Predicting Neonatal Perchlorate Dose and Inhibition of Iodide Uptake in the Rat during Lactation Using Physiologically-Based Pharmacokinetic Modeling

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Abstract
Perchlorate (ClO4−), a contaminant in drinking water, competitively inhibits active uptake of iodide (I−) into various tissues, including mammary tissue. During postnatal development, inhibition of I− uptake in the mammary gland and neonatal thyroid and the active concentration ClO4− in milk indicate a potentially increased susceptibility of neonates to endocrine disruption. A physiologically based pharmacokinetic (PBPK) model was developed to reproduce measured ClO4− distribution in the lactating and neonatal rat and predict resulting effects on I− kinetics from competitive inhibition at the sodium iodide symporter (NIS). Kinetic I− and ClO4− behavior in tissues with NIS (thyroid, stomach, mammary gland, and skin) was simulated with multiple subcompartments, Michaelis-Menten (M-M) kinetics and competitive inhibition. Physiological and kinetic parameters were obtained from literature and experiment. Systemic clearance and M-M parameters were estimated by fitting simulations to tissue and serum data. The model successfully describes maternal and neonatal thyroid, stomach, skin, and plasma, as well as maternal mammary gland and milk data after ClO4− exposure (from 0.01 to 10 mg/kg-day ClO4−) and acute radioiodide (2.1 to 33,000 ng/kg I−) dosing. The model also predicts I− uptake inhibition in the maternal thyroid, mammary gland, and milk. Model simulations predict a significant transfer of ClO4− through milk after maternal exposure; approximately 50% to 6% of the daily maternal dose at doses ranging from 0.01 to 10.0 mg ClO4−/kg-day, respectively. Comparison of predicted dosimetrics across life-stages in the rat indicates that neonatal thyroid I− uptake inhibition is similar to the adult and approximately tenfold less than the fetus.

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