title: 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.
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR 72079, USA. jeffrey.fisher@fda.hhs.gov
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Fisher
authors.forename: Annie
authors.initials: A
authors.lastname: Lumen
authors.forename: John
authors.initials: J
authors.lastname: Latendresse
authors.forename: David
authors.initials: D
authors.lastname: Mattie
mesh_terms: D000818:Animals; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects*; D007454:Iodides / Q000493:pharmacokinetics; D010472:Perchlorates / Q000633:toxicity*; D010902:Pituitary Gland / Q000187:drug effects*; D051381:Rats; D012377:Rodentia; D013961:Thyroid Gland / Q000187:drug effects*; D018675:Toxicity Tests
chemical_list: D007454:Iodides; D010472:Perchlorates; C494474:perchlorate