Citation:

Clewell, H., F. Boellmann, C. Smith, L. Tsai, D. Rotroff, D. J. DIX, M. Andersen, S. Ferguson, E. LeCluyse, AND R. Thomas. An Integrated In Vitro and Computational Approach to Define the Exposure-Dose-Toxicity Relationships In High-Throughput Screens. Presented at Society of Toxicology Annual Meeting, Baltimore, MD, March 15 - 19, 2009.

Impact/Purpose:

Using these two pharmacokinetic parameters, equivalent oral exposures have been estimated using SimCyp® software that would result in steady state tissue concentrations comparable to the LC50 values. This integrated approach promises to provide refined exposure-dose-toxicity evaluations that will aid in interpretation of high-throughput screening results. Such context will be essential for identifying appropriate priorities for follow-up testing and risk evaluation exercises.

Description:

Research efforts by the US Environmental Protection Agency have set out to develop alternative testing programs to prioritize limited testing resources toward chemicals that likely represent the greatest hazard to human health and the environment. Efforts such as EPA’s ToxCast research program use high-throughput screening to evaluate large numbers of chemicals across a variety of in vitro assays. One challenge has been to provide a human exposure-dose context to the in vitro concentration values obtained in the in vitro assays. Organ slice cultures were established for rat liver, lung, and kidney. Cultures were exposed to 140 chemicals, a subset of the ToxCast_320, in a 5-point dose response (0.8 - 100 uM). Cytotoxicity was measured as the endpoint. Only 48 chemicals had measureable LC50 in at least one tissue, with kidney as the most sensitive organ (38 chemicals), followed by lung (10 chemicals), and liver (8 chemicals). For the 48 cytotoxic chemicals, intrinsic clearance was measured using primary human hepatocytes and protein binding was measured in human plasma.

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