Chapter 3: Toxicogenomics In vitro: Gene Expression Signatures for Differentiating Genotoxic Mechanisms

Genotoxicity testing is a fundamental component of chemical assessment. It is used to estimate the ability of a chemical to damage DNA, which can ultimately lead to cancer or heritable mutations. Although the existing genotoxicity testing paradigm is sensitive, it lacks specificity, human relevance, and mechanistic insight into a chemical's mode of action. The use of predictive in vitro toxicogenomics using human cells to complement the current genotoxicity testing battery has been proposed as a means to address these shortcomings. In this chapter, we review the development and validation of predictive toxicogenomic signatures for genotoxicity using mammalian cells in culture. We also address the issue of suboptimal metabolic activation in many of the in vitro systems, which may lead to misinterpretation of the results. We emphasize the need for validated signatures to predict genotoxic outcomes that have been robustly tested across different cell culture systems, laboratories, gene expression platforms, and experimental designs. Our review of the literature suggests that this field has matured to a stage where it is ready for specific applications in human health risk assessment. However, the public release of validated predictive signatures and analytical methods is required for full implementation in routine risk assessment.