Cross-taxa extrapolation: Is there a role for thyroid hormone conjugating liver enzymes during amphibian...

Chemical safety assessment includes evaluating the potential to disrupt the endocrine system in humans and wildlife. The thyroid hormone system shows high complexity which is conserved across vertebrates, allowing biological read-across between regulatory important taxa, namely mammals and amphibians. Potential thyroid disruption in aquatic vertebrates is typically investigated by activity assays (Amphibian Metamorphosis Assay (AMA), Xenopus Eleutheroembryo Thyroid Assay). Since neither assay is designed to provide detailed mechanistic information, mode of action analyses often rely on mammalian data, assuming overall cross-vertebrate conservation. This manuscript elaborates on the imperative that, despite overall conservation, the T-modality in metamorphosing amphibians needs to be understood in detail to justify biological read-across between mammals and amphibians. To this end, we revisit the AMA regarding amphibian developmental physiology, and the T-modality regarding mechanistic cross-vertebrate conservation. The importance of a mechanistic understanding for read-across is showcased based on the AMA's apparent insensitivity to at least one category of prototypical liver enzyme inducers. From a regulatory perspective, deeper mechanistic understanding is needed, not only to strengthen the scientific basis for designing testing strategies and interpreting study results, but also to allow the identification of data gaps and thus development of New Approach Methodologies (NAMs) to minimize vertebrate testing.