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Advancing the Use and Acceptance of the Human Thyroid Microtissue Assay
Citation:
Deisenroth, C. Advancing the Use and Acceptance of the Human Thyroid Microtissue Assay. Society of Toxicology 63rd Annual Meeting and ToxExpo, Salt Lake City, UT, March 10 - 14, 2024. https://doi.org/10.23645/epacomptox.25511350
Impact/Purpose:
This a presentation abstract for a proposed session with tentative acceptance at the SOT 2024 Annual Meeting - (ID 141) Advances in New Approach Methods for Thyroid Toxicity Testing. Session abstract: Chemical perturbations to thyroid hormone homeostasis can result in thyroid mediated adversities including interference with normal neurodevelopment. Global regulatory agencies require critical evaluation of chemicals that have the potential to disrupt thyroid hormone signaling as part of a comprehensive chemical safety assessment. Due to the complexity of the thyroid system and regulatory reliance on animal testing, there is a need for new approach methodologies (NAMs) to provide testing modalities that improve mechanistic insight, predict mode-of-action, reduce the use of animal testing, and inform next generation risk assessments for thyroid-mediated toxicity, particularly with regards to human health effects. Advances in the development, application, and validation of high-throughput screening assays and organotypic culture models aim to provide coverage of molecular initiating events (MIEs) and key events (KEs) defined in the thyroid adverse outcome pathway (AOP) network. However, interpretation of the biological and mechanistic relevance of thyroid NAMs remains a key challenge. Efforts to provide more comprehensive NAM coverage for thyroid system modes-of-action, increase confidence in NAM standardization and implementation, and promote the acceptance of NAM data are necessary to fully leverage the potential capabilities of these test systems for quantitative AOP modeling and prediction of thyroid toxicity. This session focuses on the current state-of-science regarding the evaluation of thyroid disrupting chemicals, including validation of in vitro test methods, emerging organotypic technologies, application of alternative model organisms, and filling data gaps in quantitative AOPs. This session will provide insight into the strength, limitation, and future direction toward better hazard and risk assessment for chemical-induced thyroid toxicity.
Description:
This is a presentation abstract for proposed session, ID 141, Advances in New Approach Methods for Thyroid Toxicity Testing, for the SOT 2024 Annual Meeting. Abstract: There is significant regulatory need to evaluate chemicals that may disrupt the thyroid endocrine system. Thyroid new approach methods (NAMs) using in vitro assays provide capabilities to accelerate hazard identification by informing the mechanistic and functional potential for disruption of thyroid hormone homeostasis in a manner relevant to human health outcomes. Advancements in complex in vitro culture systems comprised of primary cells from human donors enables reconfiguration of the cellular architecture and microenvironment that more closely simulates the natural structure, function, and physiology of the thyroid gland. Prior work in our laboratory established an organotypic screening assay comprised of reconstructed human thyroid microtissues to quantitatively evaluate the disruptive effects of chemicals on thyroid hormone production and secretion. Validation, defined as the process by which the reliability and relevance of a test method are established, sits at the interface between assay standardization and regulatory acceptance to ensure a rigorous science-based evaluation of fitness for a defined purpose, technical performance, and acceptance for regulatory use. Ongoing work will address efforts to increase confidence in the microtissue assay by setting appropriate donor qualification standards, defining benchmark expectations for the context of use, demonstrating method transferability, and evaluating technical performance in an inter-laboratory prevalidation study. The impact of these efforts will enable more robust assessments of thyroid disrupting chemicals using a human-based NAM approach. This abstract does not necessarily reflect U.S. EPA policy.
URLs/Downloads:
DOI: Advancing the Use and Acceptance of the Human Thyroid Microtissue Assay
2024MAR11_SOT_THYROID_DEISENROTH_V5_FINAL.PDF (PDF, NA pp, 3647.779 KB, about PDF)