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A pragmatic approach to Adverse Outcome Pathway (AOP) development and evaluation
Citation:
Svingen, T., D. Villeneuve, D. Knapen, E. Panagiotou, M. Draskau, P. Damdimopoulou, AND J. O'Brien. A pragmatic approach to Adverse Outcome Pathway (AOP) development and evaluation. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 184(2):183-190, (2021). https://doi.org/10.1093/toxsci/kfab113
Impact/Purpose:
One of the challenges related to the use of non-animal, alternative testing approaches (new approach methodologies; NAMs) in chemical safety evaluation involves the translation of biological activities observed at the molecular or cellular levels of biological organization into their potential causal connections to adverse effects on health, survival, reproduction, or growth/development. The adverse outcome pathway (AOP) framework was developed as an approach for organizing scientific information that facilitates this type of translation, thereby supporting the use of non-animal, high throughput, methods and data in chemical assessments. However, to date, the AOP knowledgebase has insufficient coverage of important toxicological pathways to provide comprehensive support for the application of NAMs. This is in part due to the daunting amount of time and effort that it can take to develop a scientifically robust AOP description, which serves as an obstacle for many potential contributors who might otherwise be willing to share their knowledge. The present paper proposes two pragmatic approaches that can reduce some of the burden on AOP developers. First, we propose that smaller units of information assembly be considered as a pragmatic unit of development and review. Second, we propose that systematic review approaches are not necessary to support relationships that are based on canonical knowledge. Rather, they are best employed when there is extensive literature pertaining to a causal relationship available, but where there are uncertainties and inconsistencies in the literature that make a relatively comprehensive, critical, transparent, and unbiased review of the literature important to establish the credibility of the relationship proposed. It is hoped that these pragmatic practices can accelerate the development of quality AOPs that will support the application of NAMs data and methods in various decision-making contexts relevant to EPA and its stakeholders.
Description:
The adverse outcome pathway (AOP) framework provides a practical means for organizing scientific knowledge that can be used to infer cause-effect relationships between stressor events and toxicity outcomes in intact organisms. It has reached wide acceptance as a tool to aid chemical safety assessment and regulatory toxicology by supporting a systematic way of predicting adverse health outcomes based on accumulated mechanistic knowledge. A major challenge for broader application of the AOP concept in regulatory toxicology, however, has been developing robust AOPs to a level where they are peer reviewed and accepted. This is because the amount of work required to substantiate the modular units of a complete AOP is considerable, to the point where it can take years from start to finish. To help alleviate this bottleneck, we propose a more pragmatic approach to AOP development whereby the focus becomes on smaller blocks. First, we argue that the key event relationship (KER) should be formally recognized as the core building block of knowledge assembly within the AOP knowledge base (AOP-KB), albeit framing them within full AOPs to ensure regulatory utility. Second, we argue that KERs should be developed using systematic review approaches, but only in cases where the underlying concept does not build on what is considered canonical knowledge. In cases where knowledge is considered canonical, rigorous systematic review approaches should not be required. It is our hope that these approaches will contribute to increasing the pace at which the AOP-KB is populated with AOPs with utility for chemical safety assessors and regulators.
URLs/Downloads:
DOI: A pragmatic approach to Adverse Outcome Pathway (AOP) development and evaluation
https://pubmed.ncbi.nlm.nih.gov/34534351/