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Adverse outcome pathway (AOP) development I: strategies and principles
Daniel L Villeneuve1, Doug Crump2, Natàlia Garcia-Reyero2
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.
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.
Insights
Adverse Outcome Pathways (AOPs) provide a framework for understanding toxicity. This study proposes five core principles for consistent AOP development, enhancing regulatory science and risk assessment.
Area of Science:
- Toxicology and Risk Assessment
- Mechanistic Toxicology
- Regulatory Science
Background:
- Adverse Outcome Pathways (AOPs) organize knowledge linking molecular disturbances to adverse outcomes.
- AOP frameworks can improve regulatory decision-making by integrating mechanistic data.
- Consistent AOP development is crucial for a robust toxicological knowledgebase.
Purpose of the Study:
- To propose five fundamental principles for consistent Adverse Outcome Pathway (AOP) development.
- To detail the rationale behind these core principles for AOP construction.
- To address uncertainties and foster consistency in the application of the AOP framework.
Main Methods:
- Synthesized experiences and scientific discourse among AOP practitioners.
- Formulated five core principles guiding AOP development.
- Detailed the strategic considerations and justifications for each principle.
Main Results:
- Five principles for AOP development were proposed: non-chemical specificity, modularity (key events/relationships), individual AOP as a unit, network utility, and evolving nature.
- These principles aim to standardize the creation and evaluation of AOPs.
- The proposed principles address current uncertainties in AOP framework application.
Conclusions:
- Adherence to these five principles will promote greater consistency in AOP development.
- Consistent AOPs will enhance their utility in human health and ecological risk assessment.
- AOPs are dynamic tools that require ongoing refinement as scientific knowledge advances.
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