Barbara A. Wetmore, Harvey J. Clewell, III, and Cory Strope. Scitovation

Bridging the Divide between Hazard and Risk: Strategies to Inform and Refine Internal and External Exposure Prediction Tools

Barbara A. Wetmore, Harvey J. Clewell, III, and Cory Strope. ScitoVation.

Recognition that exposure estimation tools are lagging behind bioactivity screening tools has led the U.S. Environmental Protection Agency (USEPA) and the chemical industry to actively support development of high-throughput efforts to inform exposure assessment. The ExpoCast program of the USEPA National Center for Computational Toxicology (NCCT) and the ExpoDat initiative are two main efforts addressing this issue. This project allows collaborative efforts previously established with the LRI-funded ExpoDat investigators and the USEPA NCCT ExpoCast group to continue in order to identify strategies to inform and refine external exposure prediction tools. In addition, efforts are underway to explore refinements of the systemic exposure prediction strategy currently incorporated with high-throughput bioactivity screening data to derive chemical oral equivalents. Also, new collaborations initiated with USEPA NCCT scientists will continue to explore integration of in silico and in vitro tools to quantitate variability across different populations and life-stages.

Implications: Reliance on in vitro assay screening data without dosimetry and exposure information is likely to rapidly identify many bioactive, but possibly irrelevant, properties of chemicals. Continued efforts to develop and refine tools to predict internal and external exposures will reinforce the value of this strategy while also providing the relevant context for identifying appropriate priorities for follow-up testing and for risk evaluation exercises.

Collaborations: USEPA NCCT, ARC Research & Consulting, University of Michigan, and University of California-Davis

Key words: exposure, prioritization, high-throughput, toxicokinetics, in vitro-in vivo extrapolation

Project start and end dates: January, 2015 – December, 2016

Peer-reviewed publication(s):

Kirman CR, Aylward LL, Wetmore BA, Thomas RS, Sochaski M, Ferguson SS, Csiszar SA, and Jolliet O. (2015). Quantitative property-property relationship for screening-level prediction of intrinsic clearance: A tool for exposure modeling for high-throughput toxicity screening data. Applied In Vitro Toxicology, 1(1): 1-7. Doi: 10.1089/aivt.2014.0008. [Epub ahead of print.]

Shin H-M, Ernstoff A, Arnot JA, Wetmore BA, Csiszar SA, Fantke P, Zhang X, McKone TE, Jolliet O, and Bennett DH. (2015). Risk-based high-throughput chemical screening and prioritization using exposure models and in vitro bioactivity assays. Environmental Science and Technology, 49(11): 6760-6771. doi.10.102/acs.est.5b00498 Epub May 14.

Wambaugh JF, Wetmore BA, Pearce R, Strope C, Goldsmith R, Sluka JP, Sedykh A, Tropsha A, Bosgra S, Shah I, Judson R, Thomas RS, and Setzer RW. (2015). Toxicokinetic triage for environmental chemicals. Toxicological Sciences, pii: kfv118. [Epub ahead of print.]

Wetmore BA. (2015). Quantitative in vitro-to-in vivo extrapolation in a high-throughput environment. Toxicology, 332: 94-101. doi. 10.1016/j.tox.2014.05.012.

Wetmore BA, Wambaugh JF, Ferguson SS, Sochaski MA, Setzer RA, Allen B, Houck KA, Cantwell K, Judson RS, LeCluyse E, Clewell III HJ, Thomas RS, and Andersen ME. (2015). Incorporating high- throughput exposure predictions with dosimetry-adjusted in vitro bioactivity to inform chemical toxicity testing. Toxicological Sciences. pii: kfv171. [Epub ahead of print.]

This abstract was prepared by the principal investigator for the project. Please see www.americanchemistry.com/lri for more information about the LRI. Abstract creation date: February 2016

This abstract was prepared by the principal investigator for the project. Please see www.americanchemistry.com/lri for more information about the LRI.