Toxic Interactions Between Fungicides That Inhibit Ergosterol Biosynthesis and Phosphorothioate Insecticides in the Male Rat and Bobwhite Quail (Colinus virginianus)

Abstract

The potential for toxic interactions between ergosterol biosynthesis-inhibiting fungicides (EBIFs), used in U.S. agriculture or clinically, and phosphorothioate insecticides was assessed in adult male rats and adult male bobwhite quail (Colinus virginianus) by measuring inhibition of plasma butyryl cholinesterase (BChE) following fungicide and insecticide treatment. Male Sprague-Dawley rats (300 g) were administered corn oil or the following EBIFs: propiconazole (400 mg/kg/day), vinclozolin (400 mg/kg/day), clotrimazole (100 mg/kg/day), or ketoconazole (100 mg/kg/day) for 3 days by oral gavage. Forty-eight hours following the final dose, a single bolus of parathion (0.4 mg/kg in corn oil) or malathion (150 mg/kg in corn oil) or corn oil alone was given po. The rats were terminated 12 hr following parathion or 4 hr following malathion dosing. Significant (p < 0.05) inhibition of BChE was observed with parathion and malathion only following clotrimazole treatment. In contrast, when a similar experiment was performed in bobwhite quail dosed with 12 mg/kg malathion following EBIF treatment, significant BChE inhibition was observed following treatment with vinclozolin or ketoconazole, but not with propiconazole or clotrimazole. Induction of cytochrome P450 in rat and quail liver by EBIFs was accompanied by enhanced oxidative desulfuration of malathion, parathion, and diazinon to toxic oxon products. Increased detoxication via oxidative dearylation/esterolytic clevage also occurred. However, while enhanced acute in vivo insecticide toxicity was observed in both species with a number of EBIF-phosphorothioate combinations, EBIF-induced oxidative activation of phosphorothioates by liver microsomes in vitro was not a good predictor of this effect.