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 toxicit y of 1-methyl-3-propylimidazole-2-thione (PTI) when administered to Cr l:CD BR rats. PTI is a chemical catalyst and is structurally similar t o the thioureas, which are known to adversely affect the thyroid. Ther efore, this study was designed to investigate the effects of PTI on th e thyroid. Male and female rats were dosed with 0, 5, 10, 25, or 75 mg PTI/kg/day for 13 weeks. Clinical pathology examinations and patholog y examination were performed and the following were measured periodica lly: serum T-3, T-4, and TSH, hepatic UDP- glucuronyltransferase activ ity, and cell proliferation of the thyroid and liver. Under the condit ions of this study, the overall no-observed-adverse-effect level (NOAE L) 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 i n 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 horm ones (Tg, T-4, and TSH) occurred predominantly at 25 and 75 mg/kg/day. Toxicologically significant alterations in T-3, T-4, and TSH levels, cell proliferation, and UDP-glucuronyltransferase activity occurred in rats dosed with 25 and 75 mg/kg/day, which correlated with organ weig ht and histopathological effects. Additionally, the effect of PTI on t hyroid peroxidase activity, a key step in thyroid hormone synthesis, w as evaluated in vitro using microswine thyroid microsomes. PTI was sho wn to inhibit thyroid peroxidase, with an IC50 of 0.02 M. These data s uggest that PTI enhances the excretion of T-4 via induction of glucuro nyltransferase and inhibits thyroid hormone synthesis via a direct aff ect on thyroid peroxidase. Both of these effects contribute to the dis ruption of the hypothalamic-pituitary-thyroid axis and result in susta ined elevation of TSH and the corresponding thyroid hypertrophy and hy perplasia. (C) 1995 Society of Toxicology