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The Analysis of Genomic Dose-Response Data in the EPA ToxCast™ Program
Citation:
DIX, D. J., R. JUDSON, F. ELLOUMI, Z. LI, F. A. WRIGHT, D. REIF, D. ROTROFF, A. V. SINGH, T. B. KNUDSEN, AND K. A. HOUCK. The Analysis of Genomic Dose-Response Data in the EPA ToxCast™ Program. Presented at Society for Risk Analysis Annual Meeting, Boston, MA, December 07 - 10, 2008.
Impact/Purpose:
An initial focus in study design and data analysis is examining the concentration-response of gene expression regulated by the nuclear receptors CAR, PXR and PPARalpha. These nuclear receptors were selected because they regulate key metabolic pathways modulated by xenobiotics such as the ToxCast chemicals, and critical to non-genotoxic carcinogenic modes of action.
Description:
The U.S. EPA must assess the potential adverse effects of thousands of chemicals, often with limited toxicity information. Accurate toxicity predictions will help prioritize chemicals for further testing, focusing resources on the greater potential hazards or risks. In vitro genomics is part of EPA’s ToxCast research program, which is developing the ability to forecast toxicity based on bioactivity profiles derived from high-throughput screening (HTS) assays. From several of the HTS assays, ToxCast is generating gene expression data from in vitro cell systems designed to model the rodent or human liver. Following exposure to each of the 320 ToxCast phase I chemicals, analysis of these data will be used to generate in vitro concentration-response curves for individual gene or protein targets, and for the biological pathways populated by these targets. The suitability of specific in vitro targets and pathways for predictive modeling of in vivo toxicity will be assessed based on several factors. First, whether the in vitro concentration-response for gene expression changes suggests that plausible in vivo tissue concentrations could have similar effects on the same targets and pathways in vivo. A second suitability factor will be whether the mode of action inferred by affected genes, targets and pathways is consistent with the demonstrated toxicity of specific ToxCast chemicals.