title: How Adverse Outcome Pathways Can Aid the Development and Use of Computational Prediction Models for Regulatory Toxicology.
abstract: Efforts are underway to transform regulatory toxicology and chemical safety assessment from a largely empirical science based on direct observation of apical toxicity outcomes in whole organism toxicity tests to a predictive one in which outcomes and risk are inferred from accumulated mechanistic understanding. The adverse outcome pathway (AOP) framework provides a systematic approach for organizing knowledge that may support such inference. Likewise, computational models of biological systems at various scales provide another means and platform to integrate current biological understanding to facilitate inference and extrapolation. We argue that the systematic organization of knowledge into AOP frameworks can inform and help direct the design and development of computational prediction models that can further enhance the utility of mechanistic and in silico data for chemical safety assessment. This concept was explored as part of a workshop on AOP-Informed Predictive Modeling Approaches for Regulatory Toxicology held September 24-25, 2015. Examples of AOP-informed model development and its application to the assessment of chemicals for skin sensitization and multiple modes of endocrine disruption are provided. The role of problem formulation, not only as a critical phase of risk assessment, but also as guide for both AOP and complementary model development is described. Finally, a proposal for actively engaging the modeling community in AOP-informed computational model development is made. The contents serve as a vision for how AOPs can be leveraged to facilitate development of computational prediction models needed to support the next generation of chemical safety assessment.
authors.affiliation: European Commission, Joint Research Centre, Ispra 21027, Italy; clemens.wittwehr@ec.europa.eu.
authors.forename: Clemens
authors.initials: C
authors.lastname: Wittwehr
authors.affiliation: Bulgarian Academy of Sciences, Sofia 1113, Bulgaria.
authors.forename: Hristo
authors.initials: H
authors.lastname: Aladjov
authors.affiliation: US Environmental Protection Agency, Duluth, Minnesota 55804.
authors.forename: Gerald
authors.initials: G
authors.lastname: Ankley
authors.affiliation: FOCAS Research Institute, Dublin 8, Ireland.
authors.forename: Hugh J
authors.initials: HJ
authors.lastname: Byrne
authors.affiliation: National Institute for Public Health and the Environment (RIVM), Bilthoven, MA 3721, The Netherlands.
authors.forename: Joop
authors.initials: J
authors.lastname: de Knecht
authors.affiliation: Universität des Saarlandes, 66123 Saarbrücken, Germany.
authors.forename: Elmar
authors.initials: E
authors.lastname: Heinzle
authors.affiliation: Johannes Kepler Universität, Linz 4040, Austria.
authors.forename: Günter
authors.initials: G
authors.lastname: Klambauer
authors.affiliation: European Commission, Joint Research Centre, Ispra 21027, Italy.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Landesmann
authors.affiliation: National Institute for Public Health and the Environment (RIVM), Bilthoven, MA 3721, The Netherlands.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Luijten
authors.affiliation: Unilever Safety and Environmenta Assurance Centre, Sharnbrook, MK44 1LQ, UK.
authors.forename: Cameron
authors.initials: C
authors.lastname: MacKay
authors.affiliation: Unilever Safety and Environmenta Assurance Centre, Sharnbrook, MK44 1LQ, UK.
authors.forename: Gavin
authors.initials: G
authors.lastname: Maxwell
authors.affiliation: University of Ottawa, Ontario K1N 6N5, Canada.
authors.forename: M E Bette
authors.initials: ME
authors.lastname: Meek
authors.affiliation: European Commission, Joint Research Centre, Ispra 21027, Italy.
authors.forename: Alicia
authors.initials: A
authors.lastname: Paini
authors.affiliation: US Army Engineer Research and Development Center, Vicksburg, Mississippi 39180.
authors.forename: Edward
authors.initials: E
authors.lastname: Perkins
authors.affiliation: European Chemicals Agency, ECHA, 00121 Helsinki, Finland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Sobanski
authors.affiliation: US Environmental Protection Agency, Duluth, Minnesota 55804.
authors.forename: Dan
authors.initials: D
authors.lastname: Villeneuve
authors.affiliation: Pacific Northwest National Laboratory, Richland, Washington 99352.
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Waters
authors.affiliation: European Commission, Joint Research Centre, Ispra 21027, Italy.
authors.forename: Maurice
authors.initials: M
authors.lastname: Whelan
mesh_terms: D000073931:Adverse Outcome Pathways / Q000592:standards*; D000818:Animals; D003198:Computer Simulation; D006801:Humans; D018675:Toxicity Tests; D014116:Toxicology / Q000592:standards*
keywords: AOP; Adverse Outcome Pathways; computational prediction model.; quantitative AOP