title: Adverse outcome pathway (AOP) development I: strategies and principles.
abstract: An adverse outcome pathway (AOP) is a conceptual framework that organizes existing knowledge concerning biologically plausible, and empirically supported, links between molecular-level perturbation of a biological system and an adverse outcome at a level of biological organization of regulatory relevance. Systematic organization of information into AOP frameworks has potential to improve regulatory decision-making through greater integration and more meaningful use of mechanistic data. However, for the scientific community to collectively develop a useful AOP knowledgebase that encompasses toxicological contexts of concern to human health and ecological risk assessment, it is critical that AOPs be developed in accordance with a consistent set of core principles. Based on the experiences and scientific discourse among a group of AOP practitioners, we propose a set of five fundamental principles that guide AOP development: (1) AOPs are not chemical specific; (2) AOPs are modular and composed of reusable components-notably key events (KEs) and key event relationships (KERs); (3) an individual AOP, composed of a single sequence of KEs and KERs, is a pragmatic unit of AOP development and evaluation; (4) networks composed of multiple AOPs that share common KEs and KERs are likely to be the functional unit of prediction for most real-world scenarios; and (5) AOPs are living documents that will evolve over time as new knowledge is generated. The goal of the present article was to introduce some strategies for AOP development and detail the rationale behind these 5 key principles. Consideration of these principles addresses many of the current uncertainties regarding the AOP framework and its application and is intended to foster greater consistency in AOP development.
authors.affiliation: *US EPA Mid-Continent Ecology Division, 6201 Congdon Blvd, Duluth, Minnesota 55804, Environment Canada, Ecotoxicology and Wildlife Health Division, Ottawa, Ontario, K1A 0H3 Canada, Mississippi State University, Institute for Genomics, Biocomputing and Biotechnology, Starkville, Mississippi 39762, University of Saskatchewan, School of the Environment and Sustainability and Toxicology Centre, Saskatoon, Saskatchewan, SK S7N 5B3, Canada, University of Plymouth, School of Biological Sciences, Plymouth, Devon, PL4 8AA, UK, University of Minnesota, Water Resources Center, St. Paul, Minnesota 55108, European Commission, Joint Research Centre, Via E. Fermi 2749, 21027 Ispra, Italy, Department of Biology and Biochemistry, University of Houston, Houston, Texas, 77004, Zebrafishlab, Veterinary Physiology and Biochemistry, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium villeneuve.dan@epa.gov.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Villeneuve
authors.affiliation: *US EPA Mid-Continent Ecology Division, 6201 Congdon Blvd, Duluth, Minnesota 55804, Environment Canada, Ecotoxicology and Wildlife Health Division, Ottawa, Ontario, K1A 0H3 Canada, Mississippi State University, Institute for Genomics, Biocomputing and Biotechnology, Starkville, Mississippi 39762, University of Saskatchewan, School of the Environment and Sustainability and Toxicology Centre, Saskatoon, Saskatchewan, SK S7N 5B3, Canada, University of Plymouth, School of Biological Sciences, Plymouth, Devon, PL4 8AA, UK, University of Minnesota, Water Resources Center, St. Paul, Minnesota 55108, European Commission, Joint Research Centre, Via E. Fermi 2749, 21027 Ispra, Italy, Department of Biology and Biochemistry, University of Houston, Houston, Texas, 77004, Zebrafishlab, Veterinary Physiology and Biochemistry, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
authors.forename: Doug
authors.initials: D
authors.lastname: Crump
