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Year : 2000  |  Volume : 3  |  Issue : 9  |  Page : 33--44

Rats exposed to toluene and noise may develop loss of auditory sensitivity due to synergistic interaction

Rasmus Brandt-Lassen, Soren P Lund, Gitte B Jepsen 
 National Institute of Occupational Health (NIOH), Copenhagen, Denmark

Correspondence Address:
Soren P Lund
National Institute of Occupational Health (NIOH),Lersø Parkallé 105, 2100 Copenhagen


Hearing loss in workers exposed to organic solvents has been shown to be the effect of interaction between the exposure to solvents and noise. Synergistic interaction has been demonstrated in rats following simultaneous exposure to toluene and noise, but only at high-level toluene exposure. The present study was initiated to investigate the potential interaction of exposure to noise and toluene on the auditory system of the rat, covering a dose-range of toluene exposure (0, 500, 1000, 1500, and 2000 ppm, 6 h/d, 10 d). Exposed to toluene only, the rats exposed at the 1500 and 2000 ppm level developed a mid-frequency ABR threshold shift, whereas rats exposed to 0, 500, and 1000 ppm did not exhibit signs of auditory impairment. Rats exposed to 500 ppm toluene and noise (96 dB SPL, 2h following the daily toluene exposure, 10 d) developed a small, but statistically significant threshold shift, equal to the hearing loss in rats exposed to noise only (0 ppm). Synergistic interaction was evident at the 1000, 1500, and 2000 ppm toluene exposure levels. There was no further hearing loss at the 2000 ppm than at the 1500 ppm level, indicating that a saturation of the auditory impairment had been reached. When acute noise exposure (105 dB SPL, 4 h) followed the toluene exposure by 30 days, interaction was noted at the 1500 ppm toluene exposure level, but not at the 1000 ppm level. However, the latter type of interaction is of indirect nature and should be distinguished from the direct interaction, taking place when toluene is physically present in the cochlea during exposure to noise. Further investigations in animal models should preferentially be carried out as long-term, low-level exposure studies, showing the possible interaction at low exposure levels, where exposure to each factor alone is without any effect.

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Brandt-Lassen R, Lund SP, Jepsen GB. Rats exposed to toluene and noise may develop loss of auditory sensitivity due to synergistic interaction.Noise Health 2000;3:33-44

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Brandt-Lassen R, Lund SP, Jepsen GB. Rats exposed to toluene and noise may develop loss of auditory sensitivity due to synergistic interaction. Noise Health [serial online] 2000 [cited 2020 Sep 29 ];3:33-44
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Human studies have shown that organic solvents may damage the auditory system in the working environment (Bergstrom and Nystrom, 1986; Jacobsen et al., 1993; Morata et al., 1993; Morata et al., 1997a; Morata et al., 1997b), and hearing loss of solvent exposed workers appear to be the effect of interaction between the exposure to organic solvents and noise. The study of Morata et al. (1997b) is of particular interest because of the finding of an increased prevalence of hearing loss among petroleum refinery workers exposed to both noise and organic solvents, even though the exposures to noise and organic solvents were below the occupational exposure limit values.

The possible ototoxic effect of toluene was first reported in rats by Pryor et al. (1983), and subsequent studies demonstrated hearing loss in rats after exposure to toluene (Rebert et al., 1983; Pryor et al., 1984a; Pryor et al., 1984b; Johnson et al., 1988; Sullivan et al., 1989; Pryor et al., 1991; Crofton et al., 1994; Rebert et al., 1995; Campo et al., 1997; Lataye and Campo, 1997), styrene (Pryor et al., 1987; Yano et al., 1992; Crofton et al., 1994), xylene (Pryor et al., 1987; Crofton et al., 1994; Rebert et al., 1995), trichloroethylene (Rebert et al., 1991; Crofton and Zhao, 1993; Jaspers et al., 1993; Crofton et al., 1994; Rebert et al., 1995), chlor benzene (Rebert et al., 1995), and n-heptane (Simonsen and Lund, 1995). When rats were exposed to combinations of two different organic solvents, the auditory impairment after combined exposure was additive with respect to equal potency of the solvents under study (Rebert et al., 1995).

