1.13.T-05 - Tiered Assessment Scheme Linking NAMs to Adverse Outcomes To Support a Weight-of-Evidence-Based Identification of Thyroid Disruptors in Aquatic Vertebrates

Abstract

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According to the World Health Organisation and European Commission definitions, substances shall be considered as endocrine disruptors if they show adverse effects, have endocrine activity and the adverse effects are a consequence of the endocrine mode-of-action (using a weight-of-evidence approach based on biological plausibility), unless the adverse effects are not relevant to humans or non-target organisms at the population level. To date, there is no decision logic on how to establish endocrine disruption via the thyroid modality in non-mammalian vertebrates. We present an evidence-based decision logic to identify thyroid-mediated effect patterns in aquatic vertebrates, i.e. currently amphibians. The decision logic includes internationally agreed test guidelines and proposes detailed considerations on how to select relevant assays and interpret the findings. It combines New Approach Methodologies with higher-tiered tests up to refined assessment including population modelling. If the mammalian dataset, including any in vitro data, is used as the starting point and indicates no thyroid-mediated adversity or mode-of-action, the Xenopus Eleutheroembryonic Thyroid Assay (XETA) may be conducted in place of the Amphibian Metamorphosis Assay (AMA) or its extended, fixed termination stage variant (EAMA) to exclude thyroid-mediated activity in non-mammalian vertebrates. The AMA or EAMA may be performed if there are indications for thyroid adversity in the mammalian dataset or following a positive XETA. The AMA and EAMA inform on both thyroid-mediated activity and potentially population-relevant adversity and consider generalized toxicity occurrence. In evaluating findings, the response patterns of all assay endpoints are considered, including both the consistency and direction of changes. Thyroid-mediated effect patterns identified at the individual level in the amphibian tests are followed by a mode-of-action analysis and where necessary a population relevance assessment. Finally, all data are considered in an overarching weight-of-evidence evaluation. The decision logic can be adapted, e.g., to accommodate fish tests once thyroid endpoints are included therein. It ensures that all scientifically relevant information are considered and that animal testing is minimised, and it can be included in regulatory assessments to facilitate the conclusion on whether substances meet the endocrine disruptor definition for the thyroid modality in non-mammalian vertebrates.

Author(s)

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Presenter: Laurent Lagadic, Bayer AG,

Authors:
Laurent Lagadic Bayer AG Crop Science Research & Development Germany
Katherine Coady Bayer Research & Development Services LLC United States
Oliver Körner ADAMA Agriculture Germany Germany
Tara Miller International Copper Association (ICA) United Kingdom
Valentin Mingo Corteva Agriscience UK Limited. Germany
Edward Salinas Bayer AG Crop Science Research & Development Germany
Ursula Sauer Scientific Consultancy – Animal Welfare, Neubiberg Germany
Christel Schopfer BASF Corporation United States
Lennart Weltje BASF SE Germany
James Wheeler Corteva Agriscience UK Limited. Netherlands