Bioassay of lasiocarpine for possible carcinogenicity.
A bioassay of lasiocarpine for possible carcinogenicity was conducted by administering the test chemical in the diet to Fischer 344 rats. Groups of 24 rats of each sex were administered lasiocarpine at one of three doses, either 7, 15, or 30 ppm, for 104 weeks. Matched controls consisted of groups of 24 untreated rats of each sex. All surviving rats were killed at 104 weeks. Mean body weights of the high-dose male and female rats were lower than those of the matched-control groups throughout most of the study, while weights of the mid-dose rats were lower only during the second year, and weights of the low-dose groups were unaffected. There was a positive dose-related trend in mortality for both sexes, with none of the high-dose animals, only five of the mid-dose animals, 23 of the low-dose animals, and 43 of the matched controls surviving to termination of the study. In spite of these early deaths, all male rats except one low-dose animal and one high-dose animal developed tumors, and among the females, 23 low-dose and 22 mid-dose animals developed tumors. Time-adjusted analysis of the incidence of tumors was performed in the female rats. In male rats, there was a positive dose-related trend (P<0.001) in the incidence of angiosarcoma of the liver; furthermore, the incidences in the mid- and high-dose groups, but not that in the low-dose, were significantly higher (P<0.001, both groups) than that in the controls (controls 0/24, low-dose 5/24, mid-dose 11/24, high-dose 13/24). In females, the incidences in both the low- and mid-dose groups, but not that in the high-dose, were significantly higher (P=0.002 and P=0.005, respectively) than that in the controls (controls 0/24, low-dose 8/24, mid-dose 7/24, high-dose 2/9). Metastatic angiosarcomas were present in the lungs from a few of the rats in all three treated groups of both sexes. In both male and female rats, there was a positive dose-related trend in the combined incidence of hepatocellular carcinoma and adenoma of the liver (males, P=0.003; females, P<0.001); furthermore, the combined incidence of these tumors in the high-dose females, but not those in the low- and mid-dose, was significantly higher (P<0.001) than that in the controls (controls 0/24, low-dose 5/24, mid-dose 1/24, high-dose 7/9). The P-value of the combined incidence in the high-dose males (P=0.025) is above the 0.016 level required by the Bonferroni inequality criterion, when multiple comparison is considered (controls 0/24, low-dose 0/24, mid-dose 3/24, high-dose 5/24). Nodular hyperplasia was observed in additional animals of each treated group of each sex. Thus, lasiocarpine was associated with proliferative lesions of hepatocytes as well as with angiosarcomas arising from endothelial cells of the liver. The combined incidence of lymphoma or leukemia was significant in both the low- and mid-dose female groups (P</= 0.018), but not in the high-dose group, perhaps because of the early deaths in this group (controls 2/24, low-dose 9/24, mid-dose 11/24, high-dose 1/23). The incidences of these tumors in the males were not significant. It is concluded that under the conditions of this bioassay, lasiocarpine was carcinogenic in Fischer 344 rats producing hepatocellular tumors and angiosarcomas of the liver in both sexes and hematopoietic tumors in female animals.