authors.affiliation: *US EPA Mid-Continent Ecology Division, 6201 Congdon Blvd, Duluth, Minnesota 55804, Environment Canada, Ecotoxicology and Wildlife Health Division, Ottawa, Ontario, K1A 0H3 Canada, Mississippi State University, Institute for Genomics, Biocomputing and Biotechnology, Starkville, Mississippi 39762, University of Saskatchewan, School of the Environment and Sustainability and Toxicology Centre, Saskatoon, Saskatchewan, SK S7N 5B3, Canada, University of Plymouth, School of Biological Sciences, Plymouth, Devon, PL4 8AA, UK, University of Minnesota, Water Resources Center, St. Paul, Minnesota 55108, European Commission, Joint Research Centre, Via E. Fermi 2749, 21027 Ispra, Italy, Department of Biology and Biochemistry, University of Houston, Houston, Texas, 77004, Zebrafishlab, Veterinary Physiology and Biochemistry, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
authors.forename: Natàlia
authors.initials: N
authors.lastname: Garcia-Reyero
authors.affiliation: *US EPA Mid-Continent Ecology Division, 6201 Congdon Blvd, Duluth, Minnesota 55804, Environment Canada, Ecotoxicology and Wildlife Health Division, Ottawa, Ontario, K1A 0H3 Canada, Mississippi State University, Institute for Genomics, Biocomputing and Biotechnology, Starkville, Mississippi 39762, University of Saskatchewan, School of the Environment and Sustainability and Toxicology Centre, Saskatoon, Saskatchewan, SK S7N 5B3, Canada, University of Plymouth, School of Biological Sciences, Plymouth, Devon, PL4 8AA, UK, University of Minnesota, Water Resources Center, St. Paul, Minnesota 55108, European Commission, Joint Research Centre, Via E. Fermi 2749, 21027 Ispra, Italy, Department of Biology and Biochemistry, University of Houston, Houston, Texas, 77004, Zebrafishlab, Veterinary Physiology and Biochemistry, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
authors.forename: Markus
authors.initials: M
authors.lastname: Hecker
authors.affiliation: *US EPA Mid-Continent Ecology Division, 6201 Congdon Blvd, Duluth, Minnesota 55804, Environment Canada, Ecotoxicology and Wildlife Health Division, Ottawa, Ontario, K1A 0H3 Canada, Mississippi State University, Institute for Genomics, Biocomputing and Biotechnology, Starkville, Mississippi 39762, University of Saskatchewan, School of the Environment and Sustainability and Toxicology Centre, Saskatoon, Saskatchewan, SK S7N 5B3, Canada, University of Plymouth, School of Biological Sciences, Plymouth, Devon, PL4 8AA, UK, University of Minnesota, Water Resources Center, St. Paul, Minnesota 55108, European Commission, Joint Research Centre, Via E. Fermi 2749, 21027 Ispra, Italy, Department of Biology and Biochemistry, University of Houston, Houston, Texas, 77004, Zebrafishlab, Veterinary Physiology and Biochemistry, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Hutchinson
authors.affiliation: *US EPA Mid-Continent Ecology Division, 6201 Congdon Blvd, Duluth, Minnesota 55804, Environment Canada, Ecotoxicology and Wildlife Health Division, Ottawa, Ontario, K1A 0H3 Canada, Mississippi State University, Institute for Genomics, Biocomputing and Biotechnology, Starkville, Mississippi 39762, University of Saskatchewan, School of the Environment and Sustainability and Toxicology Centre, Saskatoon, Saskatchewan, SK S7N 5B3, Canada, University of Plymouth, School of Biological Sciences, Plymouth, Devon, PL4 8AA, UK, University of Minnesota, Water Resources Center, St. Paul, Minnesota 55108, European Commission, Joint Research Centre, Via E. Fermi 2749, 21027 Ispra, Italy, Department of Biology and Biochemistry, University of Houston, Houston, Texas, 77004, Zebrafishlab, Veterinary Physiology and Biochemistry, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium *US EPA Mid-Continent Ecology Division, 6201 Congdon Blvd, Duluth, Minnesota 55804, Environment Canada, Ecotoxicology and