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Cross species extrapolation of the disruption of thyroid hormone synthesis by oxyfluorfen using in vitro data, physiologically based pharmacokinetic (PBPK), and thyroid hormone kinetics models
Citation:
Decrane, R., T. Stoker, A. Murr, J. Ford, AND H. El-Masri. Cross species extrapolation of the disruption of thyroid hormone synthesis by oxyfluorfen using in vitro data, physiologically based pharmacokinetic (PBPK), and thyroid hormone kinetics models. Current Research in Toxicology. Elsevier B.V., Amsterdam, Netherlands, 5:100138, (2023). https://doi.org/10.1016/j.crtox.2023.100138
Impact/Purpose:
The manuscript highlights our ongoing efforts to extrapolate highthroughput in vitro data for the inhibition of thyroid hormone synthesis into in vivo measures of the hormones in rat and human serum. Computational methods are illustrated in the manuscript for the in vitro to in vivo (IVIVE) and species (rat to human) extrapolations.
Description:
Thyroid hormones play key roles in physiological processes such as regulation of the metabolic and cardiac systems as well as the development of the brain and surrounding sympathetic nervous system. Recent efforts to screen environmental chemicals for their ability to alter thyroid hormone synthesis, transport, metabolism and/or function have identified novel chemicals that target key processes in the thyroid pathway. One newly identified chemical, oxyfluorfen, is a diphenyl-ether herbicide used for control of annual broadleaf and grassy weeds in a variety of tree fruit, nut, vine, and field crops. Using in vitro high-throughput screening (HTS) assays, oxyfluorofen was identified to be a potent inhibitor of the thyroidal sodium-iodide symporter (NIS). To quantitatively assess this inhibition mechanism in vivo, we extrapolated in vitro NIS inhibition data to in vivo disruption of thyroid hormones synthesis in rats using physiologically based pharmacokinetic (PBPK) and thyroid hormone kinetics models. The overall computational model was calibrated against in vivo data for the levels of oxyfluorfen in thyroid tissue and serum and against serum levels of thyroid hormones triiodothyronine (T3) and thyroxine (T4) in rats. The rat thyroid model was then extrapolated to humans using human in vitro HTS data for NIS inhibition and the chemical specific hepatic clearance rate in humans. The overall species extrapolated PBPK-thyroid kinetics model can be used to predict dose-response (% drop in thyroid serum levels compared to homeostasis) relationships in humans. These relationships can be used to estimate points of departure for health risks related to a drop in serum levels of TH hormones based on HTS assays, IVIVE, toxicokinetics, and physiological principles.
URLs/Downloads:
DOI: Cross species extrapolation of the disruption of thyroid hormone synthesis by oxyfluorfen using in vitro data, physiologically based pharmacokinetic (PBPK), and thyroid hormone kinetics models
https://pubmed.ncbi.nlm.nih.gov/38074188/