title: Quantitative Adverse Outcome Pathways and Their Application to Predictive Toxicology.
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.
authors.affiliation: U.S. Environmental Protection Agency , Office of Research and Development, National Health and Environmental Effects Research Laboratory, Integrated Systems Toxicology Division, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Rory B
authors.identifier: 0000-0001-7201-1823
authors.initials: RB
authors.lastname: Conolly
authors.affiliation: U.S. Environmental Protection Agency , Office of Research and Development, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, Duluth, Minnesota 55804, United States.
authors.forename: Gerald T
authors.identifier: 0000-0002-9937-615X
authors.initials: GT
authors.lastname: Ankley
authors.affiliation: U.S. Environmental Protection Agency , Office of Research and Development, National Health and Environmental Effects Research Laboratory, Integrated Systems Toxicology Division, Research Triangle Park, North Carolina 27709, United States.
authors.forename: WanYun
authors.initials: W
authors.lastname: Cheng
authors.affiliation: Environmental Laboratory, U.S. Army Engineer Research and Development Center , Vicksburg, Mississippi 39180, United States.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Mayo
authors.affiliation: U.S. Environmental Protection Agency , Office of Research and Development, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, Grosse Isle, Michigan 48138, United States.
authors.forename: David H
authors.initials: DH
authors.lastname: Miller
authors.affiliation: Environmental Laboratory, U.S. Army Engineer Research and Development Center , Vicksburg, Mississippi 39180, United States.
authors.forename: Edward J
authors.identifier: 0000-0003-1693-7714
authors.initials: EJ
authors.lastname: Perkins
authors.affiliation: U.S. Environmental Protection Agency , Office of Research and Development, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, Duluth, Minnesota 55804, United States.
authors.forename: Daniel L
authors.identifier: 0000-0003-2801-0203
authors.initials: DL
authors.lastname: Villeneuve
authors.affiliation: School of Mathematical and Natural Sciences, Arizona State University , West Campus, Glendale, Arizona 85306, United States.
authors.forename: Karen H
authors.initials: KH
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D047072:Aromatase Inhibitors / Q000633:toxicity*; D003530:Cyprinidae; D004958:Estradiol / Q000378:metabolism; D017316:Fadrozole / Q000633:toxicity*; D008962:Models, Theoretical; D011237:Predictive Value of Tests; D014819:Vitellogenins / Q000378:metabolism
chemical_list: D047072:Aromatase Inhibitors; D014819:Vitellogenins; D004958:Estradiol; D017316:Fadrozole