AOP Development in Collaboration with Systematic Review Methods
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The adverse outcome pathway (AOP) is a simplified, organizational construct that links molecular initiating events (MIEs) and early key events (KEs) at lower levels of biological organization to adverse outcomes to support the incorporation of mechanistic data in regulatory application. Key Event Relationships (KERs defining the structural and functional relationship between a pair of KEs) are a critical focus of AOPs, framing essential components for predictive inference and modelling of adverse outcomes.
Though often developed based on supporting information that includes challenge by reference chemicals, AOPs are chemically agnostic, often initiated by domain experts, and confined to toxicodynamic aspects of biological pathways. Their modular and chemical agnostic nature supports application for various purposes, most notably in contributing to transition to more predictive and less costly non-animal testing strategies. The identification and development of assays to measure earlier KEs and by inference adverse outcomes supports more tailored, thoughtful and mechanistically based predictive integrated approaches to testing and assessment (IATA). AOPs also provide helpful organizing constructs for toxicodynamic mechanistic evidence in stressor or chemical specific assessment (i.e., mode of action analysis) and help substantiate interpretation of biological effect(s).
Since 2012, the Organization for Economic Cooperation and Development (OECD) has hosted a program to support the development, assessment and review of AOPs internationally. Associated Guidance developed by the OECD AOP program outlines best practices for defining and documenting AOPs in a central repository, the AOP knowledge base (AOP KB) (https://www.oecd.org/chemicalsafety/testing/adverse-outcome-pathways-molecular-screening-and-toxicogenomics.htm). Crowd sourcing in the user-friendly AOP wiki of the KB supports collaborative AOP development including sharing of the modular components (MIEs, KEs, KERs, and AOs). The KB, integrating both research and regulatory input, also serves as an accessible repository for pathway-based descriptions, with application to chemical regulation.
Developer guidance in the AOP program has focused principally on transparency and consistency in the documentation of key events and key event relationships in AOP descriptions. Assessment of the weight of evidence informing KERs and the overall predictive inference of an AOP for the adverse outcome is based on systematic documentation of considerations based on AOP Development Guidelines. Recently, there has been interest, in exploring the potential application of systematic review methods and tools in evidence assimilation, consideration, and documentation in AOP development to contribute additionally to objectivity, comprehensiveness and transparency (Devries et al., 2019: Sebastien et al., in press). Application, however, of these methods to AOP development is challenging. This relates in part, to the need for consideration of broad evidence bases for integrative mechanistic constructs and framing those considerations under the purview of systematic method workflows.
Complementary to other efforts, an initiative to consider the appropriate nature and value of the application of SR tools in AOP development is underway in the OECD program. This manuscript/communication outlines the nature of the initiative and progress and recommendations to date.