Utility of Transgenic Mice Carrying Human Prototype c-Ha-ras Gene for Alternative Carcinogenicity Testing of Chemicals—Negative Results with Methapyrilene Hydrochloride

Abstract

This study was conducted as part of an international evaluation on transgenic mouse models as potential alternatives to the standard two-year bioassay. Methapyrilene hydrochloride (MP), a non-genotoxic rat-specific hepatocarcinogen, in the diet was given to male and female transgenic CB6F₁ mice carrying copies of a human prototype c-Ha-ras gene (rasH2 mice) at doses of 0, 1, 750, 3, 500, and 7, 000 ppm and to male and female non-transgenic littermates (non-Tg mice) at 0 and 7000 ppm for 26 weeks and subsequently sacrificed. N-methyl-N-nitrosourea (MNU) was used as a positive control compound to confirm that a positive response is elicited in the rasH2 model. Complete autopsies were performed and all organs of mice were histologically examined. Lung alveolar/bronchiolar adenomas and carcinomas, a thymic lymphoma, splenic hemangiosarcomas, skin squamous cell papillomas/carcinomas and hemangiosarcoma, a Harderian gland adenoma, and uterus and testicular hemangiosarcomas were detected in rasH2 mice receiving MP or basal diet. Only one neoplasm was found in the non-Tg group, in a non-treated male. However, there were no effects of MP on tumor incidence or multiplicity, although rasH2 mice were sensitive to the carcinogenic activity of MNU. Slight hepatotoxicity, as evidenced by hepatocyte hypertrophy and small bile duct proliferation, was noted in rasH2 and non-Tg mice treated with MP, but no hepatic foci were noted in any mice. The results indicate that negative carcinogenicity of MP was confirmed even at doses higher than those employed earlier in B6C3F₁ mice, and suggest that this non-genotoxic rat specific carcinogen may not be a human carcinogen. Thus, the rasH2 mouse model has utility as an alternative for the detection of carcinogenicity of environmental chemicals.