Incorporating High-Throughput Exposure Predictions With Dosimetry-Adjusted In Vitro Bioactivity to Inform Chemical Toxicity Testing

• Published in: Toxicological sciences 2015-11, Vol.148 (1), p.121-136
• Main Authors: Wetmore, Barbara A, Wambaugh, John F, Allen, Brittany, Ferguson, Stephen S, Sochaski, Mark A, Setzer, R Woodrow, Houck, Keith A, Strope, Cory L, Cantwell, Katherine, Judson, Richard S, LeCluyse, Edward, Clewell, Harvey J, Thomas, Russell S, Andersen, Melvin E
• Format: Article
• Language: English
• Subjects: Adult; Bayes Theorem; Blood Proteins - metabolism; Caco-2 Cells; Cell Membrane Permeability - drug effects; Cells, Cultured; Drug Evaluation, Preclinical - methods; Drug Evaluation, Preclinical - standards; Enterocytes - drug effects; Enterocytes - metabolism; Female; Hepatocytes - cytology; Hepatocytes - drug effects; High-Throughput Screening Assays; Humans; Intestinal Absorption; Linking High Throughput Exposure Estimates with Biological Activity for Toxicity Testing; Male; Models, Biological; Pharmacokinetics; Risk Assessment - methods; Risk Assessment - trends; Toxicity Tests - methods; Toxicity Tests - standards; Toxicokinetics; United States; United States Environmental Protection Agency
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfv171

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 (ie, Phase II) beyond food-use pesticides toward 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. Environmental Protection Agency (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, 3 or 13 chemicals possessed AERs < 1 or < 100, respectively. Diverse bioactivities across a range of assays and concentrations were 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.