In general, the auditory impairment shown in rats exposed to organic solvents is a mid-frequency hearing loss at 8-20 kHz following a loss of outer hair cells (OHC) in the middle and basal turns of the cochlea (Pryor et al., 1984a; Sullivan et al., 1989; Yano et al., 1992; Jaspers et al., 1993; Crofton et al., 1994; Johnson and Canlon, 1994a; Johnson and Canlon, 1994b; Campo et al., 1997; Lataye and Campo, 1997). There seems, however, to be a certain exposure threshold concentration for the organic solvent ototoxicity in rats, below which even prolonged exposure does not seem to induce any signs of ototoxicity (Pryor et al., 1984b; Nylen et al., 1987; Pryor et al., 1991; Jaspers et al., 1993). An ototoxic threshold concentration of 40­60 mg/ml toluene in blood has been shown in rats (Pryor et al., 1991), and it seems to be toluene itself rather than a metabolite that is responsible for the auditory impairment (Pryor et al.; 1991).

Only a few studies have examined the nature of the interaction between exposure to noise and organic solvents on hearing in animal experiments. When rats were exposed sequentially to toluene (1000 ppm 16 hours/day, 5 days/week for 2 weeks) and noise (100 dB Leq 10 hours/day, 7 days/week for 4 weeks), a potentiation was found when the toluene exposure preceded the noise exposure (Johnson et al., 1988). The reverse exposure order resulted only in an additive effect (Johnson et al., 1990). In an experiment conducted by Lataye and Campo (1997), synergistic interaction was demonstrated in rats following simultaneous exposure to toluene (2000 ppm) and noise (92 dB SPL) for 6 hours a day, 5 days a week for 4 weeks. However, this interaction was investigated only at high-level toluene exposure, which caused considerable auditory impairment even without noise exposure.

Human long-term low-level exposure to toluene has not been shown to induce hearing loss without simultaneous exposure to noise. At present, the risk of human auditory impairment due to organic solvent exposure seems primarily to be a problem concerning the effect of interaction of combined exposure to solvents and noise. Consequently, the ototoxicity of organic solvents demonstrated so far in animal models may have only limited relevance for the risk human auditory impairment in the working environment. Of particular interests are studies in animal models of the possible interaction of low-level exposure to organic solvents and noise, where the exposure to each factor alone is without any effect.

The present study was initiated to further investigate the potential interaction of exposure to noise and toluene on the auditory system of the rat, covering a dose range of four toluene exposure concentrations.

 Materials and Methods


Male Wistar rats (MOL:Wist Han) from the local breeder (M & B, Ltd.) arrived at the laboratory one week before they were employed in any experimental procedures. At arrival the rats were 6-7 weeks of age and weighed 175-200 g. The rats were housed two by two in polypropylene cages (425 x 266 x 150 mm) with steam cleaned pinewood bedding (Lignosel S 8). Municipal water and rodent chow (Altromin 1324) was accessible ad libitum. In the animal quarters, the temperature was maintained at 21 ± 1oC and humidity at 50 ± 5%. Lights were on from 5.30 PM to 5.30 AM.

Experimental procedure

[Figure 1] gives an overview of the experimental procedure. All animals were tested audiometrically approximately one week after their arrival (AT1), and the animals were divided into two groups to be exposed to either toluene (group I) or to both toluene and noise (group II). Both groups were further subdivided into five dosage groups (n=12) with exposure to either 2000, 1500, 1000, 500, or 0 ppm toluene (7609, 5706, 3804, 1902, or 0 mg/m3), 6 hours a day for 10 consecutive days. At the end of the daily toluene exposure, the rats from group II were transferred to the noise exposure booth and exposed to Gaussian noise (4-20 kHz, 96 dB SPL) for 2 hours.

The rats of both exposure groups were again tested audiometrically (AT2) 12 days after the last day of exposure, whereupon the rats from of exposure group II left the experiment. The rats of exposure group I were again tested audiometrically on the 56th day (AT3), and three days later they received a single 4-hour noise exposure (4-20 kHz Gaussian noise, 105 dB SPL). On the 12th day after the noise exposure, the rats of exposure group I were tested audiometrically (AT4) for the last time.

