Extrapolation of Hypothalamic-Pituitary-Thyroid Axis Perturbations and Associated Toxicity in Rodents to Humans: Case Study with Perchlorate

Abstract

Functional aspects of the Hypothalamic-Pituitary-Thyroid (HPT) axis in rats and humans are compared, exposing why extrapolation of toxicant-induced perturbations in the rat HPT axis to the human HPT axis cannot be accomplished using default risk assessment methodology. Computational tools, such as biologically based dose response models for the HPT axis, are recommended to perform complex animal to human extrapolations involving the HPT axis. Experimental and computational evidence are presented that suggest perchlorate acts directly on the thyroid gland in rats. The apparent escape from perchlorate-induced inhibition of thyroidal uptake of radioactive iodide in humans is discussed along with “rebound” or increased thyroidal uptake of radioactive iodide observed after discontinued clinical treatment with perchlorate.

Keywords:

• thyroid gland
• rat
• human
• perchlorate
• BBDR models
• HPT axis

Acknowledgements

We thank Drs. Fred Beland and Luisa Camacho for their editorial review and suggestions to improve this manuscript. Funding for A. Lumen was provided by the USAF (AFCEE and 711 HPW/RHDJ) through a cooperative agreement with the Henry M. Jackson Foundation for the Advancement of Military Medicine at Wright-Patterson AFB, OH.

The views of the authors do not necessarily reflect those of the US FDA or USAF.