The Tg rasH2 Mouse in Cancer Hazard Identification

Abstract

The Tg rasH2 transgenic mouse has been developed as an alternative to the lifetime mouse bioassay to predict the carcinogeni c potential of chemicals. Unlike the p53 / mouse, the Tg rasH2 mouse is sensitive to both genotoxic and nongenotoxi c carcinogens . The Tg rasH2 mouse, of cially designated CB6F1-TgN (RasH2), contains multiple copies of the human c-Ha-ras oncogen e and promoter within its genome. These mice develop spontaneou s and chemically induced neoplasms earlier in life and in greater numbers than wild-type mice, re ecting their enhanced sensitivity to neoplasia. The most common spontaneous neoplasms in control Tg rasH2 mice 8 to 9 months of age are lung adenomas and carcinomas (7.4% incidence), splenic hemangioma s and hemangiosarcoma s (5.4%), forestomach squamous cell papillomas and carcinomas (2.4%), and skin neoplasms (1.2%). Simulations have demonstrated that 20 to 25 mice/sex/treatment group are required to provide the assay with adequate statistical power. Four of 6 known or suspected human carcinogens tested in Tg rasH2 mice were positive in this assay. For 19 nonmutageni c agents testing positive in conventiona l rodent bioassays, 7 chemicals were positive, 10 chemicals were negative, and 2 were equivocal. None of the 10 nonmutageni c rodent carcinogen s that were negative in the Tg rasH2 mouse model are considered to be human carcinogens . All nonmutageni c chemicals that were negative in the conventiona l rodent bioassays were also negative in the Tg rasH2 model. Results for 15 of 18 mutageni c chemicals tested in Tg rasH2 mice agreed with the results of conventiona l rodent bioassays, and 3 results were equivocal. The Tg rasH2 mouse model appears to predict known or suspected human carcinogen s as well as the traditional mouse bioassay, but with fewer positive results for nongenotoxi c compounds that are not considered human carcinogens . The Tg rasH2 mouse model is the most thoroughly tested in vivo alternative to the lifetime mouse bioassay for nongenotoxi c compounds administered by oral or parenteral routes. The U.S. FDA Carcinogenicit y Assessment Committee has determined that the Tg rasH2 model has been adequately evaluated for consideration for carcinogenicity testing of pharmaceutica l candidates and its use could contribute to the weight of evidence for carcinogenicity assessment. The FDA will consider proposals to replace lifetime mouse carcinogenicity studies with 6-month Tg rasH2 mouse studies to support pharmaceutical registration on a case-by-cas e basis.

N-Methyl-N-Nitrosourea (MNU): A Positive Control Chemical for p53+/− Mouse Carcinogenicity Studies

“…MNU is the accepted positive control chemical for the six-month rasH2 mouse alternative carcinogenicity model (Morton et al 2002;Takaoka et al 2003;Urano et al 2001;Usui et al 2001). In rasH2 mice, a single injection of MNU produces a high incidence of thymic malignant lymphoma with frequent involvement of spleen, lymph nodes, liver, and other parenchymal organs (Takaoka et al 2003;Urano et al 2001).…”

Scientific Opinion on the use of Resorcinol as a food additive

“…Administration of resorcinol to CB6F1-Tg rasH2 mice by gavage at a dose of 225 mg/kg bw/day, 5 days per week, for 26 weeks was reported by 2 independent laboratories not to be associated with tumour development (Yamamoto et al, 1998;Maronpot et al, 2000;Morton et al, 2002).…”

A 26-Week Carcinogenicity Study of 2-Amino-3-Methylimidazo[4,5-f]Quinoline in rasH2 Mice

“…As the standard protocol of short-term carcinogenicity test using rasH2 mice, 15 animals/sex/group were used in validation studies by ILSI/HESI (Robinson and MacDonald, 2001), and 20-25 animals/sex/group are recommended from the viewpoint of statistical power currently (Morton et al, 2002). To save the number of animals used in this study, we used the minimum number of animals based on this information.…”

“…Based on previous studies, it is well recognized that rasH2 mice are very susceptible to genotoxic carcinogens; therefore, they are generally accepted as an alternative animal model and used in place of long-term carcinogenicity tests (Yamamoto et al, 1996;Usui et al, 2001;Morton et al, 2002). On the other hand, since rasH2 mice cannot always detect all types of carcinogens, it is necessary to validate the carcinogenic susceptibility of these mice to various chemicals for appropriate evaluation of carcinogenic substances.…”