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Research ArticleMinireview

Adverse Outcome Pathways—Organizing Toxicological Information to Improve Decision Making

Stephen W. Edwards, Yu-Mei Tan, Daniel L. Villeneuve, M.E. Meek and Charlene A. McQueen
Journal of Pharmacology and Experimental Therapeutics January 2016, 356 (1) 170-181; DOI: https://doi.org/10.1124/jpet.115.228239
Stephen W. Edwards
Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory (S.W.E., C.A.M.), and Human Exposure & Atmospheric Sciences Division, National Exposure Research Laboratory (Y.-M.T.), Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina; Mid-Continent Ecology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Duluth, Minnesota (D.L.V.); and McLaughlin Centre for Risk Science, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada (M.E.M.)
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Yu-Mei Tan
Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory (S.W.E., C.A.M.), and Human Exposure & Atmospheric Sciences Division, National Exposure Research Laboratory (Y.-M.T.), Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina; Mid-Continent Ecology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Duluth, Minnesota (D.L.V.); and McLaughlin Centre for Risk Science, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada (M.E.M.)
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Daniel L. Villeneuve
Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory (S.W.E., C.A.M.), and Human Exposure & Atmospheric Sciences Division, National Exposure Research Laboratory (Y.-M.T.), Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina; Mid-Continent Ecology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Duluth, Minnesota (D.L.V.); and McLaughlin Centre for Risk Science, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada (M.E.M.)
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M.E. Meek
Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory (S.W.E., C.A.M.), and Human Exposure & Atmospheric Sciences Division, National Exposure Research Laboratory (Y.-M.T.), Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina; Mid-Continent Ecology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Duluth, Minnesota (D.L.V.); and McLaughlin Centre for Risk Science, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada (M.E.M.)
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Charlene A. McQueen
Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory (S.W.E., C.A.M.), and Human Exposure & Atmospheric Sciences Division, National Exposure Research Laboratory (Y.-M.T.), Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina; Mid-Continent Ecology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Duluth, Minnesota (D.L.V.); and McLaughlin Centre for Risk Science, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada (M.E.M.)
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Abstract

The number of chemicals for which environmental regulatory decisions are required far exceeds the current capacity for toxicity testing. High-throughput screening commonly used for drug discovery has the potential to increase this capacity. The adverse outcome pathway (AOP) concept has emerged as a framework for connecting high-throughput toxicity testing (HTT) and other results to potential impacts on human and wildlife populations. As a result of international efforts, the AOP development process is now well-defined and efforts are underway to broaden the participation through outreach and training. One key principle is that AOPs represent the chemical-agnostic portions of pathways to increase the generalizability of their application from early key events to overt toxicity. The closely related mode of action framework extends the AOP as needed when evaluating the potential risk of a specific chemical. This in turn enables integrated approaches to testing and assessment (IATA), which incorporate results of assays at various levels of biologic organization such as in silico; HTT; chemical-specific aspects including absorption, distribution, metabolism, and excretion (ADME); and an AOP describing the biologic basis of toxicity. Thus, it is envisaged that provision of limited information regarding both the AOP for critical effects and the ADME for any chemical associated with any adverse outcome would allow for the development of IATA and permit more detailed AOP and ADME research, where higher precision is needed based on the decision context.

Footnotes

    • Received August 1, 2015.
    • Accepted November 3, 2015.
  • The information in this document has been funded wholly (or in part) by the U. S. Environmental Protection Agency. It has been subjected to review by the National Health and Environmental Effects Research Laboratory and approved for publication. Approval does not signify that the contents reflect the views of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.

  • dx.doi.org/10.1124/jpet.115.228239.

  • U.S. Government work not protected by U.S. copyright
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Journal of Pharmacology and Experimental Therapeutics: 356 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 356, Issue 1
1 Jan 2016
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Research ArticleMinireview

Adverse Outcome Pathways

Stephen W. Edwards, Yu-Mei Tan, Daniel L. Villeneuve, M.E. Meek and Charlene A. McQueen
Journal of Pharmacology and Experimental Therapeutics January 1, 2016, 356 (1) 170-181; DOI: https://doi.org/10.1124/jpet.115.228239

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Research ArticleMinireview

Adverse Outcome Pathways

Stephen W. Edwards, Yu-Mei Tan, Daniel L. Villeneuve, M.E. Meek and Charlene A. McQueen
Journal of Pharmacology and Experimental Therapeutics January 1, 2016, 356 (1) 170-181; DOI: https://doi.org/10.1124/jpet.115.228239
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  • Article
    • Abstract
    • Introduction
    • Adverse Outcome Pathways—Evolution of the Concept
    • Adverse Outcome Pathways—Where Are We Now?
    • Developing a MOA from an AOP and Absorption, Distribution, Metabolism, and Excretion (ADME) Information
    • Applications for the AOP/MOA Framework
    • Conclusions and Future Directions
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