Chapter 15. In Vivo Genetic Toxicology: Application to Cancer Risk Assessment

Abstract

Genotoxicity studies conducted in animals are a key component in carcinogenicity risk assessment, offering advantages over in vitro methods by accounting for chemical/drug dispositional effects and intact homeostatic mechanisms. In vivo genotoxicity assays can be classified as either those measuring DNA damage (rodent micronucleus (MN), unscheduled DNA synthesis (UDS), Comet assay), or mutations (Hprt loci, Pig-a, transgenic rodent models). Currently, in vivo genotoxicity tests measuring DNA damage are more widely used in safety evaluation and risk assessment, although both the rodent MN and UDS assays have relatively high false-negative rates. The Comet assay shows better predictivity; however, further refinements in protocol and data evaluation criteria are needed. Technological advancements in measuring DNA damage in peripheral blood (MN and Comet assays, DNA adducts) allow monitoring for genotoxicity in a surrogate tissue across several species. Mutagenicity assays are useful for understanding the relevance of DNA damage, and although endogenous gene assays (e.g., Hprt, Pig-a), as well as genomic technologies are not widely used for risk assessment, they hold promise as genotoxicity biomarkers given their application across species. Transgenic rodents with exogenous reporter genes have been used successfully to assess mutagenicity; however, these models are expensive and not widely used. Although much progress has been made in the refinement and application of in vivo genotoxicity testing, only through the comprehensive integration of chemical/drug disposition, dose–response, and mode-of-action (MoA) data, with extrapolations to human use and/or exposure, will cancer risk to exposed populations be more accurately predicted.