The pharmacokinetics of perchlorate and its effect on the hypothalamus-pituitary-thyroid axis in the male rat.
Perchlorate, an environmental contaminant, is known to disturb the hypothalamus-pituitary-thyroid (HPT) axis by blocking iodide accumulation in the thyroid. Iodide deficiency can lead to hypothyroidism and goiter in rats. The objective of the study was to characterize the pharmacokinetics of perchlorate in male Sprague-Dawley rats relative to inhibition of thyroidal radiolabeled iodide uptake and onset of up-regulation of the HPT axis. Radiolabeled perchlorate (3.3 mg/kg (36)ClO(-)(4)) was excreted in urine (99.5% over a 48-h period). (36)ClO(-)(4) is rapidly distributed into tissues with preferential sequestration into skin, gastrointestinal tract (GT), and thyroid. Calculated half-lives of (36)ClO(-)(4) from the skin, thyroid, plasma, GT, and GT contents were 32.0, 7.6, 7.3, 10.0, and 8.6 h, respectively. Perchlorate was very effective at inhibiting thyroidal uptake of radiolabeled iodide ((125)I(-)). In animals iv dosed with perchlorate followed by an iv challenge of (125)I(-), thyroidal (125)I(-) uptake was diminished by 11, 29, 55, and 82% at 11 h postdosing in the 0.01, 0.1, 1.0, and 3.0 mg/kg perchlorate dose groups, respectively. In perchlorate drinking water studies, dose-dependent inhibition in thyroidal uptake of (125)I(-) initially occurred with corresponding increases in serum thyroid-stimulating hormone (TSH) levels and decreases in thyroid hormone levels. TSH stimulated recovery from the initial perchlorate blocking effects was evident during 14 days of treatment in the 1.0 and 3.0 mg/kg per day treatment groups. However, recovery of serum thyroid hormones at these doses was much slower despite evidence for iodide sufficiency in the thyroid. These results suggest that the typical homeostatic mechanisms of the thyroid may respond differently at high doses of perchlorate used in this rat study (above 1 mg/kg per day) or perchlorate may be acting on the HPT axis by mechanisms other than thyroidal (125)I(-) uptake inhibition.
Yu
Kyung O
KO
AFRL/HEST, Operational Toxicology Branch, Air Force Research Laboratory, Wright-Patterson AFB, Ohio 45433-7400, USA. kyung.yu@wpafb.af.mil
Narayanan
Latha
L
Mattie
David R
DR
Godfrey
Richard J
RJ
Todd
Paula N
PN
Sterner
Teresa R
TR
Mahle
Deirdre A
DA
Lumpkin
Michael H
MH
Fisher
Jeffrey W
JW
D000818:Animals; D002469:Cell Separation; D005260:Female; D005456:Fluorescent Dyes; D017629:Gap Junctions / Q000187:drug effects; D001556:Hexachlorocyclohexane / Q000494:pharmacology*; D007306:Insecticides / Q000494:pharmacology*; D007546:Isoquinolines; D008297:Male; D009215:Myometrium / Q000187:drug effects; D010740:Phospholipases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014590:Uterine Contraction / Q000187:drug effects*
D005456:Fluorescent Dyes; D007306:Insecticides; D007546:Isoquinolines; D001556:Hexachlorocyclohexane; C017475:lucifer yellow; D010740:Phospholipases