ToxSci Advance Access originally published online on January 3, 2008
Toxicological Sciences 2008 102(2):241-253; doi:10.1093/toxsci/kfm312
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A Biologically Based Dose-Response Model for Dietary Iodide and the Hypothalamic-Pituitary-Thyroid Axis in the Adult Rat: Evaluation of Iodide Deficiency
* University of Georgia, Interdisciplinary Toxicology Program, Athens, Georgia 30602
The Hamner Institutes for Health Sciences, Division of Computational Biology, Research Triangle Park, North Carolina 27709
1 To whom correspondence should be addressed at 206 Environmental Health Sciences Department, University of Georgia, Athens, GA 30602-2102. Fax: (706) 542-7472. E-mail: jwfisher{at}uga.edu.
Received October 2, 2007; revision received December 18, 2007; accepted December 24, 2007
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Abstract |
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A biologically based dose-response (BBDR) model was developed for dietary iodide and the hypothalamic-pituitary-thyroid (HPT) axis in adult rats. This BBDR-HPT axis model includes submodels for dietary iodide, thyroid-stimulating hormone (TSH), and the thyroid hormones, T4 and T3. The submodels are linked together via key biological processes, including (1) the influence of T4 on TSH production (the HPT axis negative feedback loop), (2) stimulation of thyroidal T4 and T3 production by TSH, (3) TSH upregulation of the thyroid sodium (Na+)/iodide symporter, and (4) recycling of iodide from metabolism of thyroid hormones. The BBDR-HPT axis model was calibrated to predict steady-state concentrations of iodide, T4, T3, and TSH for the euthyroid rat whose dietary intake of iodide was 20 µg/day. Then the BBDR-HPT axis model was used to predict perturbations in the HPT axis caused by insufficient dietary iodide intake, and simulation results were compared to experimental findings. The BBDR-HPT axis model was successful in simulating perturbations in serum T4, TSH, and thyroid iodide stores for low-iodide diets of 0.33–1.14 µg/day. Model predictions of serum T3 concentrations were inconsistent with observations in some cases. BBDR-HPT axis model simulations show a steep dose-response relationship between dietary intake of iodide and serum T4 and TSH when dietary iodide intake becomes insufficient (less than 2 µg/day) to sustain the HPT axis. This BBDR-HPT axis model can be linked with physiologically based pharmacokinetic models for thyroid-active chemicals to evaluate and predict dose-dependent HPT axis alterations based on hypothesized modes of action. To support continued development of this model, future studies should include time course data after perturbation of the HPT axis to capture changes in endogenous iodide, serum TSH, T4, and T3.
Key Words: iodide; BBDR model; HPT axis; thyroxine; TSH; pharmacokinetics.