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Relative Impact of Incorporating Pharmacokinetics on Predicting In Vivo Hazard and Mode of Action from High-Throughput In Vitro Toxicity Assays
Citation:
WETMORE, B. A., J. F. WAMBAUGH, S. S. FERGUSON, L. LI, H. J. CLEWEL III, R. JUDSON, K. FREEMAN, W. BAO, M. A. SOCHASKI, T. CHU, M. B. BLACK, E. HEALY, B. ALLEN, M. E. ANDERSEN, R. D. WOLFINGER, AND R. S. THOMAS. Relative Impact of Incorporating Pharmacokinetics on Predicting In Vivo Hazard and Mode of Action from High-Throughput In Vitro Toxicity Assays . TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 132(2):327-346, (2013).
Impact/Purpose:
The results from this study demonstrate that although adjusting the high-throughput in vitro assays for pharmacokinetics did not necessarily improve the ability to predict in vivo hazard, incorporating pharmacokinetics allowed the identification of in vitro assays that were concordant with in vivo responses on a dose basis and provided a conservative estimate of the in vivo point-of-departure in a margin-of-exposure framework. Using in vitro assays for estimating in vivo points-of-departure in a dose-response assessment provides a data-driven method to triage a significant percentage of chemicals from additional in vivo testing, while the development and interpretation of the in vitro assays within the MOA framework continue to mature.
Description:
The use of high-throughput in vitro assays has been proposed to play a significant role in the future of toxicity testing. In this study, rat hepatic metabolic clearance and plasma protein binding were measured for 59 ToxCast phase I chemicals. Computational in vitro-to-in vivo extrapolation was used to estimate the daily dose in a rat, called the oral equivalent dose, which would result in steady-state in vivo blood concentrations equivalent to the AC50 or lowest effective concentration (LEC) across more than 600 ToxCast phase I in vitro assays. Statistical classification analysis was performed using either oral equivalent doses or unadjusted AC50/LEC values for the in vitro assays to predict the in vivo effects of the 59 chemicals. Adjusting the in vitro assays for pharmacokinetics did not improve the ability to predict in vivo effects as either a discrete (yes or no) response or a low effect level (LEL) on a continuous dose scale. Interestingly, a comparison of the in vitro assay with the lowest oral equivalent dose with the in vivo endpoint with the lowest LEL suggested that the lowest oral equivalent dose may provide a conservative estimate of the point of departure for a chemical in a dose-response assessment. Furthermore, comparing the oral equivalent doses for the in vitro assays with the in vivo dose range that resulted in adverse effects identified more coincident in vitro assays across chemicals than expected by chance, suggesting that the approach may also be used to identify potential molecular initiating events leading to adversity.
URLs/Downloads:
Relative Impact of Incorporating Pharmacokinetics on Predicting In Vivo Hazard and Mode of Action from High-Throughput In Vitro Toxicity Assays