Logistic regression analysis of age-specific prevalences for neoplastic and non-neoplastic liver lesions was used to examine treatment responses for B6C3F1 and B6D2F1 male mice continuously exposed to
chlordane (55 p.p.m.) and to determine whether
neoplasms were dependent on continuous exposure in the B6C3F1 mice. In order to determine if ras oncogene activation plays a role in the carcinogenicity of
chlordane and whether the activation is dependent on genetic background, liver
tumors from
chlordane-treated B6C3F1 and B6D2F1 mice were analyzed for the presence 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 or more
tumors per liver than B6D2F1 mice at their respective terminal 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 (568 days). Over the same time period the prevalence of
hepatocellular carcinomas significantly decreased from 80 to 54% and
adenomas from 100 to 93% by terminal killing in B6C3F1 'stop-group' mice.
Chlordane induced diffuse hepatocellular centrilobular
hypertrophy, frequent multinucleate hepatocytes, toxic change and hepatoproliferative lesions composed predominantly of acidophilic hepatocytes in nearly 100% of both the B6C3F1 and B6D2F1 mice. The development of histological evidence of toxicity closely paralleled the temporal development of hepatocellular
neoplasia and decreased in severity when the
tumor burden was maximal. No H- or K-ras mutations were detected in the
chlordane-induced hepatocellular
tumors in B6C3F1 mice (15
adenomas and 15
carcinomas) or B6D2F1 mice (10
adenomas and 10
carcinomas). In conclusion,
chlordane induced liver
tumors in both B6C3F1 and B6D2F1 male mice by mechanisms independent of ras oncogene activation and 30% of both benign and malignant liver
tumors in the B6C3F1 mice regressed after exposure was discontinued.