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Adverse outcome pathway (AOP) development II: Best practices
Citation:
Villeneuve, Dan, D. Crump, N. Garcia-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 II: Best practices. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 142(2):321-330, (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. Development of formal AOP descriptions is a new process for most scientists and regulators in the field. Construction of a knowledgebase of AOP descriptions, one of the primary goals of CSS Project 12.01, has great potential as an information source to complement the mechanistically-oriented high throughput, high content, and in silico data being generated using new technologies. However, unless AOPs are developed in a shared environment, according to a common set of guiding principles, conventions, and best practices, it will be difficult for scientists, regulators, and decision-makers to access and utilize this knowledge in an efficient and meaningful manner. This paper defines a set of conventions and best practices related to AOP development and description. It also addresses some of the common questions and challenges encountered when developing and AOP and presents model AOP descriptions as supporting material. Dissemination of these conventions, rules of thumb, and best practices within EPA and to the broader scientific community, will help facilitate consistent and effective AOP development that will support EPA’s need to more effectively utilize new data streams as a basis for regulatory decision-making.
Description:
Organization of existing and emerging toxicological knowledge into adverse outcome pathway (AOP) descriptions can facilitate greater application of mechanistic data, including high throughput in vitro, high content omics and imaging, and biomarkers, in risk-based decision-making. A previously ad hoc process of AOP development is being formalized around a set of internationally harmonized guidance and principles. The goal of this paper was to outline the information content desired for formal AOP description and some rules of thumb and best practices that are intended to facilitate reuse and connectivity of elements of an AOP description in a knowledgebase and network context. For example, key events (KEs) are measurements of change in biological state that are indicative of progression of a perturbation toward a specified adverse outcome. Best practices for KE description suggest that each KE should be defined as an independent measurement made at a particular level of biological organization. The concept of “functional equivalence” can help guide both decisions about how many KEs to include in an AOP and the specificity with which they’re defined. Likewise, in describing both KEs and evidence that supports a causal linkage or statistical association between them (i.e., a key event relationship; KER) best practice is to build from and contribute to an existing KE or KER description in the AOP knowledgebase rather than creating redundant descriptions. The best practices proposed address many of the challenges and uncertainties related to AOP development and help promote a consistent and reliable, yet flexible approach.
