Competitive Inhibition of Thyroidal Uptake of Dietary Iodide by Perchlorate Does Not Describe Perturbations in Rat Serum Total T 4 and TSH

Abstract

Background Perchlorate (ClO₄⁻) is an environmental contaminant known to disrupt the thyroid axis of many terrestrial and aquatic species. ClO₄⁻ competitively inhibits iodide uptake into the thyroid at the sodium/iodide symporter and disrupts hypothalamic–pituitary–thyroid (HPT) axis homeostasis in rodents. Objective We evaluated the proposed mode of action for ClO₄⁻-induced rat HPT axis perturbations using a biologically based dose–response (BBDR) model of the HPT axis coupled with a physiologically based pharmacokinetic model of ClO₄⁻. Methods We configured a BBDR-HPT/ClO₄⁻ model to describe competitive inhibition of thyroidal uptake of dietary iodide by ClO₄⁻ and used it to simulate published adult rat drinking water studies. We compared model-predicted serum thyroid-stimulating hormone (TSH) and total thyroxine (TT₄) concentrations with experimental observations reported in these ClO₄⁻ drinking water studies. Results The BBDR-HPT/ClO₄⁻ model failed to predict the ClO₄⁻-induced onset of disturbances in the HPT axis. Using ClO₄⁻ inhibition of dietary iodide uptake into the thyroid, the model underpredicted both the rapid decrease in serum TT₄ concentrations and the rise in serum TSH concentrations. Conclusions Assuming only competitive inhibition of thyroidal uptake of dietary iodide, BBDR-HPT/ClO₄⁻ model calculations were inconsistent with the rapid decrease in serum TT₄ and the corresponding increase in serum TSH. Availability of bound iodide in the thyroid gland governed the rate of hormone secretion from the thyroid. ClO₄⁻ is translocated into the thyroid gland, where it may act directly or indirectly on thyroid hormone synthesis/secretion in the rat. The rate of decline in serum TT₄ in these studies after 1 day of treatment with ClO₄⁻ appeared consistent with a reduction in thyroid hormone production/secretion. This research demonstrates the utility of a biologically based model to evaluate a proposed mode of action for ClO₄⁻ in a complex biological process.