Subchronic toxicity study in rats with 1-methyl-3-propylimidazole-2-thione (PTI): effects on the thyroid.
A 90-day gavage study was performed to evaluate the subchronic toxicity of 1-methyl-3-propylimidazole-2-thione (PTI) when administered to Crl:CD BR rats. PTI is a chemical catalyst and is structurally similar to the thioureas, which are known to adversely affect the thyroid. Therefore, this study was designed to investigate the effects of PTI on the thyroid. Male and female rats were dosed with 0, 5, 10, 25, or 75 mgPTI/kg/day for 13 weeks. Clinical pathology examinations and pathology examination were performed and the following were measured periodically: serum T3, T4, and TSH, hepatic UDP-glucuronyltransferase activity, and cell proliferation of the thyroid and liver. Under the conditions of this study, the overall no-observed-adverse-effect level (NOAEL) for the subchronic effects of PTI in male and female rats was 10 mg PTI/kg/day. The NOAEL was based on the effects on the thyroid gland in male and female rats dosed with 25 and 75 mg PTI/kg/day, as well as the hepatic centrilobular fatty change, increased severity of chronic progressive nephropathy, fatty change in the adrenal medulla, and the substantial reduction in body weight and body weight gain. The primary target organs were the thyroid and liver. Alterations in thyroid hormones (T3, T4, and TSH) occurred predominantly at 25 and 75 mg/kg/day. Toxicologically significant alterations in T3, T4, and TSH levels, cell proliferation, and UDP-glucuronyltransferase activity occurred in rats dosed with 25 and 75 mg/kg/day, which correlated with organ weight and histopathological effects. Additionally, the effect of PTI on thyroid peroxidase activity, a key step in thyroid hormone synthesis, was evaluated in vitro using microswine thyroid microsomes. PTI was shown to inhibit thyroid peroxidase, with an IC50 of 0.02 M. These data suggest that PTI enhances the excretion of T4 via induction of glucuronyltransferase and inhibits thyroid hormone synthesis via a direct affect on thyroid peroxidase. Both of these effects contribute to the disruption of the hypothalamic-pituitary-thyroid axis and result in sustained elevation of TSH and the corresponding thyroid hypertrophy and hyperplasia.
E.I. du Pont de Nemours and Company, Haskell Laboratory for Toxicology and Industrial Medicine, Newark, Delaware 19714, USA.
L B
LB
Biegel
J C
JC
Cook
J C
JC
O'Connor
M
M
Aschiero
A J
AJ
Arduengo
T W
TW
Slone
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism; D066298:In Vitro Techniques; D007441:Intubation, Gastrointestinal; D007453:Iodide Peroxidase / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008297:Male; D008713:Methimazole / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D013552:Swine; D013556:Swine, Miniature; D013959:Thyroid Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D013961:Thyroid Gland / Q000201:enzymology / Q000473:pathology; D013963:Thyroid Hormones / Q000097:blood
D013963:Thyroid Hormones; C097373:1-methyl-3-propylimidazole-2-thione; D008713:Methimazole; D007453:Iodide Peroxidase; D014453:Glucuronosyltransferase