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Tiered Approaches to Incorporate the Adverse Outcome Pathway Framework into Chemical-Specific Risk-Based Decision Making

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A Systems Biology Approach to Advancing Adverse Outcome Pathways for Risk Assessment

Abstract

The concept of Adverse Outcome Pathways (AOPs) arose as a means of addressing the challenges associated with establishing relationships between high-throughout (HT) in vitro dose response data and in vivo biological outcomes. However, AOP development has also been met with challenges of its own, such as the time, effort, and expertise necessary to achieve a scientifically sound construct able to support ecotoxicology and human health risk assessment. Thus, a staged development process has been developed to match the information content of an AOP with the decision context in which it will be used. This approach allows effort to be spent on detailed evidence evaluation and quantitative assessment of the dose-response characteristics for those AOPs where this level of confidence and precision is needed. In addition, through advances in computational analytical methodologies that integrate HT data (e.g., transcriptomic data) with traditional toxicology information spanning a broad chemical and biological space, computationally predicted AOPs can be rapidly generated to help accelerate the curation of AOPs. AOPs are chemical agnostic thereby allowing a single AOP to be coupled with in vitro dose-response information from a variety of chemicals. To predict an in vivo outcome, however, exposure and pharmacokinetic characteristics (i.e., absorption, metabolism, distribution, and elimination) must be considered. As with the staged development process for AOPs, it is possible to develop ADME predictions in a tiered manner such that lower tiers provide qualitative or semi-quantitative predictions when data is lacking, and higher tiers provide quantitative predictions with increasing confidence when data is abundant. Tiered approaches to AOP development and ADME predictions provide a mechanism for using AOPs, with chemical-specific exposure and pharmacokinetic considerations, for risk assessment both in data poor and data rich scenarios. They also provide a natural mechanism for identifying areas of research that would have the highest impact on risk-based decision making by highlighting AOPs and/or ADME predictions that are insufficient to address the decision context in which they could be used.

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Authors and Affiliations

  1. Oak Ridge Institute for Science and Education, Oak Ridge, TN, 37831, USA

    Jeremy Leonard, Noffisat Oki & Mark Nelms

  2. National Institute of Environmental Health Sciences, Research Triangle Park, NC, 27709, USA

    Shannon Bell

  3. National Exposure Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, NC, 27709, USA

    Yu-Mei Tan

  4. National Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, 109 TW Alexander Dr. Mail Code B105-03, Research Triangle Park, NC, 27709, USA

    Stephen Edwards

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  1. Jeremy Leonard
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  2. Shannon Bell
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  4. Mark Nelms
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  6. Stephen Edwards
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Correspondence to Stephen Edwards .

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  1. Environmental Laboratory, US Army Engineer Research & Development Center, Vicksburg, Mississippi, USA

    Natàlia Garcia-Reyero

  2. Department of Fisheries and Wildlife, Michigan State University, East Lansing, Michigan, USA

    Cheryl A. Murphy

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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.

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Leonard, J., Bell, S., Oki, N., Nelms, M., Tan, YM., Edwards, S. (2018). Tiered Approaches to Incorporate the Adverse Outcome Pathway Framework into Chemical-Specific Risk-Based Decision Making. In: Garcia-Reyero, N., Murphy, C. (eds) A Systems Biology Approach to Advancing Adverse Outcome Pathways for Risk Assessment. Springer, Cham. https://doi.org/10.1007/978-3-319-66084-4_12

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