Studying endocrine disrupting chemicals from molecular targets to mixture model approach: lessons from the thyroid model.

Endocrine-disrupting chemicals (EDCs) pose a significant global health risk by interfering with hormonal balance. The thyroid is particularly suitable for studying endocrine disruption due to its crucial role in development, metabolism, and cognitive function, alongside established molecular targets and regulatory frameworks. This review summarizes current knowledge on thyroid-disrupting chemicals (TDs), focusing on mechanistic pathways acting at both intrathyroidal and extrathyroidal levels. Particular attention is given to molecular initiating events, such as interference with iodide uptake, thyroperoxidase activity, thyroglobulin processing, and thyroid hormone signaling, and to their integration within the adverse outcome pathway (AOP) framework. In addition, the review discusses methodological strategies for assessing thyroid disruption, spanning in silico, in vitro, in vivo, and human epidemiological approaches. Finally, emerging challenges related to real-world exposure to chemical mixtures are addressed, highlighting the need for AOP-informed, mixture-based strategies to improve risk assessment and regulatory decision-making.