Bioassays of Aldrin and Dieldrin for Possible Carcinogenicity
(CAS No. 309-00-2) (CAS No. 60-57-1)
Aldrin and dieldrin are organochlorine insecticides of the cyclodiene group. These chemicals are neurotoxins, and their predominant effect is the stimulation of the nervous system. Both aldrin and dieldrin are lipophilic and accumulate in mammalian tissues. Aldrin undergoes metabolic conversion to the epoxide, dieldrin, and because of this structural relationship, reports of the bioassays of both chemicals have been combined in this single report.
Bioassays of technical-grade aldrin and dieldrin for possible carcinogenicity were conducted by administering the test materials in feed to Osborne-Mendel rats and B6C3F1 mice.
Groups of 50 rats of each sex were administered aldrin at one of two doses, either 30 or 60 ppm. Male rats were treated for 74 weeks, followed by 37-38 weeks of observation; female rats were treated for 80 weeks, followed by 32-33 weeks of observation. Matched controls consisted of groups of 10 untreated rats of each sex; pooled controls, used for statistical evaluation, consisted of the matched-control groups combined with 58 untreated males and 60 untreated females from similar bioassays of other chemicals. All surviving rats were killed at 111-113 weeks.
Groups of 50 mice of each sex were administered aldrin at one of two doses for 80 weeks, then observed for 10-13 weeks. Time-weighted average doses were 4 or 8 ppm for males and 3 or 6 ppm for females. Matched controls consisted of groups of 20 untreated male mice and 10 female mice; pooled controls, used for statistical evaluation, consisted of the matched-control groups combined with 92 untreated male and 79 untreated female mice from similar bioassays of other chemicals. All surviving mice were killed at 90-93 weeks.
Mean body weights attained by the rats and mice fed diets containing aldrin were similar to those of the controls during the first year of the study; however, mean body weights of the treated rats were lower than those of the controls during the second year of the study. Hyperexcitability was observed in all treated groups with increasing frequency and severity during the second year. Aldrin produced no significant effect on the mortality of rats or of male mice, but there was a dose-related trend in the mortality of female mice, primarily due to the early deaths in the high-dose groups.
There was an increased combined incidence of follicular-celladenoma and carcinoma of the thyroid both in male rats fed aldrin (matched controls 3/7, pooled controls 4/48, low-dose 14/38, high-dose 8/38) and female rats fed aldrin (matched controls 1/9, pooled controls 3/52, low-dose 10/39, high-dose 7/46). These incidences were significant in the low-dose but not in the high-dose groups both of males (P=0.001) and females (P=0.009) when compared with the pooled controls. Comparisons with matched controls, however, were not significant.
Cortical adenoma of the adrenal gland was also observed in aldrin-treated rats in significant proportions (P=0.001) in low-dose (8/45) but not in high-dose (1/48) females when compared with pooled controls (0/55). Because these increased incidences were not consistently significant when compared with matched rather than pooled control groups, it is questionable whether the incidences of any of these adrenal tumors were associated with treatment.
In male mice, there was a significant dose-related increase in the incidence of hepatocellular carcinomas (matched controls 3/20, pooled controls 17/92, low-dose 16/49, high-dose 25/45) when compared with either matched controls (P=0.001), or pooled controls (P<0.001). The incidence in the high-dose group was significant when compared with matched controls (P=0.002) or pooled controls (P<0.001).
Groups of 50 rats and 50 mice of each sex were administered dieldrin at one of two doses. Low-dose rats and both low-and high-dose mice were treated for 80 weeks, followed by observation periods of 30-31 weeks for rats and 10-13 weeks for mice. Treatment of high-dose rats was terminated after 59 weeks and followed by 51-52 weeks of observation. Time-weighted average doses for rats were 29 or 65 ppm; doses for mice were 2.5 or 5 ppm. Matched controls consisted of groups of 10 untreated rats of each sex and 20 untreated male mice and 10 female mice; pooled controls, used for statistical evaluation, consisted of the matched-control groups combined with untreated animals from similar bioassays of other chemicals (58 male and 60 female rats, 92 male and 79 female mice). All surviving rats were killed at 110-111 weeks, and all surviving mice at 90-93 weeks.
Mean body weights attained by the rats and mice fed diets containing dieldrin showed little or no differences compared with those of the controls during the first year of the study; however, mean body weights of the treated rats were lowerthan those of the controls during the second year of the study. Hyperexcitability was observed in all treated groups with increasing frequency during the second year, especially in high-dose rats.
There was a marked increase in the mortality rate of rats during the first 90 weeks of the study. However, because of the high rates of mortality in the control groups during the remaining 20 weeks, survival could not be shown to be statistically dose responsive.
In rats, there was a significant (P=0.007) difference between the combined incidence of adrenal cortical adenoma or carcinoma in the low-dose females (6/45) and that in the pooled controls (0/55). Although this tumor was also found in animals treated with aldrin, it is not clearly associated with treatment, because the incidence in the high-dose (2/40) was not significant, and the incidences were not significant when matched, rather than pooled, controls were used for comparison.
In male mice, there was a significant positive dose-related trend (P=0.020) in the incidence of hepatocellular carcinomas using the pooled controls (pooled controls 17/92, low-dose 12/50, high-dose 16/45). When high-dose males were compared with the pooled controls, the results were also significant (P=0.025).
It is concluded that under the conditions of these bioassays, none of the tumors occurring in Osborne-Mendel rats treated with aldrin or dieldrin could clearly be associated treatment.
Aldrin was carcinogenic for the liver of male B6C3F1 mice producing hepatocellular carcinomas. With dieldrin, there was a significant increase in the incidence of hepatocellular carcinomas in the high-dose males which may be associated with treatment.
Levels of Evidence of Carcinogenicity:
Note: Dieldrin was also studied by administration in feed to F344 rats (See TR-022, reported 1978).
Report Date: 1978