Due to incorrect settings of the exposure system during the acute 4 hour noise exposure of the 0, 1000, and 2000 ppm toluene dosage groups, the measurements on these groups were excluded from the study. Therefore, two additional dosage groups of 0 and 1000 ppm were established, and the 2000 ppm group was excluded from this part of the study.


Determination of auditory thresholds was performed by analysis of the Auditory Brainstem Response (ABR) to pure tone stimulation on anesthetized rats (65 mg/kg pentobarbital sodium i.p.). Testing was performed in a closed sound booth (80x70x60 cm), lined with sound absorbing material (Rockfon®). The rats were placed ventrally on a heating plate with the vertex situated vertically below the centre of a horn speaker. The audiometric measurements consisted of 256 averaged ABR recordings elicited by 4.0, 8.0, 12.5, 16.0, 20.0 or 31.5 kHz tone-pips at a stimulus repetition rate of 11.3 sec -1 . Stimulus levels ranged from 25 to 100 dBlin SPL peak in steps of 5 dB. During the measurements, the rectal temperature of the rats was kept at 38.0 ± 0.5 oC.

The ABRs were recorded with a silver wire inserted subcutaneously at the back of the head as active electrode, a small roll of silver wire in the mouth as reference electrode and a stainless steel needle in the tail as ground electrode. After amplification (20,000 x) with a EMG-amplifier (Dantec 15C01), 11 msec ABR was sampled at a rate of 46.5 kHz with 16 bit data acquisition board (Keithley MetraByte DAS-HRES) on a personal computer using the ASYST 4.0 software package. High-pass and low-pass filter setting of the EMG ­amplifier was 50 Hz and 10 kHz, respectively, and the sampled ABR was further digitally filtered by the computer using a zero-phase low-pass filter with a 2.4 kHz cut-off frequency and a 4.0 kHz stop band.

The pure tone stimuli were generated by a programmable function generator (Hameg 8130) as a 1.4 msec cosine bell tapered symmetrical tone pips with a 1.0 msec plateau and filtered through a 44 kHz high-pass anti-aliasing filter. After amplification by an audio amplifier (NAD 2100), equipped with a computer controlled digital attenuator, the pure-tone stimuli were emitted from a piezoelectric horn tweeter (Motorola® Type 1016).

At each frequency, the full range stimuli levels were calibrated using Bruel & Kjaer ½" free-field condenser microphones (Type 4165 and Type 4133), a Bruel & Kjaer sound level meter (Type 2209) with a third octave filter (Type 1616), and a Bruel & Kjaer sound level calibrator (Type 4230). The calibration of the stimuli levels was later verified with the same microphones, a Bruel & Kjaer preamplifier (Type 2669) and a FFT spectrum analyser (HP 35670A). The general background noise level inside the test booth was measured to be 18 dBlin SPL rms in the 2 - 48 kHz frequency range.

The adequacy of the system for determination of hearing thresholds were further evaluated with stimulus levels down to 15 dBlin SPL peak on a group of 10 unexposed rats. These measurements were performed with twice the normal number of sweeps (512), and the stimulus level was calibrated using the microphones and the spectrum analyser mentioned above.

Thresholds were evaluated through visual inspection of the audiometric data [Figure 2] by the same person. During the evaluation, this person had no knowledge of the exposure history of the individual rats. The lowest sound pressure level, which caused a clear first peak, was set to be the auditory threshold of the rat at the given frequency.

Toluene exposure

The exposures were performed in dedicated inhalation chambers with walls of stainless steel and glass. The air exchange rate was 15 per hour with an air temperature of 22 ± 2oC and a humidity of 50 ± 10 % RH. During the exposures, which were performed between 7.30 AM and 2.30 PM with the animals in their normal waking state, the rats were housed in wire mesh cages without access to food and water. The noise level within the exposure chambers was measured to be around 35 dBlin SPLrms in the 2 - 48 kHz frequency range, with the highest single frequency contribution being 25 dB SPLrms at 4.8 kHz.

