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Exposure to aromatic organic solvents may induce hearing loss in rats, the cochlea being the primary target. The aim of this study which was carried out in rat, was to evaluate the impact of the hepatic metabolism of toluene on its ototoxic potency. To this end, the solvent hepatic metabolism was shifted by treating the rats with 50 mg/kg/d of phenobarbital (PhB), a potent inducer of the microsomal cytochromes P450 system, alcohol and aldehyde dehydrogenases, and glutathione-S-transferases. The two main urinary metabolites of the oxidative and conjugate pathways [hippuric (HA) and benzyl mercapturic acids (BMA) respectively] confirmed the efficacy of the PhB treatment. For the PhB-induced rats, the amount of excreted HA increased by 43% and the amount of BMA by 35%. Auditory function impairments were assessed using auditory-evoked potentials. On completion of the auditory tests, the organs of Corti were dissected to evaluate hair cell losses. The permanent auditory threshold shifts were approximately 15 dB greater in the toluene-exposed rats than in the PhB-induced rats. Both the functional and morphological data confirmed that PhB treatment can decrease the ototoxic potency of toluene.

From previous in vivo investigations, it has been shown that toluene can mimic the effects of cholinergic receptor antagonists and may thereby modify the response of protective acoustic reflexes. The current study aimed to define the relative effects of aromatic solvents on the middle ear and inner ear acoustic reflexes. Toward this end, the cochlear microphonic (CMP) elicited with a band noise centered at 4 kHz, and the compound action potential (CAP) elicited with 4-kHz tone pips was measured in rats. Both potentials were recorded before, during, and after triggering the protective reflexes by a 110-dB SPL contralateral octave band noise centered at 12.5 kHz (12.5 kHz-OBN). In several rats, the middle ear muscles were severed to identify the relative effects of toluene on the two reflexes. While the reflex elicitor was capable of decreasing both the CMP and CAP amplitudes, an injection of 116.2 mM toluene cancelled this suppressor effect induced by the contralateral sound. In the rats with nonfunctional middle ear muscles, a solvent injection did not modify the electrophysiological responses of the cochlea. Different solvents were tested to study the relationship of the chemical structure of the solvents on the acoustic reflexes. The present study showed that aromatic solvents can inhibit the action of the middle ear reflex by their anticholinergic effect on the efferent motoneurons. An aromatic nucleus and the presence of one side chain of no more than 3 C seem to be required in the solvent structure to inhibit the efferent motoneurons.

Human and animal studies have shown that toluene can cause hearing loss. In the rat, the outer hair cells are first disrupted by the ototoxicant. Because of their particular sensitivity to toluene, the cochlear microphonic potential (CMP) was used for monitoring the cochlea activity of anesthetized rats exposed to both noise (band noise centered at 4 kHz) and toluene. In the present experiment, the conditions were specifically designed to study the toluene effects on CMP and not those of its metabolites. To this end, 100-microL injections of a vehicle containing different concentrations of solvent were made into the carotid artery connected to the tested cochlea. Interestingly, an injection of 116.2-mM toluene dramatically increased in the CMP amplitude (approximately 4 dB) in response to an 85-dB SPL noise. Moreover, the rise in CMP magnitude was intensity dependent at this concentration suggesting that toluene could inhibit the auditory efferent system involved in the inner-ear or/and middle-ear acoustic reflexes. Because acetylcholine is the neurotransmitter mediated by the auditory efferent bundles, injections of antagonists of cholinergic receptors (AchRs) such as atropine, 4-diphenylacetoxy-N-methylpiperidine-methiodide (mAchR antagonist) and dihydro-beta-erythroidine (nAchR antagonist) were also tested in this investigation. They all provoked rises in CMP having amplitudes as large as those obtained with toluene. The results showed for the first time in an in vivo study that toluene mimics the effects of AchR antagonists. It is likely that toluene might modify the response of protective acoustic reflexes.

There is clear evidence that aromatic solvents can disrupt the auditory system in humans and animals. As far as animal models are concerned, solvent-induced hearing loss seems to be species-dependent. Indeed, most published data have been obtained with the rat, which shows mid-frequency cochlear deficits, whereas the guinea pig does not show any permanent hearing loss after solvent exposure. In the current investigation, the effects of two solvents, toluene (600 ppm) and styrene (1000 ppm), were studied in both Long-Evans rats and pigmented guinea pigs exposed 6 h/day for 5 consecutive days. Cochlear function was tested by using distortion product otoacoustic emissions (DPOAE) measured prior to the solvent exposure, 20 min after the end of the exposure and successively at 2 and 4 weeks post-exposure. In addition to cochlear testing, solvent concentrations in blood and urinary metabolites were measured. A cochlear histological analysis was performed at the end of the experiment. No decrease in DPOAE amplitude was observed in the guinea pig, even immediately following the end of exposure. The rat model showed severe disruption of auditory function and cochlear pathology, whereas the guinea pig had no disruption of DPOAE or cochlear pathological alterations. Therefore, the vulnerability of the cochlear function was strictly dependent on the species. As expected, an important difference in the styrene concentration in blood was observed: the solvent concentrations were fourfold higher in the rat than in the guinea pig. Therefore, it is clear that a pharmacokinetic or an uptake difference might explain the difference in susceptibility observed between the two species. Moreover, the metabolism pathways of the solvents were different depending on the species. Attempts to explain differences of vulnerability between the rat and guinea pig are addressed in the present paper.

