Adverse outcome pathways (AOPs) offer a pathway-based toxicological framework to support hazard assessment and regulatory decision-making. However, little has been discussed about the scientific confidence needed, or how complete a pathway should be, before use in a specific regulatory application. Here we review four case studies to explore the degree of scientific confidence and extent of completeness (in terms of causal events) that is required for an AOP to be useful for a specific purpose in a regulatory application: (i) Membrane disruption (Narcosis) leading to respiratory failure (low confidence), (ii) Hepatocellular proliferation leading to cancer (partial pathway, moderate confidence), (iii) Covalent binding to proteins leading to skin sensitization (high confidence), and (iv) Aromatase inhibition leading to reproductive dysfunction in fish (high confidence). Partially complete AOPs with unknown molecular initiating events, such as ‘Hepatocellular proliferation leading to cancer’, were found to be valuable. We demonstrate that scientific confidence in these pathways can be increased though the use of unconventional information (eg, computational identification of potential initiators). AOPs at all levels of confidence can contribute to specific uses. A significant statistical or quantitative relationship between events and/or the adverse outcome relationships is a common characteristic of AOPs, both incomplete and complete, that have specific regulatory uses. For AOPs to be useful in a regulatory context they must be at least as useful as the tools that regulators currently possess, or the techniques currently employed by regulators.

A peer-reviewed open access journal published by the National Institute of Environmental Health Sciences

Our ability to conduct whole‐organism toxicity tests to understand chemical safety has been outpaced by the synthesis of new chemicals for a wide variety of commercial applications. As a result, scientists and risk assessors are turning to mechanistically based studies to increase efficiencies in chemical risk assessment and making greater use of in vitro and in silico methods to evaluate potential environmental and human health hazards. In this context, the adverse outcome pathway (AOP) framework has gained traction in regulatory science because it offers an efficient and effective means for capturing available knowledge describing the linkage between mechanistic data and the apical toxicity end points required for regulatory assessments. A number of international activities have focused on AOP development and various applications to regulatory decision‐making. These initiatives have prompted dialogue between research scientists and regulatory communities to consider how best to use the AOP framework. Although expert‐facilitated discussions and AOP development have been critical in moving the science of AOPs forward, it was recognized that a survey of the broader scientific and regulatory communities would aid in identifying current limitations while guiding future initiatives for the AOP framework. To that end, a global horizon scanning exercise was conducted to solicit questions concerning the challenges or limitations that must be addressed to realize the full potential of the AOP framework in research and regulatory decision‐making. The questions received fell into several broad topical areas: AOP networks, quantitative AOPs, collaboration on and communication of AOP knowledge, AOP discovery and development, chemical and cross‐species extrapolation, exposure/toxicokinetics considerations, and AOP applications. Expert ranking was then used to prioritize questions for each category, where 4 broad themes emerged that could help inform and guide future AOP research and regulatory initiatives. In addition, frequently asked questions were identified and addressed by experts in the field. Answers to frequently asked questions will aid in addressing common misperceptions and will allow for clarification of AOP topics. The need for this type of clarification was highlighted with surprising frequency by our question submitters, indicating that improvements are needed in communicating the AOP framework among the scientific and regulatory communities. Overall, horizon scanning engaged the global scientific community to help identify key questions surrounding the AOP framework and guide the direction of future initiatives. Environ Toxicol Chem 2017;36:1411–1421. © 2017 SETAC