Willemin Marie-Emilie, Lumen Annie
Division of Biochemical Toxicology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA.
Division of Biochemical Toxicology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA.
Toxicol Appl Pharmacol. 2016 Sep 15;307:19-34. doi: 10.1016/j.taap.2016.07.011. Epub 2016 Jul 18.
Thyroid homeostasis can be disturbed due to thiocyanate exposure from the diet or tobacco smoke. Thiocyanate inhibits both thyroidal uptake of iodide, via the sodium-iodide symporter (NIS), and thyroid hormone (TH) synthesis in the thyroid, via thyroid peroxidase (TPO), but the mode of action of thiocyanate is poorly quantified in the literature. The characterization of the link between intra-thyroidal thiocyanate concentrations and dose of exposure is crucial for assessing the risk of thyroid perturbations due to thiocyanate exposure. We developed a PBPK model for thiocyanate that describes its kinetics in the whole-body up to daily doses of 0.15mmol/kg, with a mechanistic description of the thyroidal kinetics including NIS, passive diffusion, and TPO. The model was calibrated in a Bayesian framework using published studies in rats. Goodness-of-fit was satisfactory, especially for intra-thyroidal thiocyanate concentrations. Thiocyanate kinetic processes were quantified in vivo, including the metabolic clearance by TPO. The passive diffusion rate was found to be greater than NIS-mediated uptake rate. The model captured the dose-dependent kinetics of thiocyanate after acute and chronic exposures. Model behavior was evaluated using a Morris screening test. The distribution of thiocyanate into the thyroid was found to be determined primarily by the partition coefficient, followed by NIS and passive diffusion; the impact of the latter two mechanisms appears to increase at very low doses. Extrapolation to humans resulted in good predictions of thiocyanate kinetics during chronic exposure. The developed PBPK model can be used in risk assessment to quantify dose-response effects of thiocyanate on TH.
饮食或烟草烟雾中的硫氰酸盐暴露可能会扰乱甲状腺的内环境稳定。硫氰酸盐通过钠-碘同向转运体（NIS）抑制甲状腺对碘的摄取，并通过甲状腺过氧化物酶（TPO）抑制甲状腺中甲状腺激素（TH）的合成，但硫氰酸盐的作用模式在文献中的量化程度较低。甲状腺内硫氰酸盐浓度与暴露剂量之间联系的特征描述对于评估硫氰酸盐暴露导致甲状腺紊乱的风险至关重要。我们开发了一个硫氰酸盐的生理药代动力学（PBPK）模型，该模型描述了其在全身的动力学，直至每日剂量达到0.15mmol/kg，并对甲状腺动力学进行了机制描述，包括NIS、被动扩散和TPO。该模型在贝叶斯框架下使用已发表的大鼠研究进行了校准。拟合优度令人满意，尤其是对于甲状腺内硫氰酸盐浓度。硫氰酸盐的动力学过程在体内进行了量化，包括TPO的代谢清除。发现被动扩散速率大于NIS介导的摄取速率。该模型捕捉了急性和慢性暴露后硫氰酸盐的剂量依赖性动力学。使用莫里斯筛选试验评估了模型行为。发现硫氰酸盐在甲状腺中的分布主要由分配系数决定，其次是NIS和被动扩散；后两种机制的影响在非常低的剂量下似乎会增加。外推至人类后，对慢性暴露期间硫氰酸盐动力学的预测效果良好。所开发的PBPK模型可用于风险评估，以量化硫氰酸盐对TH的剂量反应效应。
