Mode of action considerations in the use of transgenic animals for mutagenicity and carcinogenicity evaluations

Genetically altered rodent models can be useful in facilitating the extrapolation of results from animal carcinogenicity studies to human risk assessment by contributing mode of action data. Transgenic mutation models make it possible to analyze mutations in vivo in any tissue of interest. Validation studies using genotoxic and epigenetic carcinogens indicated a good correlation between mutation induction and the tumor target tissues and have provided data on mode of tumorigenic action. However, carcinogenesis is a complex process and mutation induction in a given tissue does not always lead to tumors in that tissue. Genetically altered animal models such as the p53 +/- mouse can be useful in differentiating genotoxic carcinogens from those operating by non-genotoxic mechanisms. An understanding of the tumor responses of these short-term alternative transgenic and knockout mice to epigenetic events such as tissue injury and enzyme induction at high maximum tolerated doses will eventually increase our level of confidence in these animal models for hazard evaluation and mechanistic studies.