title: Development and application of the adverse outcome pathway framework for understanding and predicting chronic toxicity: II. A focus on growth impairment in fish.
abstract: Adverse outcome pathways (AOPs) organize knowledge on the progression of toxicity through levels of biological organization. By determining the linkages between toxicity events at different levels, AOPs lay the foundation for mechanism-based alternative testing approaches to hazard assessment. Here, we focus on growth impairment in fish to illustrate the initial stages in the process of AOP development for chronic toxicity outcomes. Growth is an apical endpoint commonly assessed in chronic toxicity tests for which a replacement is desirable. Based on several criteria, we identified reduction in food intake to be a suitable key event for initiation of middle-out AOP development. To start exploring the upstream and downstream links of this key event, we developed three AOP case studies, for pyrethroids, selective serotonin reuptake inhibitors (SSRIs) and cadmium. Our analysis showed that the effect of pyrethroids and SSRIs on food intake is strongly linked to growth impairment, while cadmium causes a reduction in growth due to increased metabolic demands rather than changes in food intake. Locomotion impairment by pyrethroids is strongly linked to their effects on food intake and growth, while for SSRIs their direct influence on appetite may play a more important role. We further discuss which alternative tests could be used to inform on the predictive key events identified in the case studies. In conclusion, our work demonstrates how the AOP concept can be used in practice to assess critically the knowledge available for specific chronic toxicity cases and to identify existing knowledge gaps and potential alternative tests.
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; D002104:Cadmium / Q000009:adverse effects; D004435:Eating / Q000187:drug effects*; D054750:Ecotoxicology / Q000379:methods* / Q000639:trends; D004785:Environmental Pollutants / Q000009:adverse effects*; D005399:Fishes / Q000254:growth & development*; D006801:Humans; D008124:Locomotion / Q000187:drug effects*; D008954:Models, Biological; D011722:Pyrethrins / Q000009:adverse effects; D018570:Risk Assessment / Q000379:methods; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects; D013045:Species Specificity; D036401:Toxicity Tests, Chronic / Q000379:methods*
chemical_list: D002104:Cadmium; D004785:Environmental Pollutants; D011722:Pyrethrins; D017367:Selective Serotonin Reuptake Inhibitors
keywords: 3R (replacement, reduction, refinement); Adverse outcome pathway; Behavior; Cadmium; Pyrethroid; Selective serotonin reuptake inhibitor