Induction of thyroid lesions in 14-week toxicity studies of 2 and 4-methylimidazole in Fischer 344/N rats and B6C3F1 mice

Fifteen-day and 14-week studies of 2-methylimidazole (2MI) and 4-methylimidazole (4MI) were conducted because of widespread human exposure via ingestion of food products containing the compounds and lack of toxicity data. Groups of five male and five female Fischer rats and B6C3F1 mice were administered 2MI by dosed feed at 0, 1,200, 3,300, or 10,000 ppm or 4MI at 0, 300, 800, or 2,500 ppm for 15 days, and groups of 10 male and 10 female Fischer rats and B6C3F1 mice were administered 2MI or 4MI at 0, 625, 1,250, 2,500, 5,000 or 10,000 ppm for 14 weeks. In the 15-day studies, 2MI induced thyroid follicular-cell hyperplasia and pituitary pars-distalis hypertrophy in rats and thyroid follicular-cell hypertrophy and spleen hematopoietic-cell proliferation in mice; 4MI induced no histopathological changes in rats and mice. In the 14-week studies, 2MI increased concentrations of thyroid-stimulating hormone (TSH) and decreased those of thyroxine (T4) and triiodothyroxine (T3) in male and female rats according to the dosage. Incidences of diffuse follicular-cell hyperplasia of the thyroid gland increased significantly in male rats exposed to 1,250 ppm or greater and female rats exposed to 2,500 ppm or greater. Thyroid follicular-cell adenoma was diagnosed in two males in the 10,000-ppm group. A dose-related anemia occurred in female rats. In mice, follicular-cell hypertrophy of the thyroid gland, anemia, splenic hematopoietic-cell proliferation, and hemosiderin in kidney tubules appeared. In rats, 4MI induced tremors and ataxia in the high-dose groups. Serum T3, T4, and TSH levels were not altered, and no thyroid lesions occurred. Anemia, hepatocytic vacuolation, testicular degeneration, and prostatic atrophy were observed. In mice, anemia, liver cytoplasmic vacuolization, and renal degeneration and dilation occurred. Our studies demonstrated that, in rats and mice, 2MI induces thyroid hyperplasia and hypertrophy, and both 2MI and 4MI induce anemia; 2MI induces thyroid follicular-cell adenoma in male rats.