Adverse outcome pathway (AOP) development I: strategies and principles

Affiliations

¹ *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.
² *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.
³ *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.

PMID: 25466378
PMCID: PMC4318923
DOI: 10.1093/toxsci/kfu199

Adverse outcome pathway (AOP) development I: strategies and principles

Daniel L Villeneuve et al. Toxicol Sci. 2014 Dec.

. 2014 Dec;142(2):312-20.

doi: 10.1093/toxsci/kfu199.

Affiliations

¹ *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.
² *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.
³ *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.

PMID: 25466378
PMCID: PMC4318923
DOI: 10.1093/toxsci/kfu199

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.

Keywords: adverse outcome pathway; extrapolation; knowledgebase; predictive toxicology; regulatory toxicology.

Published by Oxford University Press on behalf of the Society of Toxicological 2014. This work is written by US Government employees and is in the public domain in the US.

PubMed Disclaimer

Figures

**FIG. 1.**
Graphical representation of a generalized adverse outcome pathway (AOP; A). Each AOP is composed of two key components (B), key events (KEs) and key event relationships (KERs). Additionally, there are two specialized KEs, molecular initiating events (MIEs) and adverse outcomes (AOs) that anchor an AOP description. Individual AOPs sharing KEs or KERs can be represented as an AOP network (C). The AOP network depicted is composed of four individual AOPs, each representing a unique sequence of KEs linking an MIE to AO: AOP 1 [MIE1, KE1, KE2, KE3, AO1, AO2]; AOP 2 [MIE2, KE4, KE1, KE2, KE3, AO1, AO2]; AOP 3 [MIE1, KE1, KE2, KE5, KE6, AO3]; AOP 4 [MIE2, KE4, KE1, KE2, KE5, KE6, AO3]. Color image is available in the online version of the article.

See this image and copyright information in PMC

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Adverse outcome pathway (AOP) development I: strategies and principles

Affiliations

Adverse outcome pathway (AOP) development I: strategies and principles

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Abstract

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