Conazoles are a class of
azole based fungicides used in agriculture and as
pharmaceutical products. They have a common mode of antifungal action through inhibition of
ergosterol biosynthesis. Some members of this class have been shown to be hepatotoxic and will induce mouse hepatocellular
tumors and/or rat thyroid follicular cell
tumors. The particular mode of toxic and tumorigenic action for these compounds is not known, however it has been proposed that
triadimefon-induced rat thyroid
tumors arise through the specific mechanism of increased TSH. The present study was designed to identify commonalities of effects across the different conazoles and to determine unique features of the tissue responses that suggest a toxicity pathway and a mode of action for the observed thyroid response for
triadimefon. Male Wistar/Han rats were treated with
triadimefon (100, 500, 1800 ppm),
propiconazole (100, 500, 2500 ppm), or
myclobutanil (100, 500, 2000 ppm) in feed for 4, 30, or 90 days. The rats were evaluated for clinical signs, body and liver weight, histopathology of thyroid and liver, hepatic metabolizing
enzyme activity, and serum T3, T4, TSH, and
cholesterol levels. There was a dose-dependent increase in liver weight but not
body weight for all treatments. The indication of
cytochrome induction,
pentoxyresorufin O-dealkylation (
PROD) activity, had a dose-related increase at all time points for all conazoles.
Uridine diphopho-glucuronosyl
transferase (UDPGT), the T4 metabolizing
enzyme measured as glucuronidation of
1-naphthol, was induced to the same extent after 30 and 90 days for all three conazoles. Livers from all high dose treated rats had centrilobular hepatocyte
hypertrophy after 4 days, while only
triadimefon and
propiconazole treated rats had hepatocyte
hypertrophy after 30 days, and only
triadimefon treated rats had hepatocyte
hypertrophy after 90 days. Thyroid follicular cell
hypertrophy, increased follicular cell proliferation, and
colloid depletion were present only after 30 days in rats treated with the high dose of
triadimefon. A dose-dependent decrease in T4 was present after 4 days with all 3 compounds but only the high doses of
propiconazole and
triadimefon produced decreased T4 after 30 days. T3 was decreased after high-dose
triadimefon after 4 days and in a dose-dependent manner for all compounds after 30 days.
Thyroid hormone levels did not differ from control values after 90 days and TSH was not increased in any exposure group. A unique pattern of toxic responses was not identified for each conazole and the hypothesized mode of action for
triadimefon-induced thyroid gland
tumors was not supported by the data.