Wildlife Health Division, Ottawa, Ontario, K1A 0H3 Canada, Mississippi State University, Institute for Genomics, Biocomputing and Biotechnology, Starkville, Mississippi 39762, University of Saskatchewan, School of the Environment and Sustainability and Toxicology Centre, Saskatoon, Saskatchewan, SK S7N 5B3, Canada, University of Plymouth, School of Biological Sciences, Plymouth, Devon, PL4 8AA, UK, University of Minnesota, Water Resources Center, St. Paul, Minnesota 55108, European Commission, Joint Research Centre, Via E. Fermi 2749, 21027 Ispra, Italy, Department of Biology and Biochemistry, University of Houston, Houston, Texas, 77004, Zebrafishlab, Veterinary Physiology and Biochemistry, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
authors.forename: Carlie A
authors.initials: CA
authors.lastname: LaLone
authors.affiliation: *US EPA Mid-Continent Ecology Division, 6201 Congdon Blvd, Duluth, Minnesota 55804, Environment Canada, Ecotoxicology and Wildlife Health Division, Ottawa, Ontario, K1A 0H3 Canada, Mississippi State University, Institute for Genomics, Biocomputing and Biotechnology, Starkville, Mississippi 39762, University of Saskatchewan, School of the Environment and Sustainability and Toxicology Centre, Saskatoon, Saskatchewan, SK S7N 5B3, Canada, University of Plymouth, School of Biological Sciences, Plymouth, Devon, PL4 8AA, UK, University of Minnesota, Water Resources Center, St. Paul, Minnesota 55108, European Commission, Joint Research Centre, Via E. Fermi 2749, 21027 Ispra, Italy, Department of Biology and Biochemistry, University of Houston, Houston, Texas, 77004, Zebrafishlab, Veterinary Physiology and Biochemistry, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Landesmann
authors.affiliation: *US EPA Mid-Continent Ecology Division, 6201 Congdon Blvd, Duluth, Minnesota 55804, Environment Canada, Ecotoxicology and Wildlife Health Division, Ottawa, Ontario, K1A 0H3 Canada, Mississippi State University, Institute for Genomics, Biocomputing and Biotechnology, Starkville, Mississippi 39762, University of Saskatchewan, School of the Environment and Sustainability and Toxicology Centre, Saskatoon, Saskatchewan, SK S7N 5B3, Canada, University of Plymouth, School of Biological Sciences, Plymouth, Devon, PL4 8AA, UK, University of Minnesota, Water Resources Center, St. Paul, Minnesota 55108, European Commission, Joint Research Centre, Via E. Fermi 2749, 21027 Ispra, Italy, Department of Biology and Biochemistry, University of Houston, Houston, Texas, 77004, Zebrafishlab, Veterinary Physiology and Biochemistry, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
authors.forename: Teresa
authors.initials: T
authors.lastname: Lettieri
authors.affiliation: *US EPA Mid-Continent Ecology Division, 6201 Congdon Blvd, Duluth, Minnesota 55804, Environment Canada, Ecotoxicology and Wildlife Health Division, Ottawa, Ontario, K1A 0H3 Canada, Mississippi State University, Institute for Genomics, Biocomputing and Biotechnology, Starkville, Mississippi 39762, University of Saskatchewan, School of the Environment and Sustainability and Toxicology Centre, Saskatoon, Saskatchewan, SK S7N 5B3, Canada, University of Plymouth, School of Biological Sciences, Plymouth, Devon, PL4 8AA, UK, University of Minnesota, Water Resources Center, St. Paul, Minnesota 55108, European Commission, Joint Research Centre, Via E. Fermi 2749, 21027 Ispra, Italy, Department of Biology and Biochemistry, University of Houston, Houston, Texas, 77004, Zebrafishlab, Veterinary Physiology and Biochemistry, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
authors.forename: Sharon
authors.initials: S
authors.lastname: Munn
