title: Ototoxicity of the three xylene isomers in the rat.
abstract: Numerous experiments have shown that the aromatic solvents can affect the auditory system in the rat, the cochlea being targeted first. Solvents differ in cochleotoxic potency: for example, styrene is more ototoxic than toluene or xylenes. The goal of this study was to determine the relative ototoxicity of the three isomers of xylene (o-, m- or p-xylene). Moreover, by dosing with the two urinary metabolites of xylene, methylhippuric (MHAs) and mercapturic acids (MBAs), this study points toward a causal relationship between the cochleotoxic effects and potential reactive intermediates arising from the biotransformation of the parent molecules. Separate groups of rats were exposed by inhalation to one isomer following this schedule: 1800 ppm, 6 h/d, 5 d/wk for 3 wk. Auditory thresholds were determined with brainstem-auditory evoked potentials. Morphological analysis of the organ of Corti was performed by counting both sensory and spiral ganglion cells. Among the three isomers, only p-xylene was cochleotoxic. A 39-dB permanent threshold shift was obtained over the tested frequencies range from 8 to 20 kHz. Whereas outer hair cells were largely injured, no significant morphological change was observed within spiral ganglia. The concentrations of urinary p-, o- or m-MHA were greater (p-MHA: 33.2 g/g; o-MHA: 7.8 g/g; m-MHA: 20.4 g/g) than those obtained for MBAs (p-MBA: 0.04 g/g; o-MBA: 6.2 g/g; m-MBA: 0.03 g/g). Besides, there is a large difference between o-MBA (6.2 g/g) and p-MBA (0.04 g/g). As a result, since the cysteine conjugates are not determinant in the ototoxic process of xylenes, the location of the methyl groups around the benzene nucleus could play a key role.
authors.affiliation: Laboratoire de Neurotoxicité, Institut National de Recherche et de Sécurité, Avenue de Bourgogne, BP 27, Vandoeuvre, 54501 cédex, France.
authors.forename: Katy
authors.initials: K
authors.lastname: Maguin
authors.forename: Robert
authors.initials: R
authors.lastname: Lataye
authors.forename: Pierre
authors.initials: P
authors.lastname: Campo
authors.forename: Benoît
authors.initials: B
authors.lastname: Cossec
authors.forename: Manuella
authors.initials: M
authors.lastname: Burgart
authors.forename: Delphine
authors.initials: D
authors.lastname: Waniusiow
mesh_terms: D000818:Animals; D001299:Audiometry; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003051:Cochlea / Q000473:pathology; D006311:Hearing Disorders / Q000139:chemically induced*; D006626:Hippurates / Q000378:metabolism; D007536:Isomerism; D008297:Male; D009474:Neurons / Q000473:pathology; D051381:Rats; D020318:Rats, Long-Evans; D013136:Spiral Ganglion / Q000473:pathology; D016707:Tissue Fixation; D014992:Xylenes / Q000493:pharmacokinetics / Q000633:toxicity* / Q000652:urine
chemical_list: D006626:Hippurates; D014992:Xylenes; C015356:N-methylhippuric acid