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Health Implications of Perchlorate Ingestion (2005)

Chapter: Appendix D Sensitivity of Perchlorate-Induced Iodide Uptake Inhibition to Serum Iodide Concentrations

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Suggested Citation:"Appendix D Sensitivity of Perchlorate-Induced Iodide Uptake Inhibition to Serum Iodide Concentrations." National Research Council. 2005. Health Implications of Perchlorate Ingestion. Washington, DC: The National Academies Press. doi: 10.17226/11202.
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Page 216
Suggested Citation:"Appendix D Sensitivity of Perchlorate-Induced Iodide Uptake Inhibition to Serum Iodide Concentrations." National Research Council. 2005. Health Implications of Perchlorate Ingestion. Washington, DC: The National Academies Press. doi: 10.17226/11202.
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Page 217
Suggested Citation:"Appendix D Sensitivity of Perchlorate-Induced Iodide Uptake Inhibition to Serum Iodide Concentrations." National Research Council. 2005. Health Implications of Perchlorate Ingestion. Washington, DC: The National Academies Press. doi: 10.17226/11202.
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Page 218

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Appendix D Sensitivity of Perchlorate-Induced Iodide Uptake Inhibition to Serum Iodide Concentrations THE committee performed calculations on the effect of variations in basal serum iodide concentrations in humans on the perchlorate-induced inhibi- tion of the rate of sodium-iodide symporter (NIS)-mediated uptake of iodide by thyroid cells. The committee used the same Michaelis-Menten competi- tive inhibition equation and parameters for iodide uptake that were used in the human physiologically based pharmacokinetic models as follows: VmaxTFI * CTS I RupTFI = , CTS P K mTFI (1 + ) + CTS I K mTFP competitive inhibition with ClO4! where RupTFI = rate of uptake of iodide from thyroid stroma (capillary bed) to thyroid cells mediated by NIS (in nanograms per hour [ng/hr]), VmaxTFI = maximal velocity (capacity) for transport of iodide by NIS (1.31 × 106 ng/hr for 70-kg human), KmTFI = Michaelis constant (affinity) for iodide transport by NIS (4.0 × 106 nanograms per liter [ng/L]), 216

Appendix D 217 KmTFP = Michaelis constant (affinity) for perchlorate transport by NIS (1.8 × 105 ng/L), CTSI = concentration of iodide in thyroid stroma (capillary bed) (in ng/L, to simulate a range of steady-state con- centrations), CTSP = concentration of perchlorate in thyroid stroma (capil- lary bed) (in ng/L, to simulate a range of steady-state concentrations). The committee calculated the percent inhibition of the iodide uptake induced by perchlorate at various concentrations that span the range of values measured in humans, from a typical basal iodide concentration of 1.5 micrograms per deciliter (:g/dL) to 15 :g/dL. The calculations assume that steady-state thyroid stroma concentrations are the same as serum concentra- tions of perchlorate and iodide. Results are shown in Figure D-1. The overlapping curves in Figure D-1 show that variations in basal iodide concentrations have no effect on the competitive inhibition by perchlorate of the rate of iodide uptake by thyroid cells. Thus, one could conclude that serum iodide concentrations (assumed to be the same as thyroid stroma concentrations in these calculations) in humans ranging from 1.5 to 15 :g/dL would not alter the sensitivity of a study performed to evaluate the impact of perchlorate on the determination of iodide uptake by thyroid cells via the NIS. The committee also ran calculations of ever-increasing basal iodide concentrations to determine the concentrations that would have to be present before a decrease in sensitivity to perchlorate would be observed. These simulations are shown in Figure D-2. As shown in Figure D-2, a basal iodide concentration over 100 :g/dL would be needed to shift the dose-response curve for the effects of perchlor- ate on the inhibition of iodide uptake by thyroid cells; that is, concentrations would have to approach the Michaelis constant (affinity) for NIS transport of iodide. Such high concentrations do not seem plausible. Thus, the committee concludes that humans who have serum iodide concentrations of 0-100 :g/dL would be equally sensitive to perchlorate's effects on thyroid iodide uptake (all other things being equal).

218 Health Implications of Perchlorate Ingestion 100 90 Basal iodide % Inhibition of Iodide Uptake 80 concentration in 70 stroma: 60 1.5 ug/dL I- 50 3 ug/dL I- 40 6 ug/dL I- 30 12 ug/dL I- 20 15 ug/dL I- 10 0 0.01 0.1 1 10 100 1000 10000 Pe rchlorate in Thyroid Stroma (µg/dL) FIGURE D-1 Dose-dependent inhibition of iodide uptake by perchlorate over a range of basal iodide concentrations in thyroid stroma (1.5-15 :g/dL). Abbrevia- tions: I!, iodide; :g/dL, micrograms per deciliter. 100 Basal iodide 90 concentration in 80 stroma: % Inhibition of Iodide Uptake 70 1.5 ug/dL I- 60 3 ug/dL I- 6 ug/dL I- 50 12 ug/dL I- 40 15 ug/dL I- 30 100 ug/dL I- 20 1,000 ug/dL I- 10 10,000 ug/dL I- 0 0.01 0.1 1 10 100 1000 10000 Pe rchlorate in Thyroid Stroma (µg/dL) FIGURE D-2 Dose-dependent inhibition of iodide uptake by perchlorate over 105-fold range in basal iodide concentrations in thyroid stroma (1.5-10,000 :g/dL). Abbreviations: I-, iodide; :g/dL, micrograms per deciliter.

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Perchlorate—a powerful oxidant used in solid rocket fuels by the military and aerospace industry—has been detected in public drinking water supplies of over 11 million people at concentrations of at least 4 parts per billion (ppb). High doses of perchlorate can decrease thyroid hormone production by inhibiting the uptake of iodide by the thyroid. Thyroid hormones are critical for normal growth and development of the central nervous system of fetuses and infants. This report evaluates the potential health effects of perchlorate and the scientific underpinnings of the 2002 draft risk assessment issued by the U.S. Environmental Protection Agency (EPA).

The report finds that the body can compensate for iodide deficiency, and that iodide uptake would likely have to be reduced by at least 75% for months or longer for adverse health effects, such as hypothryroidism, to occur. The report recommends using clinical studies of iodide uptake in humans as the basis for determining a reference dose rather than using studies of adverse health effects in rats that serve as EPA’s basis. The report suggests that daily ingestion of 0.0007 milligrams of perchlorate per kilograms of body weight—an amount more than 20 times the reference dose proposed by EPA—should not threaten the health of even the most sensitive populations.

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