title: Development and application of the adverse outcome pathway framework for understanding and predicting chronic toxicity: I. Challenges and research needs in ecotoxicology.
abstract: To elucidate the effects of chemicals on populations of different species in the environment, efficient testing and modeling approaches are needed that consider multiple stressors and allow reliable extrapolation of responses across species. An adverse outcome pathway (AOP) is a concept that provides a framework for organizing knowledge about the progression of toxicity events across scales of biological organization that lead to adverse outcomes relevant for risk assessment. In this paper, we focus on exploring how the AOP concept can be used to guide research aimed at improving both our understanding of chronic toxicity, including delayed toxicity as well as epigenetic and transgenerational effects of chemicals, and our ability to predict adverse outcomes. A better understanding of the influence of subtle toxicity on individual and population fitness would support a broader integration of sublethal endpoints into risk assessment frameworks. Detailed mechanistic knowledge would facilitate the development of alternative testing methods as well as help prioritize higher tier toxicity testing. We argue that targeted development of AOPs supports both of these aspects by promoting the elucidation of molecular mechanisms and their contribution to relevant toxicity outcomes across biological scales. We further discuss information requirements and challenges in application of AOPs for chemical- and site-specific risk assessment and for extrapolation across species. We provide recommendations for potential extension of the AOP framework to incorporate information on exposure, toxicokinetics and situation-specific ecological contexts, and discuss common interfaces that can be employed to couple AOPs with computational modeling approaches and with evolutionary life history theory. The extended AOP framework can serve as a venue for integration of knowledge derived from various sources, including empirical data as well as molecular, quantitative and evolutionary-based models describing species responses to toxicants. This will allow a more efficient application of AOP knowledge for quantitative chemical- and site-specific risk assessment as well as for extrapolation across species in the future.
authors.affiliation: Eawag, Swiss Federal Institute of Aquatic Science and Technology, 8600 Dübendorf, Switzerland; ETH Zürich, Department of Chemistry and Applied Biosciences, 8093 Zürich, Switzerland. Electronic address: ksenia.groh@eawag.ch.
authors.forename: Ksenia J
authors.initials: KJ
authors.lastname: Groh
authors.affiliation: European Commission, Joint Research Centre, Institute for Environment and Sustainability, Water Resources Unit, 21027 Ispra, Italy.
authors.forename: Raquel N
authors.initials: RN
authors.lastname: Carvalho
authors.affiliation: University of Birmingham, B15 2TT Birmingham, UK.
authors.forename: James K
authors.initials: JK
authors.lastname: Chipman
authors.affiliation: University of Florida, Department of Physiological Sciences, Center for Environmental and Human Toxicology and Genetics Institute, 32611 Gainesville, FL, USA.
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Denslow
authors.affiliation: European Commission, Joint Research Centre, Institute for Health and Consumer Protection, Systems Toxicology Unit, 21027 Ispra, Italy.
authors.forename: Marlies
authors.initials: M
authors.lastname: Halder
authors.affiliation: Michigan State University, Fisheries and Wildlife, Lyman Briggs College, 48824 East Lansing, MI, USA.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Murphy
authors.affiliation: VU University, Institute of Ecological Science, 1081 HV Amsterdam, The Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: Roelofs
authors.affiliation: European Commission, Joint Research Centre, Institute for Health and Consumer Protection, Systems Toxicology Unit, 21027 Ispra, Italy.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Rolaki
authors.affiliation: Eawag, Swiss Federal Institute of Aquatic Science and Technology, 8600 Dübendorf, Switzerland; ETH Zürich, Department of Environmental Systems Science, 8092 Zürich, Switzerland; EPF Lausanne, School of Architecture, Civil and Environmental Engineering, 1015 Lausanne, Switzerland.
authors.forename: Kristin
authors.initials: K
authors.lastname: Schirmer
authors.affiliation: Oregon Health & Science University, Institute of Environmental Health, Division of Environmental and Biomolecular Systems, 97239-3098 Portland, OR, USA.
authors.forename: Karen H
authors.initials: KH
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D054750:Ecotoxicology / Q000379:methods* / Q000639:trends; D004777:Environment; D004785:Environmental Pollutants / Q000009:adverse effects*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D006801:Humans; D012106:Research / Q000639:trends*; D018570:Risk Assessment / Q000379:methods*; D013045:Species Specificity; D036401:Toxicity Tests, Chronic / Q000379:methods*
chemical_list: D004785:Environmental Pollutants
keywords: Adverse Outcome Pathway (AOP); Chronic toxicity; Cross-species extrapolation; Ecotoxicological risk assessment; Extrapolation from individual to population; Toxicokinetics