Increasing Scientific Confidence in Adverse Outcome Pathways: Application of Tailored Bradford-Hill Considerations for Evaluating Weight of Evidence

• Published in: Regulatory toxicology and pharmacology 2015-08, Vol.72 (3), p.514-537
• Main Authors: Becker, Richard A., Ankley, Gerald T., Edwards, Stephen W., Kennedy, Sean W., Linkov, Igor, Meek, Bette, Sachana, Magdalini, Segner, Helmut, Van Der Burg, Bart, Villeneuve, Daniel L., Watanabe, Haruna, Barton-Maclaren, Tara S.
• Format: Article
• Language: English
• Subjects: Adverse outcome pathway; Animals; Aromatase Inhibitors - toxicity; Bradford-Hill considerations; Drug-Related Side Effects and Adverse Reactions; Female; Fishes; Mode of action; Reproduction - drug effects; Risk Assessment - methods; Weight of evidence
• ISSN: 0273-2300; 1096-0295
• DOI: 10.1016/j.yrtph.2015.04.004

•Weight of evidence (WoE) method to evaluate key events in adverse outcome pathways.•Biological plausibility, empirical evidence and essentiality are WoE determinants.•Application to human health and ecological AOPs is illustrated with six examples.•A prototype quantitative decision analysis (MCDA) WoE model for AOPs is described. 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 determinatio