Collaborations on adverse outcome pathways
An AOP is a conceptual framework for organizing information and evidence on toxicity. It defines a causal relationship between perturbation of a biological pathway at the molecular, biochemical, or cellular level and one or more resulting adverse outcomes to human or ecosystem health. AOPs are useful in supporting both the development and application of NAMs and DAs in chemical safety assessment because they can:
- Organize information about biological interactions and toxicity mechanisms into sequential steps that describe how exposure to a substance might cause illness or injury.
- Suggest cell- or biochemical-based tests for pathway elements that could be used to develop testing strategies for targeted toxicity.
- Identify steps in a toxicity mechanism that need improved characterization.
EPA is an active partner in the OECD adverse outcome pathways development workplan, managed under OECD’s Working Party for Hazard Assessment and Working Party of the National Test Guidelines program. EPA is also an active participant in the Society for the Advancement of Adverse Outcome Pathways, which promotes and advances scientific research that fosters the development and use of AOPs. The Society hosts the AOP-Wiki, which is one component of a larger OECD-coordinated AOP Knowledgebase, also supported by EPA. EPA scientists were among the speakers at a 2023 workshop on AOP-Wiki 3.0, which was presented in two sessions in July and August 2023.
EPA and NIEHS also participate with international partners in the Methods2AOP Collaboration, which seeks to develop an infrastructure to accommodate the integration of defined method details with key events in AOPs, including molecular initiating events. This connection between specific test methods/assays and key events in AOPs can facilitate improved interpretation of likely chemical hazards of substances shown to elicit a given assay or endpoint response. A poster describing the Methods2AOP Collaboration (Wittwehr et al.) was presented at the 2023 annual meeting of the Society of Toxicology, and collaboration leader Clemens Wittwehr was profiled in an article in the September 2022 NIEHS Environmental Factor newsletter. Ongoing activities of the collaboration include development of a prototype for the next version of the AOP-Wiki to demonstrate functionalities and data model improvements that better reflect the importance of test method information in the AOP Framework. This includes an increased focus on method validation and readiness status, better communication of various stakeholder roles, and the introduction and implementation of ontologies to tag methods in a way that makes them better identifiable in neighboring initiatives (e.g., the OECD test guidelines program). An outreach event for regulators is planned April 2024 and a second version of the M2AOP prototype is under development. The collaboration will provide recommendations to OECD beyond information and communications technology aspects, as well as a publication summarizing activities and outcomes to be submitted to a peer-reviewed journal.