Methylsulphonyl-chlorobenzenes and the olfactory system : Comparative toxicity of the 2,5- and 2,6-dichlorinated isomers in mice

Abstract: Methyl sulphone metabolites of chlorinated aryl hydrocarbons are persistentenvironmental pollutants that can bioaccumulate in animals and humans. Little is known about the toxicological effects of these metabolites and this thesis is an attempt to increase this limited knowledge. Tissue-binding, toxicity and neuro-behavioural effects of methylsulphonyl-2,6dichlorobenzene [2,6-(diCl-MeSO2-B)] and methylsulphonyl-2,5-dichlorobenzene [2,5-(diCl-MeSO2-B)] were examined on mice.Both substances resulted in a strong uptake in the olfactory mucosa (OM). Only 2,6-(diCl-MeSO2-B) induced toxicity in the OM, originating from a primary lesion in the Bowman's glands (BG). An in situ CYP-catalysed activation of 2,6-(diCl-MeSO2-B) seems to occur in the BG giving rise to reactive intermediates which either conjugate with glutathione or induce local toxicity. Subsequent secondary lesions in the OM include: severe degenerationof the neuroepithelium, fibrosis, ossification and polyposis. These effects resulted from a single ip dose and were permanent. Long lasting induction of GFAP in the olfactory bulb (OB) and behavioural deficits were also observed and considered to be caused by damaged olfactory neurons and/or metabolites translocated to the OB. Although the OM was more damaged in male mice, acquisition deficits occurred only in female mice.2,5-(diCl-MeSO2-B) did not induce OM toxicity, GFAP or learning deficits in either sex. However, observed motor activity responses indicate that, although 2,5-(diCl-MeSO2-B) is not olfacto-toxic, it is neuro-toxic.1,3-Dichloro-, 1,4-dichloro- or 1,2,3-trichloro-benzene did not induce damage in the OM indicating that an electron withdrawing substituent in the primary position and 2,6-positioned chlorine atoms is a structural requirement for OM toxicity. Persistent, dose-, time-, tissue- and sex-dependent effects on the olfactory system induced by 2,6-(diCl-MeS2-B) together with the lack of lesions in the OM or brain by 2,5-(diCl-MeSO2-B), makes this chemical pair a reliable and versatile tool for olfactory research.