Abstract
Toxicogenomics is a mature field which provides invaluable information on the molecular events preceding or accompanying toxicity. Most traditional uses of transcriptional profiling and other –omics data in toxicology are: mode-of-action analysis, classification/prediction, and biomarker discovery. While these applications are very informative for the regulatory decisions, they do not contribute to quantitative evaluation of the margin of safety and/or characterization of the uncertainties in species-to-species extrapolation and population variability. Studies that explore the shape of dose-response relationships at the molecular pathway level, and the impact that inter-individual differences in gene expression patterns may have on both efficacy and safety outcomes, represent some of the novel frontiers in toxicogenomics. Dose-response toxicogenomic data may be used for calculating the point-of-departure at which either adverse or adaptive “molecular pathology” phenotypes are observed after exposure to chemicals. Aggregation of the dose-response genes into pathways further improves the linkages between mechanistic understanding and estimating the margin of safety. In addition, the challenge of elucidating the genetic determinants of inter-individual differences in toxicity may be met through a combined analysis of the toxicity phenotypes, genetic polymorphisms and gene expression data from the population-based experimental in vivo and in vitro model systems. The intricate interplay between genetic polymorphisms and gene expression requires careful consideration of the genetic background-dependent and –independent toxicity pathways. Collectively, as the number of toxicogenomic studies which incorporate dose-response and/or population-based study designs is on the rise, the applicability of such data to next-generation human health risk assessments will also increase.
