title: Interspecies differences in susceptibility to perturbation of thyroid homeostasis: a case study with perchlorate.
abstract: Despite many physiological similarities, humans and rats exhibit notably different susceptibilities to thyroid perturbation. Considerable research has recently been conducted on the thyroid-active chemical perchlorate, a chemical of emerging environmental and regulatory interest. While the data indicate humans and rats exhibit similar dose-response relationships in terms of acute inhibition of thyroidal iodide uptake, the two species appear to exhibit notable differences in terms of thyroid hormone response, the toxicologically significant consequence of iodide uptake inhibition. We analyzed dose-response data for changes in serum T(3), T(4), and TSH levels from studies in humans, rats, mice, and rabbits. We found that thyroid homeostasis in the rat appears to be strikingly more sensitive to perchlorate than any of the other species. Rats exhibited an increase in serum TSH at 0.1mg/kg-day whereas other species remained unresponsive even at doses of 10mg/kg-day. Less pronounced but consistent effects were seen with serum T(3) and T(4). These cross-species comparisons provide strong evidence that data obtained from rat studies should be critically evaluated for their relevance to humans. If rat data are used to develop toxicity criteria for perchlorate, we propose that this is an instance where an inter-species uncertainty factor less than one is supportable. DISCLOSURE STATEMENT: One of the authors (BDB) has been hired by Lockheed Martin Corporation as an expert in litigation involving perchlorate. A portion of the initial research presented in this paper was conducted in conjunction with her role in that matter.
authors.affiliation: Gradient Corporation, 600 Stewart St., Suite 803, Seattle, WA 98101, USA. tlewandowski@gradientcorp.com
authors.forename: T A
authors.initials: TA
authors.lastname: Lewandowski
authors.forename: M R
authors.initials: MR
authors.lastname: Seeley
authors.forename: B D
authors.initials: BD
authors.lastname: Beck
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007454:Iodides / Q000378:metabolism; D023421:Models, Animal; D010472:Perchlorates / Q000494:pharmacology* / Q000592:standards / Q000633:toxicity; D051381:Rats; D018570:Risk Assessment; D017670:Sodium Compounds / Q000494:pharmacology* / Q000592:standards / Q000633:toxicity; D013045:Species Specificity; D027981:Symporters / Q000378:metabolism; D013961:Thyroid Gland / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D013972:Thyrotropin / Q000097:blood / Q000378:metabolism; D013974:Thyroxine / Q000097:blood / Q000378:metabolism; D023382:Toxicity Tests, Acute; D014284:Triiodothyronine / Q000097:blood / Q000378:metabolism; D035501:Uncertainty; D000099209:Sodium-Iodide Symporters
chemical_list: D007454:Iodides; D010472:Perchlorates; D017670:Sodium Compounds; D027981:Symporters; D013972:Thyrotropin; D013974:Thyroxine; D014284:Triiodothyronine; D000099209:Sodium-Iodide Symporters; C031068:sodium perchlorate