Olfactory mucosal necrosis in rats following acute intraperitoneal administration of 1,2-diethylbenzene and 1,2-diacetylbenzene: Possible role of regional bioactivation

Exposure to 1,2-diethylbenzene (1,2-DEB) has been shown to induce peripheral neuropathy in rats. 1,2-diacetylbenzene (1,2-DAB), a g-diketone-like compound, is thought to be the active metabolite responsible for the neurotoxicity observed. Moreover, an autoradiographic study in male Sprague-Dawley rats showed a high and fast uptake of 1,2-DEB in the nasal mucosa. Based on this previous autoradiographic study, a histopathological study of the nasal mucosa was carried out in rats exposed to 1,2-DEB and 1,2-DAB. The results were compared to those obtained in rats exposed to the other two isomers 1,3-diethylbenzene (1,3-DEB) and 1,4-diethylbenzene (1,4-DEB) and to two other neurotoxic compounds, n-hexane and its g-diketone metabolite, 2,5-hexanedione (2,5-HD). Results showed that a single intraperitoneal dose of 1,2-DEB (200 mg/kg) induced time-dependent necrosis in the olfactory epithelium and Bowman’s glands. The lesions appeared as soon as the early time of observation (14 hours) in the dorsomedial part of the olfactory mucosa. The lesions extended through the lateral and ventral parts of the ethmoturbinates in the following days. Regeneration began first, in the dorsal and medial zones of the nasal cavity as early as 72 hours after treatment but the new epithelium showed metaplasia. One month after treatment, the majority of the olfactory epithelium had returned to normal. Intraperitoneal injection of 1,3-DEB (800 mg/kg), 1,4-DEB (800 mg/kg) and n-hexane (2 g/kg) did not cause any abnormality in the nasal mucosa. Intraperitoneal injection of 1,2-DAB (40 mg/kg) caused the same lesions as those observed after treatment with 1,2-DEB. Treatment with 2,5-HD caused lesions of the olfactory epithelium mainly observed at level IV, but the severity of the lesions was relatively less important than that observed after 1,2-DEB treatment. 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 in the olfactory mucosa is responsible for the toxicity observed.