Toluene (Merck p.a.; purity >99,5% GC; CAS-No. [108-88-3]) was evaporated in the air-inlet of each exposure chamber by means of a HPLC-pump (Merck-Hitachi L-7110) feeding toluene to the top of a glass spiral, which was slightly heated by circulating water (36oC). The toluene concentration was measured with an infrared gas cell spectrophotometer (Foxboro MIRAN-1A) on one chamber every 5 minutes automatically changing from chamber to chamber. The system was calibrated directly in units of concentration (ppm) and all exposure data were collected on a computer for later analysis. For control, the daily quantity of toluene used for each chamber was measured and checked against the toluene concentration. The means and standard deviations of the toluene exposure concentrations at steady state, which was reached approximately 20 min. after the start of the dosage pumps, were calculated to be 501 ± 13 ppm, 999 ± 16 ppm, 1500 ± 36 ppm, and 2001 ± 27 ppm, respectively.

Noise exposure

The noise exposures were carried out in a ventilated laboratory animal transport container (Scanbur Scantainer B-110) lined with sound absorbing material (Rockfon®). Exactly 30 minutes after stopping the toluene dosage pumps, the inhalation chambers were opened, and the rats from group II still in their wire mesh cages were transferred to the noise exposure booth. While the rats from group II were exposed to noise, group I stayed inside the inhalation chambers, and both groups were given free access to drinking water.

The rats were exposed to Gaussian noise, generated on a computer with a digital signal processing board (Ariel DSP16+), an audio amplifier (NAD 216 THX), and 8 dome tweeters (Vifa D26TG-05-06) located symmetrically two by two 20 cm above the lid of each of the 4 cages. The noise had a flat frequency distribution at 4-20 kHz when measured inside the noise exposure booth with the equipment mentioned above in the context of calibration of the ABR stimulus. The spectrum of the noise at 96 dBlin SPLrms is depicted in [Figure 3]. The frequency distribution at the other noise exposure levels used in this study was similar to the one shown in the figure. The sound field inside the chamber was quite uniform, varying less than ± 2 dB, but to further minimize the differences in noise exposure levels, the individual cages were rotated inside the booth every day. Following the noise exposure, all rats were transferred back to their polypropylene cage and kept within the animal quarters.

To establish the noise level for the study of combined exposure to toluene and noise, groups of rats (n=8) were exposed to different levels of the 4-20 kHz Gaussian noise (90, 93, 96, 99 or 105 dB SPL) for 10 days, 2 hours a day (not shown). The 96 dB level was chosen due to the small, but statistically significant hearing loss caused by noise exposure at this level.


Comparison of the effects in different dosage groups was performed using t-test for two samples with different variance. Interaction was tested using a two way factorial model (GLM: General Linar Models). In the following, the term significant is used unless stated otherwise when tests are rejected at a 5 % level.


The average audiogram of all rats prior to exposure (AT1) is depicted in [Figure 4]. The lowest sensitivity appears at the lowest (4.0 kHz) and highest (31.5 kHz) test frequencies with thresholds of 38.5 and 42.6 dB SPL, respectively. At the four middle test frequencies (8.0, 12.5, 16.0 and 20.0 kHz), some individual rats showed a clear auditory response even at the lowest stimulus level (25 dB SPL). The threshold of these rats was set to 25 dB SPL, and consequently, the average auditory thresholds at the four middle test frequencies are close to the detection level of 25 dB SPL.

The average auditory thresholds shifts (AT2 - AT1) caused by exposure to toluene (group I) are shown in [Figure 5] (top). Exposure to toluene at concentrations up to 1000 ppm did not show any detectable change in the auditory thresholds of the rats at any of the test frequencies. However, after exposure to 1500 ppm toluene, the thresholds in the middle frequency range (12.5, 16.0 and 20.0 kHz) were clearly elevated. After exposure to 2000 ppm, the auditory thresholds were raised considerably at all frequencies except 31.5 kHz, which seemed more or less unaffected.

