Validation of transgenic mice harboring the human prototype c-Ha-ras gene as a bioassay model for rapid carcinogenicity testing

Abstract

Studies were conducted to validate the transgenic (Tg) mice harboring human prototype c-Ha-ras gene, namely the rasH2 mice (CB6F1), as a model for rapid carcinogenicity testing. Short-term (26 weeks) carcinogenicity testing of 18 mutagenic (Salmonella) trans-species carcinogens, two mutagenic single-species (mouse-only) carcinogens six non-mutagenic trans-species carcinogens, one non-mutagenic single-species (mouse-only) carcinogen, four mutagenic non-carcinogens and four non-mutagenic non-carcinogens were completed. The studies revealed that the Tg mice are able to detect various types of mutagenic carcinogens and may also detect various non-mutagenic carcinogens within 26 weeks. Dose-dependent tumor responses were observed with various carcinogens except for a few equivocal cases. The validation studies also revealed that the Tg mice are generally much more susceptible to both mutagenic and non-mutagenic carcinogens than control non-Tg mice. Most of the malignant tumors were observed in the carcinogen-treated Tg mice and only very few or none in the corresponding non-Tg mice. Most of the carcinogens tested induced some of the target organ tumors observed in B6C3F1 mice in a 2-year bioassay as well as certain types of tumors specific to the Tg mice, i.e. lung alveolar epithelial tumors, spleen hemangiosarcomas, forestomach squamous cell tumors. No significant tumor induction has been observed in the Tg mice either with mutagenic or non-mutagenic non-carcinogens. Although further validation studies are still required, the rasH2 mouse seems to be a promising candidate as an animal model for the development of a rapid carcinogenicity testing system.