Principles and Practice of Genetic Toxicology in Drug Development and Safety Evaluation

Genetic toxicology is the study of physical and chemical agents that can damage genetic material such as DNA and chromosomes. Genetic toxicology plays an important role in all phases of drug evaluation and development. Genetic toxicology testing used in a regulatory setting can identify agents that could cause genetic damage that may ultimately lead to development of cancer faster than conduct of a regulatory required 2-year carcinogenicity study. A tiered approach is taken for genotoxicity testing because one test alone is not capable of detecting all carcinogens. This tiered approach or standard battery is required by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) [ICH S2(R1), guidance for genotoxicity testing and data interpretation for pharmaceuticals intended for human use]. It involves assessing mutagenicity in an Ames test and evaluating genotoxicity in mammalian cells using in vitro and/or in vivo tests. This chapter covers the purpose and rationale, basic procedures and evaluation, critical assessment, and modifications to the most commonly used genetic toxicology assays, based on guidance, for drug development. These commonly used assays are the Ames test, the in vitro and in vivo micronucleus, and the comet assay.