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Eva D. McLanahan,^1,* Melvin E. Andersen,² Jerry L. Campbell Jr.,^1,** and Jeffrey W. Fisher¹

¹University of Georgia, Department of Environmental Health Sciences, Athens, Georgia, USA; ²Hamner Institutes for Health Sciences, Division of Computational Biology, Research Triangle Park, North Carolina, USA

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.

Key words: BBDR model, HPT axis, iodide, mode of action, PBPK model, perchlorate, rat, sodium/iodide symporter, thyroid, thyroid hormone secretion. Environ Health Perspect 117:731–738 (2009) . doi:10.1289/ehp.0800111 available via http://dx.doi.org/ [Online 5 January 2009]

Address correspondence to J.W. Fisher, 206 Environmental Health Sciences Department, University of Georgia, Athens, GA 30602-2102 USA. Telephone: (706) 542-1001. Fax: (706) 542-7472. E-mail: jwfisher@uga.edu

Supplemental Material is available online at http://www.ehponline.org/members/2009/0800111/suppl.pdf

*Current address: U.S. Environmental Protection Agency, Office of Research and Development, National Center for Environmental Assessment, Research Triangle Park, North Carolina.

**Current address: Hamner Institutes for Health Sciences, Division of Computational Biology, Research Triangle Park, North Carolina.

Funding was provided by a U.S. Environmental Protection Agency (EPA) Science to Achieve Results (STAR) research grant (RD83213401-0) and a U.S. EPA STAR fellowship (FP-91679301-0 to E.D.M.) . Views expressed in this article are those of the authors and do not represent official opinions of the U.S. EPA.

The authors declare they have no competing financial interests.

Received 19 August 2008 ; accepted 5 January 2009.