ToxSci Advance Access published online on October 27, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfi017
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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1 Geo-Centers, Inc., Wright-Patterson AFB, OH 45433
* To whom correspondence should be addressed. Detection of perchlorate (ClO4-) in several drinking water sources across the U.S. has lead to public concern over health effects from chronic low-level exposures (U.S. EPA, 2003). 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 ClO4- in healthy adult humans and simulates the subsequent inhibition of thyroid uptake of radioactive I- by ClO4-. The model successfully predicts the measured levels of serum and urinary ClO4- from drinking water exposures, ranging from 0.007 to 12 mg ClO4-/kg/day, 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 (Merrill et al., 2003; Clewell et al., 2003a, b), can be used to estimate parameters in a pregnant or lactating human, that haven't been or cannot be easily measured 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 (Clewell et al., 2001). 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.
Accepted September 17, 2004
Biotransformation and Toxicokinetics
PBPK Model for Radioactive Iodide and Perchlorate Kinetics and Perchlorate-Induced Inhibition of Iodide Uptake in Humans
2 ManTech Environmental Technology, Inc., Dayton, OH 45437
3 National Center for Environmental Assessment (NCEA), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
4 Operational Technologies Corp., Dayton, OH 45432
5 AFRL/HEST, Wright-Patterson AFB, OH 45433
Elaine A. Merrill, E-mail: Elaine.Merrill{at}wpafb.af.mil
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