Quantitative Adverse Outcome Pathways and Their Application to Predictive Toxicology

Rory B. Conolly, Gerald T. Ankley, Wanyun Cheng, Michael L. Mayo, David H. Miller, Edward J. Perkins, Daniel L. Villeneuve, Karen H. Watanabe

    Research output: Contribution to journalArticlepeer-review

    140 Scopus citations

    Abstract

    A quantitative adverse outcome pathway (qAOP) consists of one or more biologically based, computational models describing key event relationships linking a molecular initiating event (MIE) to an adverse outcome. A qAOP provides quantitative, dose-response, and time-course predictions that can support regulatory decision-making. Herein we describe several facets of qAOPs, including (a) motivation for development, (b) technical considerations, (c) evaluation of confidence, and (d) potential applications. The qAOP used as an illustrative example for these points describes the linkage between inhibition of cytochrome P450 19A aromatase (the MIE) and population-level decreases in the fathead minnow (FHM; Pimephales promelas). The qAOP consists of three linked computational models for the following: (a) the hypothalamic-pitutitary-gonadal axis in female FHMs, where aromatase inhibition decreases the conversion of testosterone to 17β-estradiol (E2), thereby reducing E2-dependent vitellogenin (VTG; egg yolk protein precursor) synthesis, (b) VTG-dependent egg development and spawning (fecundity), and (c) fecundity-dependent population trajectory. While development of the example qAOP was based on experiments with FHMs exposed to the aromatase inhibitor fadrozole, we also show how a toxic equivalence (TEQ) calculation allows use of the qAOP to predict effects of another, untested aromatase inhibitor, iprodione. While qAOP development can be resource-intensive, the quantitative predictions obtained, and TEQ-based application to multiple chemicals, may be sufficient to justify the cost for some applications in regulatory decision-making.

    Original languageEnglish (US)
    Pages (from-to)4661-4672
    Number of pages12
    JournalEnvironmental Science and Technology
    Volume51
    Issue number8
    DOIs
    StatePublished - Apr 18 2017

    ASJC Scopus subject areas

    • General Chemistry
    • Environmental Chemistry

    Fingerprint

    Dive into the research topics of 'Quantitative Adverse Outcome Pathways and Their Application to Predictive Toxicology'. Together they form a unique fingerprint.

    Cite this