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ToxSci Advance Access published online on April 15, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg081
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received November 20, 2002; accepted March 3, 2003
© 2003 Society of Toxicology

Biotransformation and Toxicokinetics

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

Rebecca A. Clewell 1*, Elaine A. Merrill 2, Kyung O. Yu 3, Deirdre A. Mahle 4, Teresa R. Sterner 2, David R. Mattie 3, Peter J. Robinson 4, Jeffrey W. Fisher 3, Jeffery M. Gearhart 4

1 Geo-Centers, Inc., Wright-Patterson AFB, OH 45433
2 Operational Technologies Corp., Dayton, OH 45432
3 AFRL/HEST, Wright-Patterson AFB, OH 45433
4 Mantech Environmental Technology, Inc., Dayton, OH 45437

* To whom correspondence should be addressed. E-mail: rebecca.clewell{at}wpafb.af.mil.


  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 indicate the fetal thyroid is more sensitive to inhibition than the adult.

PBPK model, pregnancy, perchlorate, iodide, thyroid, inhibition, fetal dose .


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