Citation:

Li, A., S. Makris, S. Marty, V. Strauss, M. Gilbert, A. Blacker, L. Zorilla, P. Coder, B. Hannas, S. Lordi, AND S. Schneider. Practical Considerations for Developmental Thyroid Toxicity Assessments: What’s working, what’s not, and how can we do better? REGULATORY TOXICOLOGY AND PHARMACOLOGY. Elsevier Science Ltd, New York, NY, 106:111-136, (2019). https://doi.org/10.1016/j.yrtph.2019.04.010

Impact/Purpose:

Thyroid hormones play a critical role in development. Animal studies are typically used to identify disruption of thyroid hormones in developing rodents, for use as a predictive biomarker in human health risk assessment. EPA and OECD testing guidelines provide recommendations for the collection of thyroid endpoints from studies with developmental exposures. However, they do not address best practices for sample collection, analysis, validity, or interpretation. To begin to address these issues, an SOT Roundtable was conducted in 2017. Discussions among academic, industry, and government scientists at that meeting, and the subsequent collection and analysis of thyroid assay historical control (HC) data from a group of laboratories, expanded the conversation. This manuscript summarizes some basic biology of thyroid development, methodological considerations that might affect data variability, and the need for quality control. Initial conclusions and insights from the analysis of the limited HC data include that laboratory-specific HC data are necessary, and it is crucial to validate hormone assays to reference standards in order to establish sensitivity, specificity, and precision. Insights and recommendations presented in this manuscript for best practices and possible improvements in sample collection, analytical methods, and interpretation of thyroid hormone data from developmental toxicology studies, form a basis for continuing discussion in the scientific community and a resource for regulatory decision-making. Identified knowledge gaps were identified that can guide future discussion and research.

Description:

Thyroid hormones (THs; T3 and T4) play a role in development of numerous organ systems, including cardiovascular, reproductive, immune and nervous systems. As such, the interpretation of TH changes from rat and mouse studies (during pregnancy, in fetuses, neonates, and adults) is critical in hazard characterization and risk assessment. In 2017, a roundtable session was held at the Society of Toxicology (SOT) meeting to bring together academic, industry and government scientists to share knowledge, experience and different perspectives on technical and data interpretation issues. Data from a limited group of contract research organizations (CRO) and non-CRO laboratories were compiled for technical discussions on TH measurements in serum, including good practices for the collection of reliable serum TH data. Our assessment of inter-laboratory historical control data, derived from immunoassays or mass spectrometry methods, revealed: 1) assay sensitivities vary within and across methodologies; 2) TH variability is similar across animal ages; 3) laboratories generally achieve sufficiently sensitive TH quantitation levels, although issues remain for lower levels of serum TH and TSH in fetuses and postnatal day 4 pups; thus, assay sensitivity is critical at these life stages. Best practices require a detailed validation of rat serum TH measurements across ages to establish assay sensitivity and precision, and to identify any potential matrix impacts of reference standards. Chemical-specific assessments should also be accompanied by a positive control study. Finally, issues related to data interpretation within the context of biological understanding and risk assessment were identified and discussed, but their resolution remains elusive.

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