<p>This thesis deals with the highly potent olfactory mucosa toxicant 2,6-dichlorophenyl methylsulphone (2,6-diClPh-MeSO<sub>2</sub>) and its non-toxic 2,5-chlorinated isomer (2,5-diClPh-MeSO<sub>2</sub>). In mice, both substances bind firmly in the olfactory mucosa and the olfactory bulb, which are important components of the sensory system. The 2,6-isomer induces olfactory mucosal necrosis with permanent loss of olfactory neuroepithelium and olfactory nerves. A major objective was to clarify the cause of this isomer-specific toxicity, and to identify which physicochemical characteristics determine the olfactory toxicity. The neurobehavioural toxicity of these substances was also examined.</p><p>The results revealed a rapid CYP-catalysed covalent binding of 2,6-diClPh-MeSO<sub>2</sub> in the rat olfactory mucosa, whereas the 2,5-dichlorinated isomer was not covalently bound. </p><p>Acute and chronic olfactory mucosal pathology were investigated and compared in rats and mice. Twenty-four hours after dosing to rats, 2,6-diClPh-MeSO<sub>2</sub> induced Bowman’s glands necrosis and sloughing of the olfactory epithelium similar to that previously reported in mice. At 3 weeks, however, there were dramatic differences in histological lesions. In mice, large parts of olfactory epithelium were replaced by respiratory-like epithelium. Large, bilateral, fibrous, cartilage and bone containing polyps occluding the lumen were confirmed. In rats, only minor patches of olfactory epithelium were replaced by a metaplastic atypical respiratory-like epithelium. 2,5-diClPh-MeSO<sub>2</sub> was non-toxic in rats as well as in mice.</p><p>In mice, 2,6-diClPh-MeSO<sub>2</sub> induced a dose-dependent and long-lasting ( ≥12 weeks) hyperactivity as well as long-lasting maze learning deficits. At 2 weeks hyperactivity and maze learning deficits were observed also in rats. Unexpectedly, 2,5-diClPh-MeSO<sub>2</sub> induced hyperactivity that lasted for two weeks. No effect on maze learning was observed with this isomer. No major differences between male and female rats or mice were found.</p><p>In conclusion, the results show that a CYP-catalysed formation and covalent binding of a reactive 2,6-diClPh-MeSO<sub>2</sub>-metabolite in the Bowman’s glands precede the high olfactory mucosal toxicity in rodents. As determined by QSAR-modelling, a 2,6-dichlorinated benzene derivative with a large, polar, and strong electron withdrawing substituent in the primary position has the potential of being an olfactory mucosal toxicant. The observed 2,6-diClPh-MeSO<sub>2</sub>-induced increase in motor activity, and maze learning deficits, were not correlated to the olfactory mucosal lesions. I propose that 2,6-diClPh-MeSO<sub>2</sub> causes a direct effect in the brain leading to neurobehaviuoral deficits. </p>
| Identifer | oai:union.ndltd.org:UPSALLA/oai:DiVA.org:uu-3463 |
| Date | January 2003 |
| Creators | Carlsson, Carina |
| Publisher | Uppsala University, Department of Environmental Toxicology, Uppsala : Acta Universitatis Upsaliensis |
| Source Sets | DiVA Archive at Upsalla University |
| Language | English |
| Detected Language | English |
| Type | Doctoral thesis, comprehensive summary, text |
| Relation | Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, 1104-232X ; 858 |
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