The average auditory threshold shifts (AT2 - AT1) following exposure to both toluene and noise (group II) are shown in [Figure 5] (bottom). The 0 ppm dosage group was exposed to noise only, and showed elevated auditory thresholds at 12.5, 16.0 and 20.0 kHz. Rats exposed to 500 ppm toluene and noise showed threshold shifts similar to that of the rats exposed to noise only. At the 1000 ppm toluene exposure level, the shift in auditory thresholds following combined exposure appeared slightly elevated, and a broad range of frequencies seemed affected. Rats exposed to toluene at 1500 ppm and noise had clear auditory threshold shifts at all test frequencies except at 31.5 kHz. In the 2000 ppm dosage group auditory threshold shifts were considerably increased at the same five test frequencies, whereas the average auditory threshold at 31.5 kHz was not significantly changed.

[Figure 6] shows for each of the four levels of toluene exposure the mean auditory threshold shift of rats exposed to toluene and noise, toluene, noise and control rats, respectively. In order to identify a possible interaction between noise and toluene, the dashed curve indicates the sum of the mean auditory threshold shift in the noise and in the toluene group as derived by simple addition. At 2000 and 1500 ppm it is evident that the mean auditory threshold shifts caused by combined exposures, by far exceed the sums of the equivalent single exposures (dashed curve) at the middle frequencies, indicating a considerable interaction between toluene and noise. At 2000 ppm the interaction is statistically significant at 8.0, 12.5, 16.0 and 20.0 kHz, while at 1500 ppm the interaction is statistically significant at 8.0, 12.5 and 16.0 kHz. At 1000 ppm the interaction is smaller but apparent, being statistically significant at 8.0 and 12.5 kHz. Since the auditory threshold shift is of the same magnitude whether the rats were exposed to 500 ppm toluene and noise or to noise alone, there seems to be no interaction at 500 ppm. The magnitude of the interaction (the vertical distance between the dashed curve and the toluene and noise curve) is approximately the same whether the toluene concentration was 1500 or 2000 ppm.

[Figure 7] shows the frequency specific average auditory threshold shifts caused by noise exposure (AT4 - AT3) of rats which were (35 days earlier) exposed to different concentrations of toluene (exposure group I).

The control group (0 ppm) shows the effect of the noise exposure without prior toluene exposure. When thresholds after the noise exposure (AT4) are compared to the auditory thresholds prior to the acute noise exposure (AT3), the effect of the noise exposure is statistically significant at 12.5, 16.0, 20.0 and 31.5 kHz. The effect of the noise exposure on the rats previously exposed to 500 or 1000 ppm toluene are quite similar to the effect on the rats in the control group. However, the rats previously exposed to 1500 ppm toluene did have increased auditory threshold shifts at all the test frequencies following the acute noise exposure in comparison to the rats in the other three groups. The differences in thresholds shift between the 1500 ppm group and the control group were statistically significant only at 4.0, 8.0, and 16.0 kHz.


In the previous section, it was noted that some individual rats showed a clear auditory response at the four middle test frequencies (8.0, 12.5, 16.0 and 20.0 kHz) even at the lowest stimulus level (25 dB SPL). For these animals, the auditory thresholds were set to 25 dB SPL, which in some cases could be too high.

The additional audiometric test of 10 unexposed rats performed with lowered detection level (not shown) indicated that average auditory thresholds at 4.0, 12.5 and 31.5 kHz are similar to the one obtained with a the 25 dB SPL detection level. However, at 8.0, 16.0 and 20.0 kHz the average auditory thresholds seemed to be approximately 5 dB lower when using low detection level.

If the measures of the auditory thresholds prior to a certain exposure (AT1) are estimated too high, this will lead to underestimation of the effect of the subsequent exposure (AT2 - AT1). When studying the effects of interaction, the same underestimation could make the effect of combined exposure appear greater than the sum of the effects of the equivalent single exposures, even though the effects act only in an additive manner. This would mistakenly lead the investigators to conclude that a synergistic interaction had occurred, and emphasizes the great importance of low detection levels when studying possible interaction phenomena.

The average audiogram of unexposed rats [Figure 4] shows that auditory sensitivity has its optimum in the 8-20 kHz frequency range, and [Figure 5] (bottom, 0 ppm) and [Figure 7] (0 ppm) shows that the noise exposures primarily did affect this frequency range. Hence, the frequency distribution of the noise employed in the present experiment (4-20 kHz Gaussian noise) seems appropriate for studies in the rat.

