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Applying a High-Throughput PBTK Model for IVIVE
Citation:
Honda, G., R. Pearce, L. Pham, B. Wetmore, N. Sipes, Woodrow Setzer, R. Thomas, AND J. Wambaugh. Applying a High-Throughput PBTK Model for IVIVE. Presented at Society of Toxicology Annual Meeting, San Antonio, TX, March 11 - 15, 2018.
Impact/Purpose:
This research advances our ability to quantitatively predict the in vivo dose that causes adverse effects using only in vitro data and mathematical models. This presentation will be made to the Society of Toxicology annual meeting in San Antonio TX in March, 2018.
Description:
The ability to link in vitro and in vivo toxicity enables the use of high-throughput in vitro assays as an alternative to resource intensive animal studies. Toxicokinetics (TK) should help describe this link, but prior work found weak correlation when using a TK model for in vitro-in vivo extrapolation (IVIVE) (Wetmore et al., 2013). In this work, we evaluated the assumptions in the use of a high-throughput, physiologically based (PBTK) model to relate in vitro and in vivo toxicity data. The generic, high-throughput PBTK model in this study used rat in vitro measured values of fraction unbound in plasma (f¬up) and intrinsic hepatic clearance for 92 chemicals. In vivo doses (endpoint-specific low effect levels for rat, EPA’s ToxRefDB) were transformed to concentrations (xPBTK) via the PBTK model, and compared with in vitro AC50 (EPA’s ToxCast program, 394 assays) relative to a randomly parameterized result (xrand) and untransformed dose (xdose). For each pair of in vitro assay and in vivo response, simple regressions were performed of standardized AC50 vs the three separate predictors: xPBTK, xrand, and xdose. Different combinations of assumptions in the use of the PBTK model were then evaluated based on how frequently (FPBTK, Frand, Fdose) a predictor had the largest absolute slope. The best result for the PBTK model was achieved by using maximum plasma concentration and assuming metabolism independent of fup (FPBTK = 82 %, Frand = 7 %, and Fdose = 11 %). Using in vitro free vs nominal concentration also improved results for cell based assays (FPBTK = 87 % vs 78 %). Results demonstrate that use of the PBTK model improves the correlation between the in vitro and in vivo toxicity data relative to the untransformed dose and the randomized result in the rat. This suggests that incorporating TK may enhance human IVIVE. Wetmore, B. A., et al. Tox. Sci. 2013, 132, 327-346. This abstract may not reflect U.S. EPA policy.
URLs/Downloads:
HONDA SOT 03OCT2017 CORRECTED ABSTRACT_FINAL.PDF (PDF, NA pp, 117.145 KB, about PDF)HONDA_PBTK_SOT2018_POSTER_FINAL_21FEB2018.PDF (PDF, NA pp, 903.735 KB, about PDF)