当前位置： SCI文献检索 > TOXICOLOGY AND APPLIED PHARMACOLOGY期刊下所有文献 > Development of a PBPK model of thiocyanate in rats with an extrapolation to humans: A computational study to quantify the mechanism of action of thiocyanate kinetics in thyroid.

Development of a PBPK model of thiocyanate in rats with an extrapolation to humans: A computational study to quantify the mechanism of action of thiocyanate kinetics in thyroid.

Abstract：

: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.

journal_name

Toxicol Appl Pharmacol

journal_title

Toxicology and applied pharmacology

authors

Willemin ME,Lumen A

doi

10.1016/j.taap.2016.07.011

subject

Has Abstract

pub_date

2016-09-15 00:00:00

pages

19-34

eissn

0041-008X

issn

1096-0333

pii

S0041-008X(16)30195-8

journal_volume

307

pub_type

杂志文章

在线工具

Development of a PBPK model of thiocyanate in rats with an extrapolation to humans: A computational study to quantify the mechanism of action of thiocyanate kinetics in thyroid.