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Opportunities and Challenges in Employing In Vitro-In Vivo Extrapolation (IVIVE) to the Tox21 Dataset
Citation:
Wetmore, B. Opportunities and Challenges in Employing In Vitro-In Vivo Extrapolation (IVIVE) to the Tox21 Dataset. 2017 ISES Annual Meeting, Durham, NC, October 15 - 19, 2017.
Impact/Purpose:
This talk will provide an update to an international audience on the state of science being conducted within the EPA’s Office of Research and Development to develop and refine approaches that estimate internal chemical concentrations following a given exposure, known as toxicokinetics. Toxicokinetic approaches hold great potential in their ability to link in vitro activities or toxicities identified during high-throughput screening with a quantitative external exposure metric that could be used in risk-based prioritization. Also, efforts are increasing to utilize in vitro toxicokinetics data with in vitro toxicodynamics data; these efforts will be discussed. This talk will provide greater visibility to ORD research and update the audience on recent progress in refining these approaches to address specific chemical groups of interest along with strategies to facilitate their adoption to a particular decision context.
Description:
In vitro-in vivo extrapolation (IVIVE), or the process of using in vitro data to predict in vivo phenomena, provides key opportunities to bridge the disconnect between high-throughput screening data and real-world human exposures and potential health effects. Strategies utilizing a combination of experimental and computational tools to predict chemical and drug toxicokinetics (TK) have shown made significant progress, as have evaluations of the uncertainty and variability of these predictions. A limited understanding of the linkage between in vitro assay bioactivity potencies, target site concentrations and potential downstream apical outcomes contribute to the lack of certainty in the assessment of in vitro toxicodynamics (TD), whether for chemicals or drugs. Data from the Tox21 program, designed to interrogate a discrete set of stress response pathways but across a large swath of chemical space, can be mined to explore the predictivity of IVIVE in assessing the TK and TD across pharmaceutics and commercial chemicals. This talk will describe recent IVIVE efforts on this dataset, outlining both the opportunities and challenges that have been identified. This abstract does not necessarily reflect U.S. EPA policy.
