The Adverse Outcome Pathway: A Conceptual Framework to Support Toxicity Testing in the Twenty-First Century

The need to rapidly characterize the risk of large numbers of chemicals has moved the traditional toxicological paradigm from animal testing to a pathway-based approach using in vitro assay systems and modeling where possible. Adverse Outcome Pathways (AOPs) provide a conceptual framework that can be used to link in vitro assay results to whole animal effects in a pathway context. AOPs are defined and examples are provided to demonstrate key characteristics of AOPs. To support development and application of AOPs, a knowledge base has been developed containing a Wiki site designed to permit documentation of AOPs in a crowd-sourced manner. Both empirical and computational methods are demonstrated to play a significant role in AOP development. The combination of computational approaches, including different modeling efforts, together with apical end points within the pathway-based framework will allow for a better understanding of the linkage of events from a molecular initiating event to a potential adverse outcome, therefore defining key events, AOPs, and even networks of AOPS. While these approaches are indeed very promising, the ability to understand and define key events and key event relationships will remain one of the more complex and challenging efforts within AOP development. In order to make AOPs useful for risk assessment these challenges need to be understood and overcome. An interdisciplinary approach including apical and molecular measurements, computational, and modeling efforts is currently being one of the most promising approaches to ensure AOPs become the useful framework they were designed to be.