observed for 10 or 11 weeks. Time-weighted average doses were 99 or 198 ppm for both males and females. Matched controls consisted of groups of 10 untreated mice of each sex; pooled controls consisted of the matched-control groups for toxaphene combined with 40 untreated male and 40 untreated female mice from similar bioassays of four other test chemicals. All surviving mice were killed at 90-91 weeks. Mean body weights attained by low- and high-dose female rats and high-dose male mice were lower than those of matched controls, but weights of other dosed groups were essentially unaffected by the toxaphene. Other clinical signs of toxicity in rats included generalized body tremors at week 53 in high-dose male and female animals, and later, leg paralysis, ataxia, epistaxis, hematuria, and vaginal bleeding, predominantly in the dosed groups of rats of each sex. Abdominal distention, diarrhea, dyspnea, and rough hair coats were common to both dosed rats and dosed mice. There were dose-related decreases in survival rates in mice but not in rats. Sufficient numbers of both rats and mice were at risk for the development of late-appearing tumors. In the male rats, the incidence of follicular-cell carcinomas or adenomas of the thyroid was dose related (P=0.007) using the pooled controls (matched controls 1/7, pooled controls 2/44, low-dose 7/41, high-dose 9/35). In the females, the incidence of follicular-cell adenomas of the thyroid was dose related using either the matched (P=0.022) or pooled (P=0.008) controls (matched controls 0/6, pooled controls 1/46, low-dose 1/43, high-dose 7/42). Direct comparisons of dosed and pooled-control groups but not matched controls showed significantly increased incidences of follicular-cell carcinomas or adenomas in the high-dose males (P=0.008) and of follicular-cell adenomas in the high-dose females (P=0.021). Two follicular-cell tumors in the high-dose males were carcinomas; all other follicular-cell tumors in the rats were adenomas. In the mice, the incidence of hepatocellular carcinomas was dose related (P<0.001) for both males (matched controls 0/10, pooled controls 4/48, low-dose 34/49, high-dose 45/46) and females (matched controls 0/9, pooled controls 0/48, low-dose 5/49, high-dose 34/49), using either matched or pooled controls. Direct comparisons showed that the incidences of hepatocellular carcinomas in low- and high-dose male mice and high-dose female mice were all significantly higher (P<0.001) than those in the respective matched or pooled controls. Statistical significance was maintained when the incidence of hepatocellular carcinomas was combined with that of neoplastic nodules of the liver. It is concluded that under the conditions of this bioassay, toxaphene was carcinogenic in male and female B6C3F1 mice, causing increased incidences of hepatocellular carcinomas. The test results also suggest carcinogenicity of toxaphene for the thyroid of male and female Osborne-Mendel rats.