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ToxSci Advance Access published online on April 15, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg080
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received November 19, 2002; accepted March 3, 2003
© 2003 Society of Toxicology

Biotransformation and Toxicokinetics

PBPK Predictions of Perchlorate Distribution and Its Effect on Thyroid Uptake of Radioiodide in the Male Rat

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

1 Operational Technologies Corp., Dayton, OH 45432
2 GeoCenters, Inc., Wright-Patterson AFB, OH 45433
3 ManTech Environmental Technology, Inc., Dayton, OH 45437
4 AFRL/HEST, Operational Toxicology Branch, Wright-Patterson AFB, OH 45433

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


  Abstract

Due to perchlorate's (ClO4-) ability to competitively inhibit thyroid iodide (I-) uptake through the sodium-iodide symporter (NIS), potential human health risks exist from chronic exposure via drinking water. Such risks may include hypothyroidism, goiter and mental retardation (if exposure occurs during critical periods in neurodevelopment). To aid in predicting perchlorate's effect on normal I- kinetics, we developed a physiologically-based pharmacokinetic (PBPK) model for the adult male rat. The model structure describes simultaneous kinetics for both anions together with their interaction at the NIS, in particular the inhibition of I- uptake by ClO4-. Sub-compartments and Michaelis-Menten kinetics were used to describe active uptake of both anions in the thyroid, stomach and skin. Separate compartments for kidney, liver, plasma and fat were described by passive diffusion. The model successfully predicts both 36ClO4- and 125I- kinetics after iv doses of 3.3 mg/kg and 33µg/kg, respectively, as well as inhibition of thyroid 125I- uptake by ClO4- after iv doses of ClO4- (0.01 to 3.0 mg/kg). The model also predicts serum and thyroid ClO4- concentrations from 14 day drinking water exposures (0.01 to 30.0 mg ClO4-/kg-day) and compensation of perchlorate-induced inhibition of radioiodide uptake due to upregulation of the thyroid. The model can be used to extrapolate dose metrics and correlate observed effects in perchlorate toxicity studies to other species and life stages, such as rat gestation (Clewell et al, in press). Because the model successfully predicts perchlorate's interaction with iodide, it provides a sound basis for future incorporation of the complex hypothalamic-pituitary-thyroid feedback system.

perchlorate, radioiodide, thyroid, inhibition, sodium iodide symporter, PBPK, model .


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