Citation:

Jensen, K., G. Ankley, S. Edwards, AND Dan Villeneuve. Weight of evidence evaluation of adverse outcome pathways converging at impaired vitellogenin synthesis leading to reproductive impairment. SETAC North America, Salt Lake City, UT, November 01 - 05, 2015.

Impact/Purpose:

not applicable

Description:

Adverse outcome pathways (AOPs) provide a framework that supports greater use of mechanistic data measured at lower levels of biological organization as a basis for regulatory decision-making. However, it is recognized that different types of regulatory applications and decisions require different levels of scientific confidence or certainty. Consequently, evaluation of the weight of evidence, both in terms of biological plausibility and empirical support, underlying the key event relationships depicted in an AOP is a major determinant of its “fit-for-purpose” for different regulatory applications. While many AOPs are currently being developed and described in the internationally harmonized AOP knowledgebase (aopkb.org), there remains a paucity of examples for which a comprehensive weight of evidence assembly and evaluation has been completed. This presentation illustrates key aspects of the weight of evidence evaluation using a network of three AOPs linking the molecular initiating events of aromatase inhibition, androgen receptor agonism, and estrogen receptor antagonism to reductions in vitellogenin synthesis in female fish leading, ultimately, to reproductive impairment. Empirical data from the literature were organized into tables that facilitate evaluation of the temporal and dose-response concordance of key events depicted in the AOPs. Additional elements of the Bradford Hill criteria including biological plausibility, essentiality, and incidence concordance were also considered. Although the process for weight of evidence evaluation was adapted from the International Programme on Chemical Safety’s Mode of Action (MOA) Framework, there are some key differences between MOA analysis and the weight of evidence evaluation for AOPs and AOP networks. Most notably, MOA analyses are chemical specific, while AOPs are developed in a manner that is not chemical-specific and thus can draw upon evidence from many chemical stressors. Additional challenges and efficiencies associated with applying weight of evidence evaluation to an AOP network are described. The case study provides a useful example for others in the field to draw upon as they conduct WOE evaluations for other AOPs and AOP networks.

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