title: Bioassay of heptachlor for possible carcinogenicity.
abstract: A bioassay of technical-grade heptachlor for possible carcinogenicity was conducted by administering the test material in feed to Osborne-Mendel rats and B6C3F1 mice. Groups of 50 rats of each sex were administered low or high concentrations of the heptachlor for 80 weeks, then observed for 30 weeks. Doses for females were first increased, but because of toxic effects the doses were then reduced twice for both male and female rats during the remaining course of the tests. Time-weighted average doses used for the male rats were 38.9 and 77.9 ppm; for the females, 25.7 and 51.3 ppm. Matched controls consisted of groups of 10 untreated rats of each sex; pooled controls consisted of the matched-control groups combined with 50 untreated male and 50 untreated female rats from similar bioassays of five other compounds. All surviving rats were killed at 110-111 weeks. Groups of 50 mice of each sex were administered the test material at low or high concentrations for 80 weeks, then observed for 10 weeks. The low- and high-dose groups were tested at different calendar times, but a concurrent control group was started with each. Because of toxic effects, doses were reduced once for the males at 17-18 weeks after the initiation of tests; twice for the females, at 17 and 30 weeks, after the initiation of tests. The time-weighted average doses used for the male mice were 6.1 and 13.8 ppm; for the females, 9 and 18 ppm. Matched controls consisted of groups of 10 untreated mice of each sex; pooled controls consisted of the matched-control groups combined with 90 untreated male and 70 untreated female mice from similar bioassays of five other compounds. All surviving mice were killed at 90-91 weeks. The effects of heptachlor on body weights and other clinical signs in rats and mice indicated that the dosages used were near the maximum permissible. This was evident in that average body weights of rats treated with high doses were consistently lower than those of untreated controls, while body weights of low-dose rats were unaffected. Body weights of mice given either high or low doses showed little or no differences from those of control mice; however, other adverse clinical signs were found in high-dose mice, predominantly in the females. The effects of heptachlor on survival rates indicated that mortality was dose-related for both female rats and female mice, but not for males of either species. However, a substantial proportion of all groups of animals survived to an age at which tumors could be expected to appear. In mice, hepatocellular carcinoma showed a highly significant dose-related trend in both males (matched controls 5/19, low dose 11/46, high dose 34/47, P=0.001) and females (control 2/10, low dose 3/47, high dose 30/42, P<0.0001). When pooled controls were used for the comparison, the significance of the trend in males increased to P<0.0001. Comparably high levels of significance were attained when the data were subjected to life-table adjustment. No other tumors were found in mice in sufficient numbers to justify analysis. In marked contrast to the findings observed in mice, no hepatic tumors were observed in rats administered heptachlor. There was significant statistical evidence for the induction of proliferative lesions of follicular cells of the thyroid in treated female rats, but this finding was discounted because the rates of incidence were comparatively low and are known to be variable in control rat populations. It is concluded that under the conditions of this bioassay, heptachlor is carcinogenic for the liver in mice.