Temporal and Dose-response Pathway Analysis for Predicting Chronic Chemical Toxicity

Current challenges facing chemical risk assessment are the time and resources required to meet the data standards necessary for a published assessment and the incorporation of modern biological information. The integration of toxicogenomics into the risk assessment paradigm may address both challenges by providing an efficient means to quantitatively and comprehensively evaluate molecular changes resulting from chemical exposure. To assess the value of toxicogenomics in chemical risk assessment, a series of studies was performed. In the first study, mice were exposed for 13 weeks to multiple concentrations of five chemicals that were positive in a cancer bioassay. In a second study, rats were exposed with time to multiple concentrations of six chemicals with published risk assessments. In both studies, histological changes were evaluated and transcriptional microarray analysis was performed on the target tissues. Histological and the tumor responses were analyzed using benchmark dose (BMD) methods to identify noncancer and cancer points-of-departure. Dose-related changes in gene expression were also analyzed using a pathway-based BMD approach. The transcriptional BMD values showed a high degree of correlation with apical responses for specific pathways and many of the correlated pathways have been implicated in relevant disease pathogenesis. Importantly, transcriptional BMDs for even the most sensitive pathway were on average less than three-fold different than traditional apical BMDs for both cancer and non-cancer endpoints suggesting that transcriptomic changes in signaling pathways can be used to estimate noncancer and cancer points-of-departure for use in quantitative risk assessments. This abstract does not necessarily reflect U.S. EPA policy.