Irreversible binding and toxicity of the herbicide dichlobenil (2,6-dichlorobenzonitrile) in the olfactory mucosa of mice

Abstract

Following a single ip injection (12, 25, 50 mg/kg) of the herbicide dichlobenil (2,6-dichlorobenzonitrile) into C57Bl mice or Sprague-Dawley rats, an extensive destruction of the glands of Bowman and in the neuroepithelium of the olfactory region was observed. In mice, necrosis of the Bowman's glands was evident 8 hr after the lowest dose (12 mg/kg). Degeneration and/or necrosis of the neuroepithelium developed less rapidly but appeared at all doses examined. The mucosal lesions were most severe in the dorsal meatus and in the medial aspects of the ethmoturbinates. Three to seven days after dosing, the olfactory region was covered by an attenuated surface epithelium or by a respiratory-like epithelium. Seven to twenty days after dosing, there was fibrosis of the olfactory region. Partial regeneration of the olfactory epithelium and scattered intact Bowman's glands were observed after 20 days. Autoradiograms of mice given a single iv injection of 14C-labeled dichlobenil showed a high irreversible binding of radioactivity in Bowman's glands, whereas the binding in the olfactory epithelium was insignificant. In mice pretreated with metyrapone the binding decreased markedly, indicating that the reactive metabolite was formed by a cytochrome P450-dependent mechanism. The metyrapone treatment also resulted in a decreased or completely inhibited toxicity of dichlobenil to the olfactory mucosa. Hence, the tissue-specific toxicity of dichlobenil seems to be mediated by a reactive, tissue-binding metabolite. We propose that dichlobenil induces a primary lesion in the glands of Bowman, resulting from the pronounced binding of a metabolite in these glands. The toxicity to the olfactory neuroepithelium may be secondary to the destruction of the glands of Bowman.