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

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 (2015). Increasing Scientific Confidence in Adverse Outcome Pathways: Application of Tailored Bradford-Hill Considerations for Evaluating Weight of Evidence. Regulatory toxicology and pharmacology, 72(3), pp. 514-537. Elsevier 10.1016/j.yrtph.2015.04.004

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute for Fish and Wildlife Health (FIWI)

UniBE Contributor:

Segner, Helmut

Subjects:

600 Technology > 630 Agriculture

ISSN:

0273-2300

Publisher:

Elsevier

Language:

English

Submitter:

Lucia Gugger-Raaflaub

Date Deposited:

19 Apr 2016 09:59

Last Modified:

05 Dec 2022 14:54

Publisher DOI:

10.1016/j.yrtph.2015.04.004

PubMed ID:

25863193

Uncontrolled Keywords:

Adverse outcome pathway; Bradford-Hill considerations; Mode of action; Weight of evidence

BORIS DOI:

10.7892/boris.79785

URI:

https://boris.unibe.ch/id/eprint/79785

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