Thyroid hormone system disruption (THSD) is a growing concern in chemical hazard assessment due to its impact on human and environmental health and the scarce methods available for assessing the THSD potential of chemicals. In particular, the general lack of validated in silico and in vitro methods for assessing THS activity is of high concern. This manuscript provides an inventory of test methods relevant to THSD. Building on the Organisation for Economic Co-operation and Development (OECD) Guidance Document 150 and recent international developments, we highlight progress in in silico and in vitro methods, as well as in vivo assays. The provided inventory categorizes available methods according to the levels of the OECD Conceptual Framework, with an assessment of the validation status of each method. At Level 1, 12 in silico models that have been statistically validated and are directly related to THSD have been identified. At Level 2, 67 in vitro methods have been listed including those assessed in key initiatives such as the European Union Network of Laboratories for the Validation of Alternative Methods (EU-NETVAL) validation study to identify potential thyroid disruptors. At Levels 3-5, THSD-sensitive endpoints are being included in existing fish-based OECD Test Guidelines to complement amphibian assays. In total, the inventory counts 108 entries comprising established methods (e.g., OECD Test Guidelines) as well as citable methods that are under further development and in some cases are ready for validation or in the initial stages of validation. This work aims to support the ongoing development of strategies for regulatory hazard assessment, such as integrated approaches to testing and assessment (IATAs), for endocrine disruptors, addressing critical gaps in the current testing landscape for THSD in both human and environmental health contexts.

Endocrine disruption - the potential of chemicals, such as industrial chemicals or pesticides, to disrupt hormonal systems and cause adverse health effects - is of growing concern due to its impact on human and environmental health and the scarce methods available for assessing such hazards. In particular, the limited methods available for assessing disruption of the thyroid hormone system, is of high concern. This manuscript provides an inventory of test methods relevant for the assessment of thyroid hormone system disruption. We highlight progress in different types of methods such as computer simulations, cell-based methods, non-mammalian embryo-based methods and animal methods and include an assessment of the readiness of each method for implementation in chemical evaluations. In total, the inventory counts 108 entries comprising already established methods as well as recent developments. This work aims to support the ongoing development of strategies for evaluating endocrine disruption, addressing critical gaps in the current testing landscape for thyroid hormone system disruption in both human and environmental health contexts.

Center for Gender Specific Medicine Istituto Superiore di Sanità Rome 00161 Italy

Department of Biology University of Southern Denmark Odense 5230 Denmark

Environmental Sustainability Assessment and Circularity Unit Luxembourg Institute of Science and Technology Belvaux 4422 Luxembourg

European Commission Joint Research Centre Ispra Ispra Lombardy 21027 Italy

Faculty of Chemistry University of Gdansk Gdańsk 80 308 Poland

HERACLES Research Center on the Exposome and Health Center for Interdisciplinary Research and Innovation Aristotle University of Thessaloniki Thessaloniki 570 01 Greece

Laboratory of Environmental Chemistry and Toxicology Department of Environmental Health Sciences Istituto di Ricerche Farmacologiche Mario Negri IRCCS Milan Lombardy 20156 Italy

Laboratory of Toxicological Control of Pesticides Scientific Directorate of Pesticides' Control and Phytopharmacy Benaki Phytopathological Institute Athens Attica 145 61 Greece

National Institute for Public Health and the Environment Bilthoven Utrecht 3721 The Netherlands

Radiation Chemical and Environmental Hazards Harwell Innovation Campus UK Health Security Agency Chilton OX11 0RQ UK

RECETOX Faculty of Science Masaryk University Brno 611 37 Czech Republic

Zebrafishlab Veterinary Physiology and Biochemistry University of Antwerp Wilrijk 2610 Belgium

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