A comparison of the group average audiogram of unexposed rats from different studies is difficult because of differences in subject strain, age, and choice of audiometric procedure. Campo et al. (1997) found an average audiogram of Long-Evans rats of roughly the same pattern but with thresholds approximately 10 dB SPL lower. The surgical implantation of the electrode used in their experiment as opposed to the subcutaneous recording in the present study could be the explanation for this difference. Johnson et al. (1990) found for Sprague-Dawley rats tested with a technique very similar to the one used in this study the average audiogram to be of the same pattern but with thresholds approximately 5 dB SPL higher.

Toluene exposure caused primarily a mid frequency hearing loss, and at higher dosage levels, the hearing loss spreads to a wider range of the hearing spectrum [Figure 5], top. This pattern of toluene induced auditory impairment is in close accordance with previous findings of Campo et al. (1997), Lataye and Campo (1997), Crofton et al. (1994), Johnson et al. (1988), and Johnson and Canlon (1994a). In toluene exposed rats, Campo et al. (1997) and Lataye and Campo (1997) found 16.0 kHz to be the most affected test frequency. Johnson et al. (1988) and Johnson and Canlon (1994a) found the maximal threshold shifts in the 6.3-12.5 kHz frequency range. In the present study, 12.5 kHz was the most affected test frequency following toluene exposure, but this may, at least partly, reflect the possible 5 dB underestimation of the threshold shift at 8.0, 16.0 and 20.0 kHz as discussed above.

The highest concentration of toluene, which in this study did not cause a detectable shift in auditory thresholds, was 1000 ppm. With exposure at the same concentration but a daily duration of 16 hours, Johnson et al. (1990) found auditory thresholds to be significantly elevated at all the involved test frequencies. This indicates that the duration of the daily toluene exposure is crucial for the development of solvent induced hearing damage.

The data [Figure 6] show clear signs of synergistic interaction at concentrations as low as 1000 ppm where exposure to toluene alone as mentioned above did not seem to cause any change in auditory thresholds.

Synergistic interaction appeared to be most distinct at the four middle test frequencies, where it is of quite similar magnitude. However, the possible underestimation of the effect of single exposures at 8.0, 16.0 and 20.0 kHz may have lead to overestimating the magnitude of interaction at these frequencies. Contrary to this, the observed interaction at 12.5 kHz was unquestionably not an artefact.

There seems to be no difference in the magnitude of synergistic interaction for rats exposed to 1500 and 2000 ppm toluene. Hence, the potential for synergistic interaction may have become saturated at concentrations of 1500 ppm and above. This brings support to the notion that studies of interaction should be conducted at a range of dosage levels.

Rats exposed to 1500 ppm toluene (group I) showed a long lasting increased vulnerability to the succeeding single noise exposure. Johnson et al. (1988) has earlier reported an increase in vulnerability to noise when the exposure to toluene was followed by exposure to noise with no days interposed between exposures. However, the increase in vulnerability to noise shown in the present study seems to display a critical loss of outer hair cells, which could lead to a possible decrease in the resistance to acute excessive noise exposure.

Exposure at concentrations of 1000 ppm or lower did apparently not change the rats sensitivity to noise. This is in contrast to the synergistic interaction observed when the rats were exposed to a daily combination of noise and 1000 ppm toluene. This suggests the existence of two types of interaction: One type of interaction is of indirect nature and is caused by an increase in the vulnerability to noise after a toluene induced hair cell loss. The other type of interaction is acting directly when toluene is physically present in the cochlea during exposure to noise. This type of interaction is occurring even at low-level toluene exposure that does not induce long lasting change in the vulnerability to noise. Further investigations in animal models should preferentially be carried out as long-term, low-level exposure studies, showing the possible interaction at low exposure levels, where exposure to each factor alone is without any effect.


The authors would like to thank Lotte S. Drifte (NIOH) for her efforts in taking care of the animals. Rasmus Brandt-Lassen would also like to express his gratitude to Per Rosenkilde, August Krogh Institute, University of Copenhagen, for his guidance and to Erik Holst (NIOH) for statistical tutoring.[26]


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