Perchlorate and Radioiodide Kinetics Across Life Stages in the Human: Using PBPK Models to Predict Dosimetry and Thyroid Inhibition and Sensitive Subpopulations Based on Developmental Stage

Abstract

Perchlorate (ClO₄ ⁻ ) is a drinking-water contaminant, known to disrupt thyroid hormone homeostasis in rats. This effect has only been seen in humans at high doses, yet the potential for long term effects from developmental endocrine disruption emphasizes the need for improved understanding of perchlorate’s effect during the perinatal period. Physiologically based pharmacokinetic/dynamic (PBPK/PD) models for ClO₄ ⁻ and its effect on thyroid iodide uptake were constructed for human gestation and lactation data. Chemical specific parameters were estimated from life-stage and species-specific relationships established in previously published models for various life-stages in the rat and nonpregnant adult human. With the appropriate physiological descriptions, these kinetic models successfully simulate radioiodide data culled from the literature for gestation and lactation, as well as ClO₄ ⁻ data from populations exposed to contaminated drinking water. These models provide a framework for extrapolating from chemical exposure in laboratory animals to human response, and support a more quantitative understanding of life-stage-specific susceptibility to ClO₄ ⁻. The pregnant and lactating woman, fetus, and nursing infant were predicted to have higher blood ClO₄ ⁻ concentrations and greater thyroid iodide uptake inhibition at a given drinking-water concentration than either the nonpregnant adult or the older child. The fetus is predicted to receive the greatest dose (per kilogram body weight) due to several factors, including placental sodium-iodide symporter (NIS) activity and reduced maternal urinary clearance of ClO₄ ⁻. The predicted extent of iodide inhibition in the most sensitive population (fetus) is not significant (∼1%) at the U.S. Environmental Protection Agency reference dose (0.0007 mg/kg-d).

The authors thank Annie Jarabek, Tammy Covington, and Dr. Jeff Fisher for their advice and support of the modeling effort, and Lt. Col. Dan Rogers, Dr. Kyung Yu, Dr. Darol Dodd, and the U.S. Air Force for their support of this project. We are also indebted to Dr. John Gibbs for providing the Chilean data and Latha Narayanan for perchlorate analysis.