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Chemical Selection Via In Vitro-In Vivo Correlation of ToxCast and ToxRefDB Data to Evaluate the Virtual Liver
Citation:
WAMBAUGH, J. F., K. A. HOUCK, R. JUDSON, M. T. MARTIN, D. J. DIX, AND I. A. SHAH. Chemical Selection Via In Vitro-In Vivo Correlation of ToxCast and ToxRefDB Data to Evaluate the Virtual Liver. Presented at ToxCast Data Analysis Summit, RTP, NC, May 14 - 15, 2009.
Impact/Purpose:
The Virtual Liver Project (v-LiverTM) is a US EPA effort to simulate the function of the human liver with sufficient accuracy to predict how environmental exposure to xenobiotic compounds will perturb homeostasis.
Description:
The Virtual Liver Project (v-LiverTM) is a US EPA effort to simulate the function of the human liver with sufficient accuracy to predict how environmental exposure to xenobiotic compounds will perturb homeostasis. The better we understand the liver, the better we will understand the toxicity of many chemicals. Most metabolism occurs in the liver, including first-pass of most everything that enters through the digestive tract before it moves on to the rest of the body. Our aim is to use an agent-based approached in which liver cells are represented by individual dynamic intra-cellular models, i.e. agents, that change state in response to chemical and inter-cellular signals. Chemical-specific in vitro assay results can be used to determine the inputs to the intra-cellular and chemical distribution models. These simulated cells can then be arranged in either in vitro or in vivo configurations, supporting inference of in vivo consequences from cell-based assay results. In order to characterize the range of chemical attributes that must be captured and evaluate the usefulness of predictions made by the model, we are selecting chemicals with a range of permutations of known mouse or rat in vivo tumorigenicity for model development. We have identified chemicals in four broad categories for specific evaluation: chemicals that caused tumors in rats and mice which were active for ToxCast assays related to RAR, PPAR, LXR, FXR, ER, CAR, AR, PXR, and AhR; mouse-specific tumor-causing compounds that showed activity in all but RXR and LXR assays; rat-specific tumor-causing compounds that showed activity in PXR, CAR, and PPAR assays; and non-tumor causing compounds with little activity across the assays examined. In the proof of concept we would like to predict non-genotoxic lesion progression for mouse and rat for chemicals from each of these classes.
URLs/Downloads:
Chemical Selection Via In Vitro-In Vivo Correlation of ToxCast and ToxRefDB Data to Evaluate the Virtual Liver (PDF, NA pp, 74 KB, about PDF)Chemical Selection Via In Vitro-In Vivo Correlation of ToxCast and ToxRefDB Data to Evaluate the Virtual Liver (poster) (PDF, NA pp, 209 KB, about PDF)