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Incorporating High-Throughput Exposure Predictions with Dosimetry-Adjusted In Vitro Bioactivity to Inform Chemical Toxicity Testing
Citation:
Wetmore, B., John F. Wambaugh, B. Allen, S. Ferguson, M. Sochaski, R. Woodrow Setzer, Keith A. Houck, C. Strope, K. Cantwell, Richard S. Judson, E. LeCluyse, H. Clewell III, Russell S. Thomas, AND M. Andersen. Incorporating High-Throughput Exposure Predictions with Dosimetry-Adjusted In Vitro Bioactivity to Inform Chemical Toxicity Testing. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, , 1-57, (2015).
Impact/Purpose:
This manuscript is the latest in a series resulting from an ongoing collaboration between EPA and the Hamner Institutes. Barbara Wetmore and Rusty Thomas have led the collection of in vitro data that allows characterization of the pharmacokinetics (PK) of chemicals in order to relate environmental exposures to tissue concentrations within the body. In this paper, in vitro PK data has been collected for 161 ToxCast Phase II chemicals. Using this data, exposures have been back-calculated from the ToxCast bioactivity in vitro data to determine environmental chemical exposures that might cause bioacitivity in humans. These putative bioactive exposure have then been compared with exposure estimates from the ExpoCast project in order to identify those chemicals with the smallest ratio between bioactivity and estimated exposure. This screening method identifies chemicals with small ratios between activity and exposure (the AER or Activity:Exposure Ratio) as targets for additional research.
Description:
We previously integrated dosimetry and exposure with high-throughput screening (HTS) to enhance the utility of ToxCast™ HTS data by translating in vitro bioactivity concentrations to oral equivalent doses (OEDs) required to achieve these levels internally. These OEDs were compared against regulatory exposure estimates, providing an activity-to-exposure ratio (AER) useful for a risk-based ranking strategy. As ToxCast™ efforts expand (i.e., Phase II) beyond food-use pesticides towards a wider chemical domain that lacks exposure and toxicity information, prediction tools become increasingly important. In this study, in vitro hepatic clearance and plasma protein binding were measured to estimate OEDs for a subset of Phase II chemicals. OEDs were compared against high-throughput (HT) exposure predictions generated using probabilistic modeling and Bayesian approaches generated by the U.S. EPA ExpoCast™ program. This approach incorporated chemical-specific use and national production volume data with biomonitoring data to inform the exposure predictions. This HT exposure modeling approach provided predictions for all Phase II chemicals assessed in this study whereas estimates from regulatory sources were available for only 7% of chemicals. Of the 163 chemicals assessed in this study, three or 13 chemicals possessed AERs <1 or <100, respectively. Diverse bioactivities y across a range of assays and concentrations was also noted across the wider chemical space surveyed. The availability of HT exposure estimation and bioactivity screening tools provides an opportunity to incorporate a risk-based strategy for use in testing prioritization.
