Toxicity of 2,6-dichlorothiobenzamide (chlorthiamid) and 2,6-dichlorobenzamide in the olfactory nasal mucosa of mice.
The toxic effects of the herbicide chlorthiamid (2,6-dichlorothiobenzamide) and its major environmental metabolite 2,6-dichlorobenzamide (DCBA) were examined in the nasal passages of C57Bl mice following single ip injections. Chlorthiamid (12.25, and 50 mg/kg) induced an extensive destruction of the olfactory region, similar to that previously observed with the analogue dichlobenil (2,6-dichlorobenzonitrile). Necrosis of Bowman's glands was evident first, whereas degeneration and necrosis of the olfactory neuroepithelium developed less rapidly. The lesions were most severe in the dorsomedial region of the nasal cavity. At longer post-treatment intervals, the olfactory epithelium was replaced by a respiratory-like epithelium, and there was fibrosis of the lamina propria. DCBA was also toxic to the olfactory region (100 mg/kg), inducing necrosis of the Bowman's glands and the neuroepithelium in the dorsomedial region of the nasal cavity. No lesions were observed in other parts of the nasal cavity or in the liver after administration of chlorthiamid or DCBA. Chlorthiamid (IC50 = 51 microM), but not DCBA, inhibited the covalent binding of 14C-labeled dichlobenil in the olfactory mucosa in vitro. It is proposed that the toxic effects of chlorthiamid and dichlobenil in the olfactory mucosa are mediated by common or closely related metabolites.
Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences, Uppsala.
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Brittebo
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Eriksson
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Feil
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Bakke
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Brandt
D000818:Animals; D001549:Benzamides / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D008099:Liver / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009297:Nasal Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009570:Nitriles; D009831:Olfactory Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D051381:Rats; D011919:Rats, Inbred Strains; D013854:Thioamides / Q000633:toxicity*
D001549:Benzamides; D009570:Nitriles; D013854:Thioamides; C058670:2,6-dichlorothiobenzamide; D003577:Cytochrome P-450 Enzyme System; C055869:dichlobanil