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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, T(4) and T(3). The submodels are linked together via key biological processes, including (1) the influence of T(4) on TSH production (the HPT axis negative feedback loop), (2) stimulation of thyroidal T(4) and T(3) 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, T(4), T(3), and TSH for the euthyroid rat whose dietary intake of iodide was 20 mug/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 T(4), TSH, and thyroid iodide stores for low-iodide diets of 0.33-1.14 mug/day. Model predictions of serum T(3) 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 T(4) and TSH when dietary iodide intake becomes insufficient (less than 2 mug/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, T(4), and T(3).

A panel of experts in physiologically based pharmacokinetic (PBPK) modeling and relevant quantitative methods was convened to describe and discuss model evaluation criteria, issues, and choices that arise in model application and computational tools for improving model quality for use in human health risk assessments (HHRAs). Although publication of a PBPK model in a peer-reviewed journal is a mark of good science, subsequent evaluation of published models and the supporting computer code is necessary for their consideration for use in HHRAs. Standardized model evaluation criteria and a thorough and efficient review process can reduce the number of review and revision iterations and hence the time needed to prepare a model for application. Efficient and consistent review also allows for rapid identification of needed model modifications to address HHRA-specific issues. This manuscript reports on the workshop where a process and criteria that were created for PBPK model review were discussed along with other issues related to model review and application in HHRA. Other issues include (1) model code availability, portability, and validity; (2) probabilistic (e.g., population-based) PBPK models and critical choices in parameter values to fully characterize population variability; and (3) approaches to integrating PBPK model outputs with other HHRA tools, including benchmark dose modeling. Two specific case study examples are provided to illustrate challenges that were encountered during the review and application process. By considering the frequent challenges encountered in the review and application of PBPK models during the model development phase, scientists may be better able to prepare their models for use in HHRAs.

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.

The objective of this research was to characterize the disturbances in the hypothalamic-pituitary-thyroid (HPT) axis resulting from exposure to a binary mixture, 3,3',4,4',5-pentachlorobiphenyl (PCB126) and perchlorate (ClO(4)(-)), known to cause hypothyroidism by different modes of action. Two studies were conducted to determine the HPT axis effects of ClO(4)(-) on adult male Sprague-Dawley rats pretreated with PCB126. In dosing study I, rats were administered a single oral dose of PCB126 (0, 7.5, or 75 microg/kg) on day 0 and 9 days later ClO(4)(-) (0, 0.01, 0.1, or 1 mg/kg day) was added to the drinking water until euthanasia on day 22. Significant dose-dependent trends were found for all thyroid function indices measured following ClO(4)(-) in drinking water for 14 days. Seventy-five micrograms PCB126/kg resulted in a significant increase in hepatic T(4)-glucuronide formation, causing a decline in serum thyroxine and fT(4), and resulting in increased serum thyroid-stimulating hormone (TSH). Serum TSH was also increased in animals that received 7.5 microg PCB126/kg; no other HPT axis alterations were found in these animals. When pretreated with PCB126, the ClO(4)(-) dose trends disappeared, suggesting a less than additive effect on the HPT axis. In dosing study II, animals were given lower doses of PCB126 (0, 0.075, 0.75, or 7.5 microg/kg) on day 0, and followed with ClO(4)(-) (0 or 0.01 mg/kg day) in drinking water beginning on day 1 and continuing for several days to explore transient HPT axis effects. No statistical effects were seen for PCB126 or ClO(4)(-) alone, and no perturbations were found when administered sequentially in dosing study II. In conclusion, these studies demonstrate that HPT axis disturbances following exposure to ClO(4)(-) are less than additive when pretreated with relatively high doses of PCB126. At relatively low doses, at or near the no-observed-effect-level for PCB126 and ClO(4)(-), no interactions between the chemicals occur.