authors.affiliation: *US EPA Mid-Continent Ecology Division, 6201 Congdon Blvd, Duluth, Minnesota 55804, Environment Canada, Ecotoxicology and Wildlife Health Division, Ottawa, Ontario, K1A 0H3 Canada, Mississippi State University, Institute for Genomics, Biocomputing and Biotechnology, Starkville, Mississippi 39762, University of Saskatchewan, School of the Environment and Sustainability and Toxicology Centre, Saskatoon, Saskatchewan, SK S7N 5B3, Canada, University of Plymouth, School of Biological Sciences, Plymouth, Devon, PL4 8AA, UK, University of Minnesota, Water Resources Center, St. Paul, Minnesota 55108, European Commission, Joint Research Centre, Via E. Fermi 2749, 21027 Ispra, Italy, Department of Biology and Biochemistry, University of Houston, Houston, Texas, 77004, Zebrafishlab, Veterinary Physiology and Biochemistry, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Nepelska
authors.affiliation: *US EPA Mid-Continent Ecology Division, 6201 Congdon Blvd, Duluth, Minnesota 55804, Environment Canada, Ecotoxicology and Wildlife Health Division, Ottawa, Ontario, K1A 0H3 Canada, Mississippi State University, Institute for Genomics, Biocomputing and Biotechnology, Starkville, Mississippi 39762, University of Saskatchewan, School of the Environment and Sustainability and Toxicology Centre, Saskatoon, Saskatchewan, SK S7N 5B3, Canada, University of Plymouth, School of Biological Sciences, Plymouth, Devon, PL4 8AA, UK, University of Minnesota, Water Resources Center, St. Paul, Minnesota 55108, European Commission, Joint Research Centre, Via E. Fermi 2749, 21027 Ispra, Italy, Department of Biology and Biochemistry, University of Houston, Houston, Texas, 77004, Zebrafishlab, Veterinary Physiology and Biochemistry, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Ottinger
authors.affiliation: *US EPA Mid-Continent Ecology Division, 6201 Congdon Blvd, Duluth, Minnesota 55804, Environment Canada, Ecotoxicology and Wildlife Health Division, Ottawa, Ontario, K1A 0H3 Canada, Mississippi State University, Institute for Genomics, Biocomputing and Biotechnology, Starkville, Mississippi 39762, University of Saskatchewan, School of the Environment and Sustainability and Toxicology Centre, Saskatoon, Saskatchewan, SK S7N 5B3, Canada, University of Plymouth, School of Biological Sciences, Plymouth, Devon, PL4 8AA, UK, University of Minnesota, Water Resources Center, St. Paul, Minnesota 55108, European Commission, Joint Research Centre, Via E. Fermi 2749, 21027 Ispra, Italy, Department of Biology and Biochemistry, University of Houston, Houston, Texas, 77004, Zebrafishlab, Veterinary Physiology and Biochemistry, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
authors.forename: Lucia
authors.initials: L
authors.lastname: Vergauwen
authors.affiliation: *US EPA Mid-Continent Ecology Division, 6201 Congdon Blvd, Duluth, Minnesota 55804, Environment Canada, Ecotoxicology and Wildlife Health Division, Ottawa, Ontario, K1A 0H3 Canada, Mississippi State University, Institute for Genomics, Biocomputing and Biotechnology, Starkville, Mississippi 39762, University of Saskatchewan, School of the Environment and Sustainability and Toxicology Centre, Saskatoon, Saskatchewan, SK S7N 5B3, Canada, University of Plymouth, School of Biological Sciences, Plymouth, Devon, PL4 8AA, UK, University of Minnesota, Water Resources Center, St. Paul, Minnesota 55108, European Commission, Joint Research Centre, Via E. Fermi 2749, 21027 Ispra, Italy, Department of Biology and Biochemistry, University of Houston, Houston, Texas, 77004, Zebrafishlab, Veterinary Physiology and Biochemistry, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
authors.forename: Maurice
authors.initials: M
authors.lastname: Whelan
mesh_terms: D000818:Animals; D035843:Biomedical Research / Q000379:methods*; D016208:Databases, Factual; D006801:Humans; D008954:Models, Biological; D014116:Toxicology / Q000379:methods*
keywords: adverse outcome pathway; extrapolation; knowledgebase; predictive toxicology; regulatory toxicology