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

Abstract

BackgroundPerchlorate (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.ObjectiveWe 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−.MethodsWe 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.ResultsThe 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.ConclusionsAssuming 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.

Physiologically Based Pharmacokinetic/Toxicokinetic Modeling

“…There are also a large number of good examples of PBPK models which describe the kinetics of important environmental contaminants, including methylene chloride (8,44,45), trichloroethylene (46)(47)(48), chloroform (49, 50), 2-butoxyethanol (51), kepone (52), polybrominated biphenyls (53), polychlorinated biphenyls (54) and dibenzofurans (55), dioxins (56,57), lead (58)(59)(60)(61)(62), arsenic (63,64), methylmercury (65), atrazine (66,67), acrylonitrile (68)(69)(70), perchlorate (71)(72)(73)(74)(75)(76), and BTEX components (77)(78)(79)(80)(81). The U.S. EPA is currently compiling a compendium of PBPK models including source code.…”

Dose-Response Relationship Between Orally Administered Ammonium Perchlorate and Urine Perchlorate Concentrations in Rats: Possible Biomarker to Quantify Environmental Ammonium Perchlorate Exposure on Thyroid Homeostasis

“…In the past, serum thyroid-stimulating hormone (TSH) and thyroxine (T 4 ) were considered sensitive biomarkers of thyroidal effects induced by AP in light of the compensatory mechanism. [6][7][8] However, the thyroidal function Address correspondence to Hong Xia Chen, Institute of Biomedicine, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China. E-mail: hustchenhx@163.com Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/vaeh.…”

Review on Fate, Toxicity, and Remediation of Perchlorate

“…Perchlorate is known to disrupt the thyroid axis of many terrestrial and aquatic species (McLanahan et al, 2009). Thyroid follicle cell height increases as the mean water perchlorate concentration increases (Theodorakis et al, 2006).…”