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Increasing scientific confidence in adverse outcome pathways: Application of tailored Bradford-Hill considerations for evaluating weight of evidence
Citation:
Becker, R., G. Ankley, S. Edwards, S. Kennedy, I. Linkov, B. Meek, M. Sachana, H. Segner, B. Van Der Burg, Dan Villeneuve, H. Watanabe, AND T. Barton-Maclarenk. Increasing scientific confidence in adverse outcome pathways: Application of tailored Bradford-Hill considerations for evaluating weight of evidence. REGULATORY TOXICOLOGY AND PHARMACOLOGY. Elsevier Science Ltd, New York, NY, 72(3):514-537, (2015).
Impact/Purpose:
An international expert workshop on Advancing Adverse Outcome Pathways (AOPs) for Integrated Toxicology and Regulatory Applications was held March 2-7, 2014 in Somma Lombardo, Italy. Support for the workshop was provided by the American Chemistry Council, BioDetection Systems, European Centre for Ecotoxicology and Toxicology of Chemicals, Environment Canada, European Commission Directorate General Joint Research Center, Human Toxicology Project Consortium, International Life Sciences Institute - Health and Environmental Science Institute, The Research Council of Norway (Grant no. 221455), Society for Environmental Toxicology and Chemistry, US Army Engineer Research and Development Center, and the US Environmental Protection Agency. This product is one of a number of peer-reviewed papers emanating from that workshop. Systematic consideration of scientific support is a critical element in developing and, ultimately, using adverse outcome pathways (AOPs) for various regulatory applications. This paper utilizes a transparent weight-of-evidence (WoE) based approach for assessing scientific rigor based on modified Bradford-Hill (BH) considerations for systematic assessment of confidence in a given AOP. These considerations include 1) biological plausibility and 2) empirical support (dose-response, temporality, and incidence) for key event relationships (KERs), and 3) essentiality of key events (KEs). The paper tests the application of these tailored BH considerations using a number of case examples, which should contribute to better common understanding of the nature and form of documentation required to increase confidence in the application of AOPs for specific uses. Based on the tailored BH considerations and defining questions, a prototype quantitative model for assessing the WoE of an AOP using tools of multi-criteria decision analysis also is described, and demonstrated using an AOP case example focused on aromatase inhibition leading to reproductive dysfunction in fish.
Description:
Systematic consideration of scientific support is a critical element in developing and, ultimately, using adverse outcome pathways (AOPs) for various regulatory applications. Though weight of evidence (WoE) analysis has been proposed as a basis for assessment of the maturity and level of confidence in an AOP, methodologies and tools are still being formalized. The Organization for Economic Co-operation and Development (OECD) Users’ Handbook Supplement to the Guidance Document for Developing and Assessing AOPs (OECD, 2014a; hereafter referred to as the OECD AOP Handbook) provides tailored Bradford-Hill (BH) considerations for systematic assessment of confidence in a given AOP. These considerations include 1) biological plausibility and 2) empirical support (dose-response, temporality, and incidence) for key event relationships (KERs), and 3) essentiality of key events (KEs). Here, we test the application of these tailored BH considerations and the guidance outlined in the OECD AOP Handbook using a number of case examples to increase experience in more transparently documenting rationales for assigned levels of confidence to KEs and KERs, and to promote consistency in evaluation within and across AOPs. The major lessons learned from experience are documented, and taken together with the case examples, should contribute to better common understanding of the nature and form of documentation required to increase confidence in the application of AOPs for specific uses. Based on the tailored BH considerations and defining questions, a prototype quantitative model for assessing the WoE of an AOP using tools of multi-criteria decision analysis (MCDA) is described. The applicability of the approach is also demonstrated using the case example aromatase inhibition leading to reproductive dysfunction in fish. Following the acquisition of additional experience in the development and assessment of AOPs, further refinement of parameterization of the model through expert elicitation is recommended. Overall, the application of quantitative WoE approaches hold promise to enhance the rigor, transparency and reproducibility for AOP WoE determinations and may play an important role in delineating areas where research would have the greatest impact on improving the overall confidence in the AOP.
