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TOXICITY PROFILES IN MICE TREATED WITH HEPATOTUMORIGENIC AND NON-HEPATOTUMORIGENIC TRIAZOLE CONAZOLE FUNGICIDES: PROPICONAZOLE, TRIADIMEFON, AND MYCLOBUTANIL
Citation:
ALLEN, J. W., D. C. WOLF, M. H. GEORGE, S. D. HESTER, G. SUN, S. Y. THAI, D. A. DELKER, T. MOORE, C. JONES, G. M. NELSON, B. ROOP, S. A. LEAVITT, E. WINKFIELD, W. O. WARD, AND S. NESNOW. TOXICITY PROFILES IN MICE TREATED WITH HEPATOTUMORIGENIC AND NON-HEPATOTUMORIGENIC TRIAZOLE CONAZOLE FUNGICIDES: PROPICONAZOLE, TRIADIMEFON, AND MYCLOBUTANIL. TOXICOLOGIC PATHOLOGY. Society of Toxicology, RESTON, VA, 34(7):853-862, (2006).
Impact/Purpose:
To report the results of traditional approaches to evaluate comparative P450 enzyme activities and liver toxicity/pathology effects of propiconazole, triadimefon, and myclobutanil
Description:
Conazoles comprise a class of fungicides used in agriculture and as pharmaceutical products. The fungicidal properties of conazoles are due to their inhibition of ergosterol biosynthesis. Certain conazoles are tumorigenic in rodents; both propiconazole and triadimefon are hepatotoxic and hepatotumorigenic in mice, while myclobutanil is not a mouse liver tumorigen. As a component of large-scale studies aimed at determining the relative toxicities and mode(s) of action for tumorigenic conazoles, we herein report the results of traditional approaches to evaluate comparative P450 enzyme activities and liver toxicity/pathology effects of propiconazole, triadimefon, and myclobutanil. Male CD-1 mice were treated in the feed for 4, 30 or 90 days with triadimefon (0, 100, 500 or 1800 ppm), propiconazole (0, 100, 500 or 2500 ppm) or myclobutanil (0, 100, 500 or 2000 ppm). Alkoxyresorufin O-dealkylation (AROD) assays indicated that all 3 chemicals induced similar patterns of dose-related increases in metabolizing enzyme activity. PROD activities exceeded those of MROD, and EROD with propiconazole inducing the highest activities of PROD. Mice had similar patterns of dose-dependent increases in hepatocyte hypertrophy after exposure to the 3 conazoles; these effects were most severe after propiconazole and triadimefon treatments. High-dose exposures to propiconazole and myclobutanil, but not triadimefon, were associated with early (4 days) increases in cell proliferation. All the chemicals at high doses reduced serum cholesterol and high density lipoprotein (HDL) levels at 30 days of treatment, while only triadimefon had this effect at 4 days of treatment and myclobutanil and propiconazole at 90 days of treatment. Overall, the tumorigenic and non-tumorigenic conazoles induced similar effects on mouse liver P450 enzyme activities and pathology. There was no specific pattern of tissue responses that could consistently be used to differentiate the tumorigenic conazoles, propiconazole and triadimefon, from the non-tumorigenic myclobutanil. These findings serve to anchor other transcriptional profiling studies aimed at probing differences in key events and modes of action for tumorigemc and nontumorigenic conazoles.