Toluene and styrene are industrial solvents that can severely damage the auditory function in adult rats. In the present study, toluene (1000 to 2000 ppm) and styrene doses (500 to 1500 ppm) were investigated according to the same schedule: 6 hours per day, 5 days per week, for 4 consecutive weeks. The auditory function of the animals was tested by recording evoked potentials from the inferior colliculus over a frequency range from 2 to 32 kHz, whereas pathological data were evaluated by conventional histologic techniques. The permanent threshold shifts (PTS) were obtained with a styrene dose 2.4 times lower than that of the toluene. The slope of the regression line (PTS/doses) was 2.1 steeper with styrene than that obtained with toluene in the same experimental conditions. The sequence of histopathological events along the organ of Corti, especially the orderliness and the location of the traumas, was similar for paired concentrations of styrene and toluene, which were respectively 650 ppm, 1500 ppm for the first match, and 850 ppm, 1750 ppm for the second one. Both electrophysiological and histological findings point out the higher ototoxic potency of the styrene compared to that of the toluene. Assumptions concerning the ototoxic mechanism are addressed in the present paper.

To identify the frequency range most sensitive to toluene-induced auditory damage, the auditory function of adult Long-Evans rats exposed to 1750 ppm of toluene (6 h/day, 5 days/week, 4 weeks), was tested by recording auditory-evoked potentials directly from the round window of the cochlea. The present electrocochleographic findings do not support a specific mid- to high-frequency loss of auditory sensitivity. On the contrary, the electrophysiologic data, obtained for audiometric frequencies ranging from 2 to 32 kHz, showed a hearing deficit not only in the mid-frequency region (12-16 kHz), but also in the mid-low-frequency region (3-4 kHz). Actually, the effect of toluene was independent of the frequency in our experimental conditions. Histological analysis was consistent with electrophysiologic data because a broad loss of outer hair cells occurred in both mid- and mid-apical coil of the organ of Corti.

Three experimental groups and one control group of Long-Evans rats were used to study the combined effects of toluene and ethanol on auditory function. The first experimental group was exposed to toluene vapors (1750 ppm, 6 h/day, 5 days/week, 4 weeks), the second one was daily gavaged with a saline solution of ethanol (4 g/kg, 4 weeks), and the last group was simultaneously exposed to both toluene and ethanol. Auditory function was tested by recording brain stem (inferior colliculus) auditory-evoked potentials for audiometric frequencies ranging from 2 to 32 kHz. Urinary hippuric acid was dosed to check the toluene metabolism during the experiments. Ethanol clearly modified the toluene metabolism in the present experimental conditions. As a result, the hearing loss induced by a simultaneous exposure to both ethanol and toluene was larger than that induced by exposure to toluene alone.

To study the combined effects of noise and toluene on auditory function, three experimental groups of Long-Evans adult rats were used. The first group was exposed to toluene (2000 ppm, 6 h/day, 5 days/week, 4 weeks), the second group to an octave band of noise centered at 8 kHz (92 dB SPL), and the last group to a simultaneous exposure to toluene and noise. Auditory function was tested by recording brainstem (inferior colliculus) auditory-evoked potentials. The auditory deficit induced by the combined exposure exceeded the summated losses caused by toluene alone and by noise alone within the range (2-32 kHz) of test frequencies. The nature of the cochlear damage induced by noise alone (injured stereocilia) or by toluene alone (outer hair cells loss) is different.

Inhaled toluene (from 1000 to 2000 ppm, 6 h/day, 5 days/week, 4 weeks) is anototoxic solvent that severely damaged the cochlea in adult Long-Evans rats. Auditory function was tested by recording near field potentials from the inferior colliculus. Surprisingly, the electrophysiologic results did not reflect all the cochlear damage observed by histology. Loss of outer hair cells of the organ of Corti occurred in all toluene-treated rats in middle and mid-apical turns, whereas the basal turn of the cochlea was fairly well preserved. The third row of outer hair cells was more injured than the second row, which itself was more injured than the first row. The locations of the cochlear lesions are reported in the present study with regard to the toluene dose.

Abstract: Toluene is the most widely used industrial solvent. It has been shown to cause cochlear disruptions in rats but markedly less ototoxic effects in guinea pigs. Susceptibility to the ototoxic properties of toluene is, therefore, species specific. In recent publications, an important difference in the solvent concentration in blood has been identified when rats and guinea pigs were exposed in strictly identical experimental conditions. Solvent concentrations in blood were greater in rats than in guinea pigs. The present studies were designed to compare blood affinity and toxicokinetic parameters of toluene in an attempt to understand the susceptibility differences in both species. The in vitro experiment, in which the headspace concentration of toluene was measured within a sealed vial containing blood, highlighted the greater toluene partition coefficient in rat than in guinea pig blood. The in vivo experiment showed that 10min after a single intravenous administration of 28μL of toluene, the solvent concentration is approximately two-fold lower in guinea pig than in rat blood. Based on the toxicokinetic parameters of toluene and on the relative partition coefficient of toluene in blood, it seems plausible that guinea pigs are not susceptible to organic solvents because the solvent concentration in blood does not reach the concentration required to induce permanent damage. Attempts to explain differences of vulnerability between the rat and guinea pig are addressed in the present paper. [Copyright &y& Elsevier]