Hypothesis-driven weight of evidence framework for evaluating data within the US EPA’s Endocrine Disruptor Screening Program

Abstract

"Weight of Evidence" (WoE) approaches are often used to critically examine, prioritize, and integrate results from different types of studies to reach general conclusions. For assessing hormonally active agents, WoE evaluations are necessary to assess screening assays that identify potential interactions with components of the endocrine system, long-term reproductive and developmental toxicity tests that define adverse effects, mode of action studies aimed at identifying toxicological pathways underlying adverse effects, and toxicity, exposure and pharmacokinetic data to characterize potential risks. We describe a hypothesis-driven WoE approach for hormonally active agents and illustrate the approach by constructing hypotheses for testing the premise that a substance interacts as an agonist or antagonist with components of estrogen, androgen, or thyroid pathways or with components of the aromatase or steroidogenic enzyme systems for evaluating data within the US EPA's Endocrine Disruptor Screening Program. Published recommendations are used to evaluate data validity for testing each hypothesis and quantitative weightings are proposed to reflect two data parameters. Relevance weightings should be derived for each endpoint to reflect the degree to which it probes each specific hypothesis. Response weightings should be derived based on assay results from the test substance compared to the range of responses produced in the assay by the appropriate prototype hormone and positive and negative controls. Overall WoE scores should be derived based on response and relevance weightings and a WoE narrative developed to clearly describe the final determinations.

Lessons learned, challenges, and opportunities: The U.S. Endocrine Disruptor Screening Program

“…Dr Christopher Borgert (APt, Inc.), in a presentation titled "A Weight of Evidence Approach to Examine Endocrine Activity" provided information on a recently published hypothesis-based WOe framework that utilizes data from tier 1 screening assays (Borgert et al, 2011a). the methodology is currently undergoing refinement to apply quantitative (relevance) weighting to each endocrine endpoint in the tier 1 assays, depending on whether an endpoint is: 1) a primary indicator of endocrine activity (i.e., specific for an endocrine MOA hypothesis); 2) a secondary indicator of endocrine activity (responsive to the MOA, but not as specific); or 3) supportive data to be used in conjunction with other evidence.…”

“…If primary endpoints specific for this MOA are not altered, the evidence for this MOA is tenuous. thus, the relevance of each endpoint is assigned a weight according to its importance for evaluating a specific hypothesis (Borgert et al, 2011a(Borgert et al, , 2013. Dr Borgert explained that response weighting across various endocrine MOAs is employed in the WOe assessment, in which test chemical responses can be compared to the range of responses elicited by positive and negative control compounds.…”

Assessment of PBTs in the European Union: a critical assessment of the proposed evaluation scheme with reference to plant protection products

“…A key difference between these is the recommendation for the use of weight of evidence for assessment of properties relevant to the categorization of substances for P, B, and T. We believe that the use of a formal, quantitative, and transparent process of weight of evidence should be included in the guidance for the selection of appropriate data and how these are compared to the criteria. We recommend that the analysis of weight of evidence be hypothesis-driven and evaluate the relevance and responses quantitatively such as has been suggested by Borgert et al [44].…”

Response to Kortenkamp et al. Rebuttal

“…We agree that widely endorsed weight-of-evidence methods are not readily available; indeed, several of us have publicly addressed this very lack and have proposed approaches that might be appropriate for endocrine disruption evaluation (e.g. Borgert et al, 2011;Rhomberg et al, 2010). We cited the WHO/IPCS (2002) approach to this question because, first, it seemed a reasonable approach that would be appropriate to the present case and, second, the SOTA ED itself suggested it was following this approach.…”