To examine the mechanism and toxicological significance of thyroidal
tumor observed slightly in a long-term rat study with
diethofencarb (isopropyl 3,4-diethoxycarbanilate), male Sprague-Dawley rats were fed
diethofencarb in diets at concentrations of 0, 5,000 or 20,000 ppm for 3 months. Examinations mainly for thyroid functions including thyroid uptake of 125I, serum
thyroid hormone and
thyroid stimulating hormone (TSH) level, hepatic
UDP-
glucuronyltransferase (
UDP-GT) activity and histopathological examination in thyroid were performed at week 13. Decreases of
body weights and food consumptions were observed at and above 5,000 ppm. Under these conditions, decrease of serum free T4 and increase of serum TSH level were observed only at 20,000 ppm, concurrently with liver weight increase at and above 5,000 ppm and increase of hepatic
UDP-GT activity at 20,000 ppm. However, no compound related effects were noted in thyroid weight, thyroid uptake of 125I and gross or histopathological examination in thyroid. These results indicate that the administration of
diethofencarb leads to an increase in
UDP-GT activity and acceleration of
thyroid hormone excretion from the liver. The acceleration causes a decrease in serum free T4 level, triggering the feedback mechanism of the pituitary gland, promotion of TSH release and consequently an increase in serum TSH level. Thus, the slightly higher incidence of thyroid follicular cell
tumors observed in the chronic and oncogenicity study with non-genotoxic
diethofencarb is considered to be caused by these weak pituitary-thyroid hormonal imbalances. The toxicological significance in humans is extremely low according to the well established facts that the chronic TSH stimulating would not induce thyroid
tumors in humans and humans may be less sensitive than rats in regard to the response to goitrogenic stimuli.