Pathological features of spontaneous and induced tumors in transgenic mice carrying a human prototype c-Ha-ras gene used for six-month carcinogenicity studies

To validate the transgenic (Tg) mouse carrying a human prototype c-Ha-ras gene (rasH2 mouse) as a model for short or medium-term carcinogenicity testing, 6-mo carcinogenicity studies using more than 30 chemicals, including carcinogens and noncarcinogens, have been performed. The results obtained so far indicate that rasH2 mice are generally much more susceptible to both mutagenic and nonmutagenic carcinogens than are non-Tg mice, pointing to advantageous application for detection of carcinogenic potential. In this review, histopathological features and diagnostic criteria for spontaneous and induced-tumors observed in our 6-mo carcinogenicity studies are described. Incidences of spontaneous tumors were generally low in rasH2 mice during the 6-mo studies, although values for lung adenomas and splenic hemangiosarcomas were higher than those in the control non-Tg mice. A few forestomach papillomas and skin papillomas were also observed in the control rasH2 mice. The target organs in rasH2 mice treated with known carcinogens were not always identical to those in the treated B6C3F(1) mice in 2-yr carcinogenicity bioassays, with forestomach squamous cell tumors, lung alveolar epithelial tumors and/or hemangiosarcomas in the spleen observed in addition to some but not all of the lesions in target organs observed in non-Tg mice in long-term carcinogenicity bioassays. The results of the present histological study suggest that the lung, spleen and/or forestomach, where tumors are induced in rasH2 mice treated with known carcinogens, should be regarded as informative target organs in addition to the target organs reported in previous long-term carcinogenicity bioassays in rats and mice.