1.13.T-04 - From Activity to Adversity: A Case Study Advocating Fit-for-Purpose Higher-Tier Studies in Non-Target Organism Endocrine Disruption Assessment

Abstract

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According to WHO/IPCS (2002) an endocrine disruptor is an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism. The OECD 231 Amphibian Metamorphosis Assay (AMA) is the current gold standard for investigating thyroid-disrupting activity in non-target organisms. However, as a screening-level assay, the AMA is designed to detect endocrine activity, not adversity to the organism. Within existing regulatory paradigms, a positive AMA can trigger extensive higher-tier testing, even when biological significance is uncertain. We present a case study with a model acetyl-CoA carboxylase (ACCase) inhibitor herbicide, which produced a positive finding in the AMA according to the test guideline. The Larval Amphibian Toxicity Test (LATT), a relatively new higher-tier study with greater statistical power and a more appropriate exposure window and duration, was subsequently conducted on the same compound (US EPA, 2024). The LATT showed no thyroid-related effects, demonstrating that the AMA activity screening signal did not translate to adversity that may be relevant at population level. This outcome argues for a paradigm shift in how we approach endocrine disruptor assessment for non-target organisms. Rather than using the AMA – an in vivo study with significant animal use costs –as a screen for activity, we advocate for a greater use of new approach methods (NAMs) such as mechanistic screening tools (e.g., transcriptomics assays in zebrafish embryos or eleuthero embryonic assays XETA OECD 248/ FET4Thyroid) that identify activity followed up where necessary with fit-for-purpose higher-tier studies like the LATT as a more suitable definitive test for adversity. The LATT is statistically powered to detect developmental effects compared to endpoints available in the AMA, which are not mechanistically informative nor indicative of population relevant adversity. Conducting the appropriate study for the appropriate question is not only scientifically defensible but reduces animal use, accelerates decision making and addresses the endocrine disruptor identification criteria that require demonstration of population relevant adversity effects.

Author(s)

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Presenter: Pria Mahabir, Syngenta Crop Protection AG,

Authors:
Pria Mahabir Syngenta Canada
Daniel Pickford Syngenta United Kingdom