Quantitative Adverse Outcome Pathways and Their Application to Predictive Toxicology

• DOI: 10.1021/acs.est.6b06230
• Publication Date: 2017-03-29T20:07:50Z
• Authors: Rory B. Conolly; Gerald T. Ankley; WanYun Cheng; Michael L. Mayo; David H. Miller; Edward J. Perkins; Daniel L. Villeneuve; Karen H. Watanabe
• Keywords: Vitellogenin; Pimephales promelas; Adverse Outcome Pathway; Aromatase inhibitor

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