HEPATOCARCINOGENICITY OF CHLORDANE IN B6C3F1 AND B6D2F1 MALE-MICE - EVIDENCE FOR REGRESSION IN B6C3F1 MICE AND CARCINOGENESIS INDEPENDENT OF RAS PROTOONCOGENE ACTIVATION

Logistic regression analysis of age-specific prevalences for neoplasti c and non-neoplastic liver lesions was used to examine treatment respo nses for B6C3F1 and B6D2F1 male mice continuously exposed to chlordane (55 p.p.m.) and to determine whether neoplasms were dependent on cont inuous exposure in the B6C3F1 mice, In order to determine if ras oncog ene activation plays a role in the carcinogenicity of chlordane and wh ether the activation is dependent on genetic background, liver tumors from chlordane-treated B6C3F1 and B6D2F1 mice were analyzed for the pr esence of activating mutations in the ras oncogene, The overall liver tumor prevalence at terminal killing was nearly 100% for both strains; however, the age-specific prevalence increased more rapidly in B6C3F1 mice than in B6D2F1 mice, Tumor-bearing B6C3F1 mice had an average of two more tumors per liver than B6D2F1 mice at their respective termin al killings (5.4 versus 3.3), When chlordane exposure was discontinued for a group of B6C3F1 mice ('stop' group) at 491 days of age, overall tumor multiplicity significantly decreased by 30% from an average of 4.4 per tumor-bearing-animal at 525 days to 3.1 at terminal killing (5 68 days), Over the same time period the prevalence of hepatocellular c arcinomas significantly decreased from 80 to 54% and adenomas from 100 to 93% by terminal killing in B6C3F1 'stop-group' mice, Chlordane ind uced diffuse hepatocellular centrilobular hypertrophy, frequent multin ucleate hepatocytes, toxic change and hepatoproliferative lesions comp osed predominantly of acidophilic hepatocytes in nearly 100% of both t he B6C3F1 and B6D2F1 mice, The development of histological evidence of toxicity closely paralleled the temporal development of hepatocellula r neoplasia and decreased in severity when the tumor burden was maxima l. No H- or K-ras mutations were detected in the chlordane-induced hep atocellular tumors in B6C3F1 mice (15 adenomas and 15 carcinomas) or B 6D2F1 mice (10 adenomas and 10 carcinomas), In conclusion, chlordane i nduced liver tumors in both B6C3F1 and B6D2F1 male mice by mechanisms independent of ras oncogene activation and 30% of both benign and mali gnant liver tumors in the B6C3F1 mice regressed after exposure was dis continued.