Review and meta-analysis of gene expression biomarkers predictive of chemical-induced genotoxicity in vivo.

Abstract

There is growing recognition across broad sectors of the toxicology community that gene expression biomarkers have the potential to identify genotoxic and nongenotoxic carcinogens through a weight-of-evidence approach, providing opportunities to reduce reliance on the 2-year bioassay to identify carcinogens. In August 2022, a workshop within the International Workshops on Genotoxicity Testing (IWGT) was held to critically review current methods to identify genotoxicants using various 'omics profiling methods. Here, we describe the findings of a workshop subgroup focused on the state of the science regarding the use of biomarkers to identify chemicals that act as genotoxicants in vivo. A total of 1341 papers were screened to identify those that were most relevant. While six published biomarkers with characterized accuracy were initially examined, four of the six were not considered further, because they had not been tested for classification accuracy using additional sets of chemicals or other transcript profiling platforms. Two independently derived biomarkers used in conjunction with standard computational techniques can identify genotoxic chemicals in vivo (rat liver or both rat and mouse liver) on different gene expression profiling platforms. The biomarkers have predictive accuracies of ≥92%. These biomarkers have the potential to be used in conjunction with other biomarkers in integrated test strategies using short-term rodent exposures to identify genotoxic and nongenotoxic chemicals that cause cancer.