ToxSci Advance Access originally published online on October 27, 2004
Toxicological Sciences 2005 83(1):25-43; doi:10.1093/toxsci/kfi017
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Toxicological Sciences vol. 83 no. 1 © Society of Toxicology 2005; all rights reserved.
PBPK Model for Radioactive Iodide and Perchlorate Kinetics and Perchlorate-Induced Inhibition of Iodide Uptake in Humans
* Geo-Centers, Inc., Wright-Patterson AFB, Ohio 45433; ManTech Environmental Technology, Inc., Dayton, OH 45437; National Center for Environmental Assessment (NCEA), U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711; Operational Technologies Corp., Dayton, Ohio 45432; and ¶ AFRL/HEST, Wright-Patterson AFB, Ohio 45433
Received April 29, 2004; accepted September 17, 2004
Detection of perchlorate (
) in several drinking water sources across the U.S. has lead to public concern over health effects from chronic low-level exposures. Perchlorate inhibits thyroid iodide (I–) uptake at the sodium (Na+)-iodide (I–) symporter (NIS), thereby disrupting the initial stage of thyroid hormone synthesis. A physiologically based pharmacokinetic (PBPK) model was developed to describe the kinetics and distribution of both radioactive I– and cold in healthy adult humans and simulates the subsequent inhibition of thyroid uptake of radioactive I– by . The model successfully predicts the measured levels of serum and urinary from drinking water exposures, ranging from 0.007 to 12 mg 
, as well as the subsequent inhibition of thyroid 131I– uptake. Thyroid iodine, as well as total, free, and protein-bound radioactive I– in serum from various tracer studies, are also successfully simulated. This model's parameters, in conjunction with corresponding model parameters established for the male, gestational, and lactating rat, can be used to estimate parameters in a pregnant or lactating human, that have not been or cannot be easily measured to extrapolate dose metrics and correlate observed effects in perchlorate toxicity studies to other human life stages. For example, by applying the adult male rat:adult human ratios of model parameters to those parameters established for the gestational and lactating rat, we can derive a reasonable estimate of corresponding parameters for a gestating or lactating human female. Although thyroid hormones and their regulatory feedback are not incorporated in the model structure, the model's successful prediction of free and bound radioactive I– and perchlorate's interaction with free radioactive I– provide a basis for extending the structure to address the complex hypothalamic-pituitary-thyroid feedback system. In this paper, bound radioactive I– refers to I– incorporated into thyroid hormones or iodinated proteins, which may or may not be bound to plasma proteins.
Key Words: pharmacokinetics; human; perchlorate; radioactive iodide; inhibition; thyroid.
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