Adverse outcome pathways: opportunities, limitations and open questions

Area of Science:

• Toxicology
• Regulatory Science
• Mechanistic Toxicology

Background:

• Adverse Outcome Pathways (AOPs) formalize mechanistic toxicology, linking molecular initiating events (MIEs) to adverse outcomes (AOs) via key events (KEs) and relationships (KERs).
• Established in 2010, over 200 AOPs now exist, necessitating harmonization, updating, and clarification of their application.
• The AOP framework aims to support regulatory decision-making by providing transparent, evidence-based mechanistic information.

Observation:

• This review examines the history and strengths of AOPs, including systematic evidence collection and linking mechanisms to apical endpoints.
• It addresses misconceptions, weaknesses, and limitations of the current AOP framework to guide appropriate applications.
• Case studies explore AOP linearity, event modifiers, compensatory mechanisms, and the integration of toxicokinetics and toxicodynamics.

Findings:

• AOPs offer a robust approach for organizing toxicological data and identifying knowledge gaps.
• The review highlights the need to address AOP plasticity, including event modifiers and compensatory mechanisms.
• Misconceptions and limitations are clarified to ensure appropriate use and facilitate AOP framework evolution.

Implications:

• Understanding AOP strengths and limitations is crucial for their effective regulatory application.
• Further development is needed to refine AOPs for complex toxicological scenarios, such as pathway plasticity.
• This work aims to foster broader, appropriate use of AOPs by defining open questions and guiding future research.