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Olfactory mucosal toxicity screening and multivariate QSAR modelling for chlorinated benzene derivatives
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Environmental Toxicology.
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Manuscript (Other academic)
URN: urn:nbn:se:uu:diva-90540OAI: oai:DiVA.org:uu-90540DiVA: diva2:162925
Available from: 2003-05-12 Created: 2003-05-12 Last updated: 2010-01-13Bibliographically approved
In thesis
1. Neurotoxic Effects of Dichlorophenyl Methylsulphones Related to Olfactory Mucosal Lesions
Open this publication in new window or tab >>Neurotoxic Effects of Dichlorophenyl Methylsulphones Related to Olfactory Mucosal Lesions
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis deals with the highly potent olfactory mucosa toxicant 2,6-dichlorophenyl methylsulphone (2,6-diClPh-MeSO2) and its non-toxic 2,5-chlorinated isomer (2,5-diClPh-MeSO2). 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.

The results revealed a rapid CYP-catalysed covalent binding of 2,6-diClPh-MeSO2 in the rat olfactory mucosa, whereas the 2,5-dichlorinated isomer was not covalently bound.

Acute and chronic olfactory mucosal pathology were investigated and compared in rats and mice. Twenty-four hours after dosing to rats, 2,6-diClPh-MeSO2 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-MeSO2 was non-toxic in rats as well as in mice.

In mice, 2,6-diClPh-MeSO2 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-MeSO2 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.

In conclusion, the results show that a CYP-catalysed formation and covalent binding of a reactive 2,6-diClPh-MeSO2-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-MeSO2-induced increase in motor activity, and maze learning deficits, were not correlated to the olfactory mucosal lesions. I propose that 2,6-diClPh-MeSO2 causes a direct effect in the brain leading to neurobehaviuoral deficits.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2003. 53 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 858
Biology, olfcatory toxicity, olfactory bulb, aryl methylsulphone, neurotoxicity, QSAR, Biologi
National Category
Biological Sciences
Research subject
urn:nbn:se:uu:diva-3463 (URN)91-554-5668-5 (ISBN)
Public defence
2003-06-02, Lindahlsalen, EBC, Uppsala, 13:00
Available from: 2003-05-12 Created: 2003-05-12 Last updated: 2013-07-02Bibliographically approved

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