1.13.T-02 - Using Case Study Chemicals To Evaluate New Approach Method Integration for Estrogen Receptor Activity Screening in Aquatic Vertebrates

Abstract

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New approach methods (NAMs) are increasingly proposed for endocrine activity screening in aquatic vertebrates, but practical guidance is still needed on how to interpret and weigh these data. The Health and Environmental Sciences Institute (HESI Global) and the UK National Centre for the 3Rs, with support from a diverse planning committee, convened a virtual workshop to evaluate how NAM data could be used to assess estrogen receptor agonism using anonymized chemical datasets inspired by real-world information. Participants worked in small groups to review prepared data packages that included physicochemical information, in silico predictions, existing mammalian data, in vitro assay results from human and aquatic vertebrate systems, and eleutheroembryo models, with endpoints relevant to estrogen receptor activity as well as broader endocrine and toxicity outcomes. In vivo fish data were provided at the end of the discussions for comparison. Discussions focused on how confidence changed as evidence was introduced and when data were sufficient to support prioritization and decisions about needs for additional testing.

Across groups, confidence was highest when estrogen-relevant evidence was concordant across multiple evidence streams. Early-stage physicochemical and in silico information was useful for identifying potential concerns and guiding next steps, but was generally not considered sufficient on its own to support confident activity determinations. Confidence increased when in vitro, pre-existing mammalian, or eleutheroembryo data provided similar activity assessments. Participants were more comfortable acting on consistent evidence for activity than concluding a lack of activity, especially when data gaps, out-of-domain predictions, uncertain species relevance, or incomplete endocrine pathway coverage limited confidence in the overall evidence package.

The workshop identified several areas where additional guidance is needed, including interpreting NAM outputs, weighting weak or discordant evidence, determining when negative results are sufficient, and connecting mechanistic activity data to species relevance and organism-level outcomes. Overall, the discussions showed that NAMs can support staged screening of estrogen activity, but confidence depends on problem formulation, concordance across evidence streams, and transparent criteria for determining when the data are sufficient.

Author(s)

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Presenter: Julie Krzykwa, HESI Global,

Authors:
Julie Krzykwa HESI Global United States
Amy Marriott NC3Rs United Kingdom
Michelle Embry HESI Global United States
Natalie Burden NC3Rs United Kingdom