Bioassay of chlordane for possible carcinogenicity.
A bioassay of analytical-grade chlordane 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 chlordane for 80 weeks, then observed for 29 weeks. Because of toxic effects, doses were reduced for both male and female rats during the course of the tests. Time-weighted average doses used for the male rats were 203.5 and 407.0 ppm; for the females, 120.8 and 241.5 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 109 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 each of the treated groups was tested along with a concurrent control. Because of toxic effects, doses were reduced for female mice during the course of the tests; however, it was possible to increase the doses for the male mice. The time-weighted average doses used for the male mice were 29.9 and 56.2 ppm; for the females, 30.1 and 63.8 ppm. Matched controls consisted of groups of 10 untreated mice of each sex; pooled controls consisted of the matched-control groups combined with 70 untreated male and 80 untreated female mice from similar bioassays of five other compounds. All surviving mice were killed at 90-91 weeks. The effects of chlordane 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 the average body weights of the high-dose male and female rats were consistently lower than those of the untreated controls, while differences between the low-dose and control rats were negligible. Body weights of mice given either low or high doses showed little or no effect of the chlordane; however, other adverse clinical signs were seen with greater frequency than in control mice. The effects of chlordane on survival rates indicated that mortality was dose-related for female rats and for male mice. However, a substantial proportion of most groups of animals survived to an age at which tumors could be expected to appear; male control rats, for unknown reasons, showed an abnormally low survival rate. Hepatocellular carcinoma showed a highly significant dose-related trend for mice, using either matched controls (for males, controls 2/18, low dose 16/48, high dose 43/49, P<0.0001; for females, controls 0/19, low dose 3/47, high dose 34/49, P<0.0001) or pooled controls (for males, controls 17/92, P<0.0001; for females, controls 3/78, P<0.0001). These high levels of significance were maintained when hepatocellular carcinoma was combined with nodular hyperplasia or when the data were subjected to life-table adjustment. No other tumors were found in mice in sufficient numbers to justify analysis. In contrast to findings with mice, hepatocellular carcinoma failed to appear at a significant rate of incidence in rats administered chlordane. Further, the number of lesions of the liver in rats did not become significant with the addition of nodular neoplasia or with the application of life-table adjustment to the data. There was significant statistical evidence for the induction in treated male rats of proliferative lesions of follicular cells of the thyroid and of malignant fibrous histiocytoma, but these findings were discounted because the rates of incidence were comparatively low and/or are known to be variable in control rat populations. It is concluded that under the conditions of this bioassay chlordane is carcinogenic for the liver in mice.