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Incorporating New Technologies Into Toxicity Testing and Risk Assessment: Moving From 21st Century Vision to a Data-Driven Framework
in Vitro Research Models Collection
  • Russell S. Thomas, The Hamner Institutes for Health Sciences
  • Martin A. Philbert, The University Of Michigan
  • Scott Auerbach, National Institutes of Health
  • Barbara A. Wetmore, The Hamner Institutes for Health Sciences
  • Michael J. Devito, National Institutes of Health
  • Ila Cote, U.S. Environmental Protection Agency
  • J. Craig Rowlands, The Dow Chemical Company
  • Maurice Whelan, European Commission Joint Research Centre
  • Sean M. Hays, Summit Toxicology, LLC
  • Melvin E. Andersen, The Hamner Institutes for Health Sciences
  • M.E. (Bette) Meek, University of Ottawa
  • Lawrence W. Reiter, U.S. Environmental Protection Agency
  • Jason C. Lambert, U.S. Environmental Protection Agency
  • Harvey J. Clewell, III, Hamner Institutes for Health Sciences
  • Martin L. Stephens, Johns Hopkins Bloomberg School of Public Health
  • Q. Jay Zhao, U.S. Environmental Protection Agency
  • Scott C. Wesselkamper, U.S. Environmental Protection Agency
  • Lynn Flowers, U.S. Environmental Protection Agency
  • Edward W. Carney, The Dow Chemical Company
  • Tim P. Pastoor, Syngenta Crop Protection
  • Dan D. Petersen, U.S. Environmental Protection Agency
  • Carole L. Yauk, Health Canada
  • Andy Nong, Health Canada
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Based on existing data and previous work, a series of studies is proposed as a basis toward a pragmatic early step in transforming toxicity testing. These studies were assembled into a data-driven framework that invokes successive tiers of testing with margin of exposure (MOE) as the primary metric. The first tier of the framework integrates data from high-throughput in vitro assays, in vitro-to-in vivo extrapolation (IVIVE) pharmacokinetic modeling, and exposure modeling. The in vitro assays are used to separate chemicals based on their relative selectivity in interacting with biological targets and identify the concentration at which these interactions occur. The IVIVE modeling converts in vitro concentrations into external dose for calculation of the point of departure (POD) and comparisons to human exposure estimates to yield a MOE. The second tier involves short-term in vivo studies, expanded pharmacokinetic evaluations, and refined human exposure estimates. The results from the second tier studies provide more accurate estimates of the POD and the MOE. The third tier contains the traditional animal studies currently used to assess chemical safety. In each tier, the POD for selective chemicals is based primarily on endpoints associated with a proposed mode of action, whereas the POD for nonselective chemicals is based on potential biological perturbation. Based on the MOE, a significant percentage of chemicals evaluated in the first 2 tiers could be eliminated from further testing. The framework provides a risk-based and animal-sparing approach to evaluate chemical safety, drawing broadly from previous experience but incorporating technological advances to increase efficiency.


© The Author 2013. Published by Oxford University Press on behalf of the Society of Toxicology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (, which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited.

Citation Information
Thomas, R. S., Philbert, M. A., Auerbach, S. S., Wetmore, B. A., Devito, M. J., Cote, I., ... & Meek, M. E. (2013). Incorporating new technologies into toxicity testing and risk assessment: moving from 21st century vision to a data-driven framework. toxicological sciences, 136(1), 4-18.