title: Olfactory mucosal necrosis in rats following acute intraperitoneal administration of 1,2-diethylbenzene, 1,2-diacetylbenzene and 2,5-hexanedione.
abstract: 1,2-Diethylbenzene (1,2-DEB) is used in the manufacture of some plastics. Exposure to 1,2-DEB has been shown to induce peripheral neuropathy in rats. This neurotoxicity is thought to be caused by a metabolite, 1,2-diacetylbenzene (1,2-DAB), a γ-diketone-like compound. 1,2-DEB was previously shown to be extensively and rapidly taken up by the nasal mucosa in male rats. In the present study, the nasal mucosa in rats exposed to 1,2-DEB and 1,2-DAB were examined histologically. Results were compared to sections from rats exposed to two other DEB isomers - 1,3-diethylbenzene (1,3-DEB) and 1,4-diethylbenzene (1,4-DEB) - and to two other neurotoxic compounds - n-hexane and its γ-diketone metabolite, 2,5-hexanedione (2,5-HD). A single intraperitoneal dose of 1,2-DEB (200mg/kg) induced time-dependent necrosis in the olfactory epithelium and Bowman's glands, with lesions appearing from the earliest observation time (4h) in the dorsomedial olfactory mucosa. Lesions spread through the lateral and ventral parts of the ethmoturbinates over the following days. The dorsal and medial zones of the nasal cavity started to regenerate from 72h after treatment, with the new epithelium showing metaplasia. One month after treatment, most of the olfactory epithelium had returned to normal. 1,2-DAB (40mg/kg) caused the same lesions as those observed after treatment with 1,2-DEB. Treatment with 2,5-HD (1g/kg) also caused lesions of the olfactory epithelium, mainly at level IV. However, these were comparatively less severe than those observed after exposure to 1,2-DEB. In contrast, intraperitoneal injection of 1,3-DEB (800mg/kg), 1,4-DEB (800mg/kg) and n-hexane (2g/kg) did not affect the nasal mucosa. Pretreatment of rats with 5-phenyl-1-pentyne, an inhibitor of CYP2F2 and CYP2E1 completely inhibited the olfactory toxicity caused by 1,2-DEB. These results suggest that metabolic activation of 1,2-DEB may be responsible for the toxicity observed.
authors.affiliation: Département Polluants et Santé, Institut National de Recherche et de Sécurité, Rue du Morvan, CS 60027, 54519, Vandoeuvre lès Nancy cedex, France. Electronic address: francois.gagnaire@inrs.fr.
authors.forename: François
authors.initials: F
authors.lastname: Gagnaire
authors.affiliation: Département Polluants et Santé, Institut National de Recherche et de Sécurité, Rue du Morvan, CS 60027, 54519, Vandoeuvre lès Nancy cedex, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Boucard
mesh_terms: D000098:Acetophenones / Q000633:toxicity*; D000818:Animals; D001555:Benzene Derivatives / Q000633:toxicity*; D004338:Drug Combinations; D006586:Hexanes / Q000494:pharmacology; D006588:Hexanones / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D008297:Male; D009336:Necrosis / Q000139:chemically induced; D009832:Olfactory Nerve / Q000187:drug effects* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D000098:Acetophenones; D001555:Benzene Derivatives; D004338:Drug Combinations; D006586:Hexanes; D006588:Hexanones; C064750:1,2-diethylbenzene; C026385:n-hexane; C048792:1,2-diacetylbenzene; C011269:2,5-hexanedione
keywords: 1,2-Diacetylbenzene; 1,2-Dieyhylbenzene; Bioactivation; Olfactory toxicity; Rat