STUDIES ON THE MECHANISM OF THE CARCINOGENIC ACTIVITY OF AMITROLE

Amitrole, a widely used herbicide found to produce thyroid and liver t umors in rodents and classified as possibly carcinogenic to humans, wa s investigated to acquire further information about its mechanism of a ction. A 20-hr exposure to amitrole concentrations ranging from 5.6 to 18 mM did not induce DNA fragmentation, as measured by the alkaline e lution technique, in primary cultures of human thyroid follicular cell s and of human liver cells. Under the same experimental conditions a m inimal frequency of DNA breaks was detected in primary cultures of fat hepatocytes, but this event was presumably the unspecific consequence of a cytotoxic effect. In rats given amitrole with drinking water for 12 successive days at a daily dose of approximately 200 mg/kg, plasma levels of triiodothyronine and thyroxine displayed a progressive redu ction, and a concurrent increase of both the mitotic index and frequen cy of S-phase cells revealing a clear-cut follicular cell hyperplasia was observed. In a group of these rats euthanized after 8 days of trea tment any evidence of DNA fragmentation was absent in both thyroid and liver cells. Taken as a whole these results provide further evidence that the mechanism of amitrole carcinogenic activity is most likely no ngenotoxic but due to hormone imbalance. (C) 1994 Society of Toxicolog y.