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Adverse outcome pathway (AOP) development I: Strategies and principles
Citation:
Villeneuve, Dan, D. Crump, N. Gaarcia-Reyero, M. Hecker, T. Hutchinson, C. LaLone, B. Landesmann, T. Lettieri, S. Munn, M. Nepelska, M. Ottinger, L. Vergauwen, AND M. Whelan. Adverse outcome pathway (AOP) development I: Strategies and principles. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 142(2):312-320, (2014).
Impact/Purpose:
Adverse outcome pathways (AOPs) are a conceptual framework for organizing existing knowledge concerning the linkage between molecular initiating events (i.e., perturbation of biomolecule(s) in the body through interaction with a chemical) and adverse outcomes considered relevant to regulatory decision-making. Conceptually, this framework has gained considerable attention with regard to its potential to help support a “21st century” approach to regulatory toxicology that increasingly relies on measures of the initiation or early progression of toxicity, as measured in high throughput in vitro or efficient and cost effective in vivo tests, rather than direct measurement of apical outcomes in classic whole organism toxicity tests. Broad interest in the development and application of this framework is reflected by the fact that the 53rd Annual Society of Toxicology meeting featured five technical sessions focused on the AOP concept, and three international scientific workshops focused on AOPs will be held in 2014 alone. Within EPA, development and application of AOPs is the primary focus of CSS Project 12.01. Nonetheless, to date,few beyond those working directly with OECD’s AOP Development Programme are aware of the formalization of the AOP concept and an emerging set of core principles that guide AOP development within the context of an internationally harmonized knowledgebase. This paper summarizes general AOP development strategies and core principles. Keeping this core set of guiding principles in mind during AOP development can help harness the collective expertise of the toxicology community in a coordinated manner that yields a useful AOP knowledgebase that will support EPA’s need to more effectively utilize new data streams as a basis for regulatory decision-making.
Description:
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 support greater application of mechanistic data in regulatory decision-making. 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) individual AOPs are a pragmatic unit of development and evaluation; (4) networks composed of 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 they can be expected evolve over time as new knowledge is generated. The goal of the present paper was to introduce some strategies for AOP development and detail the rationale behind these five key principles. Consideration of these principles addresses many of the current uncertainties regarding the AOP framework and its application and can foster greater consistency in AOP development.
