Predicting Fetal Perchlorate Dose and Inhibition of Iodide Kinetics during Gestation: A Physiologically-Based Pharmacokinetic Analysis of Perchlorate and Iodide Kinetics in the Rat

Abstract

Perchlorate (ClO4-) disrupts endocrine homeostasis by competitively inhibiting the transport of iodide (I-) into the thyroid. The potential for health effects from human exposure to ClO4- in drinking water is not known, but experimental animal studies are suggestive of developmental effects from ClO4- induced iodide deficiency during gestation. Normal hormone-dependent development relies, in part, on synthesis of hormones in the fetal thyroid from maternally supplied iodide. Although ClO4- crosses the placenta, the extent of inhibition in the fetal thyroid is unknown. A physiologically-based pharmacokinetic (PBPK) model was developed to simulate ClO4- exposure and the resulting effect on iodide kinetics in rat gestation. Similar to concurrent model development for the adult male rat, this model includes compartments for thyroid, stomach, skin, kidney, liver, and plasma in both mother and fetus, with additional compartments for the maternal mammary gland, fat, and placenta. Tissues with active uptake are described with multiple compartments and Michaelis-Menten (M-M) kinetics. Physiological and kinetic parameters were obtained from literature and experiment. Systemic clearance, placental-fetal transport, and M-M uptake parameters were estimated by fitting model simulations to experimental data. The PBPK model is able to reproduce maternal and fetal iodide data over five orders of magnitude (0.36 to 33,000 ng/kg 131I-), ClO4- distribution over three orders of magnitude (0.01 to 10 mg/kg-day ClO4-) and inhibition of maternal thyroid and total fetal I- uptake. The model suggests a significant fetal ClO4- dose in late gestation (up to 82% of maternal dose). A comparison of model-predicted internal dosimetrics in the adult male, pregnant, and fetal rat indicates that the fetal thyroid is more sensitive to inhibition than that of the adult.

Physiologically Based Pharmacokinetic/Toxicokinetic Modeling

“…There are also a large number of good examples of PBPK models which describe the kinetics of important environmental contaminants, including methylene chloride (8,44,45), trichloroethylene (46)(47)(48), chloroform (49, 50), 2-butoxyethanol (51), kepone (52), polybrominated biphenyls (53), polychlorinated biphenyls (54) and dibenzofurans (55), dioxins (56,57), lead (58)(59)(60)(61)(62), arsenic (63,64), methylmercury (65), atrazine (66,67), acrylonitrile (68)(69)(70), perchlorate (71)(72)(73)(74)(75)(76), and BTEX components (77)(78)(79)(80)(81). The U.S. EPA is currently compiling a compendium of PBPK models including source code.…”

Review on Fate, Toxicity, and Remediation of Perchlorate

“…In a rat study, the model simulations predicted a significant transfer of perchlorate through milk after maternal exposure (Clewell et al, 2003a;2003b). When daily maternal doses of perchlorate (0.1-10.0 mg) were administered to rats, 50%-60% of perchlorate transfer through milk was observed (Clewell et al, 2003a).…”

Iodine supplementation and drinking-water perchlorate mitigation

“…The Lumen et al model represents a synthesis of several earlier models developed to estimate perchlorate and iodide metabolism (Clewell et al, 2003a(Clewell et al, , 2003b(Clewell et al, , 2007Merrill et al, 2005). As reported by the authors, the purpose of the PBPK model is to evaluate the interactions of dietary iodide and perchlorate exposure on the hypothalamic pituitary thyroid (HPT) axis in the pregnant woman and fetus.…”