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Year : 2000  |  Volume : 2  |  Issue : 6  |  Page : 57--66

Effects of exposure to trichloroethylene and noise on hearing in rats

H Muijser, JHCM Lammers, BM Kulig 
 Department of Target Organ Toxicology, TNO Voeding, Zeist, Netherlands

Correspondence Address:
H Muijser
Department of Target Organ Toxicology, TNO Voeding, Zeist, NL-3700 AJ


Four groups of rats (n=8 per group) were exposed to either 3000 ppm trichloroethylene (TCE) alone or to 95 dB SPL noise alone or to the combination of TCE and noise or to control conditions. Exposure was carried out 18 hours/day, 5 days/week for 3 weeks. Exposure to TCE alone resulted in hearing loss at 4, 8, 16 and 20 kHz, but not at 24 and 32 kHz. Hearing loss due to exposure to noise alone occurred at frequencies of 8, 16 and 20 kHz. In general, combined exposure to TCE and noise resulted in larger auditory threshold changes than that produced by either TCE alone or noise alone when measured 1 and 2 weeks after the completion of exposure. For frequencies of 8, 16 and 20 kHz, hearing loss due to combined TCE-noise exposure was not larger than the algebraic sum of hearing loss due to exposure to TCE or noise alone. However, at a frequency of 4 kHz, hearing loss due to combined exposure was significantly larger than that produced by TCE exposure alone or noise alone, which itself had no effect at this frequency. These results suggest evidence of an interaction of combined exposure to TCE and noise at the lower edge of the range of frequencies affected.

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Muijser H, Lammers J, Kulig B M. Effects of exposure to trichloroethylene and noise on hearing in rats.Noise Health 2000;2:57-66

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Muijser H, Lammers J, Kulig B M. Effects of exposure to trichloroethylene and noise on hearing in rats. Noise Health [serial online] 2000 [cited 2021 Mar 4 ];2:57-66
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Ototoxicity has been demonstrated in experimental animals for a number of different solvents including trichloroethylene (TCE; Pryor et al, 1983, 1987; Rebert et al, 1983, 1991; Rebert and Becker, 1986). At the human level hearing loss has also been reported in persons with a history of solvent abuse (Ehyai and Freemon, 1983). The evidence from epidemiological studies that exposure to solvents alone could contribute to hearing loss in exposed workers is still limited (Biscaldi et al, 1981; Mitchell and Parsons-Smith, 1969; Muijser et al, 1988; Szulc-Kuberska et al, 1976). However, there is increasing evidence that solvent exposure may exacerbate the effects of exposure to work-related noise (Barregard and Axelsson, 1984; Morata, 1989, Morata et al, 1991, 1993). Such findings are not entirely unexpected since synergistic interactions of exposure to noise and exposure to other agents, both ototoxic and non­ototoxic, have been well documented (Bhattacharyya and Dayal, 1984; Boettcher et al, 1987, Brummett et al, 1992; Fechter, 1995; Lim, 1986).

At the animal level, surprisingly few experiments have been conducted to study the effects of simultaneous exposure to solvents and noise. Johnson et al, (1988) found that loss of auditory function in rats after exposure to toluene for 2 weeks (5 days/week, 16 hours/day, 1000 ppm) followed by exposure to noise for 4 weeks (7 days/week, 10 hours/day, 105 dB SPL (sound pressure level relative to 10 -12 W/m 2 )) was more severe than the summated loss due to exposure to noise alone or to toluene alone. Furthermore, auditory thresholds were found to be less affected when the exposure sequence was reversed (Johnson et al, 1990). In contrast, Campo et al, (1993) could not demonstrate in guinea pigs an interaction between daily consecutive exposure to toluene (14 days, 6 hours/day, 1000 ppm) and noise (8 hours/day, 85 dB, SPL). Further, Fechter (1993) was also unable to demonstrate in the same species an added effect of a single 7 hour exposure to 1200 ppm styrene over the temporary threshold shift resulting from a simultaneous 7 hour exposure to 95 dB SPL white noise. In the same laboratory synergistic interactions between simultaneous exposure to noise and exposure to carbon monoxide (CO) had been demonstrated earlier in rats (Young et al, 1987; Fechter et al, 1983, 1988). More recently, Lataye and Campo (1997) found that after simultaneous exposure of rats to noise and toluene, the auditory deficit induced by combined exposure exceeded the summated losses by toluene and noise alone.

The present experiments were designed to extend earlier results (Jaspers et al, 1993) on the ototoxicity of trichloroethylene (TCE) with an exploration of possible interactive effects of simultaneous exposure to noise and TCE. Because similar mechanisms of action of noise and of TCE on hearing are unlikely (Fechter et al, 1998), interactive effects were assessed by studying response addition rather than dose addition (Calabrese, 1991; Poch, 1993).



Thirty-two rats of the Wistar-derived Wag­Rij/Cpb//Hsd strain (Harlan, Zeist, The Netherlands) weighing 200 ± 20 g and approximately 11 weeks old were used. Because of the limitations on the exposure and testing facilities available, two cohorts (n=16/cohort) were ordered, exposed, and tested three weeks apart. Each cohort was randomly divided into two exposure groups (n=8/group). The rats in the first cohort comprised the Noise Alone and TCE and Noise exposure groups; those in the second cohort, the TCE Alone and Control exposure groups. Rats were housed 2/cage in hanging wire-mesh cages which were located in the exposure chambers. Food and water were available ad libitum. A 12-hour light/dark cycle was employed with lights on at 0700 hr. Animals were weighed weekly on Monday mornings throughout the experiment.

Exposure Conditions

The two groups of rats in the first cohort were exposed to noise alone and clean air (Noise Alone) or to trichloroethylene and noise (TCE and Noise) in identical exposure chambers (volume = 2.3 m 3 ) in which the temperature was maintained at 23 ± 1oC and the relative humidity at 55 ± 5 %. Exposure started in the sixth week after arrival and lasted 3 weeks. Subsequently, the exposure chambers were used to expose the two groups of animals in the second cohort for 3 weeks, also starting in the sixth week after arrival. For these rats, however, the noise generation was disabled and animals were exposed to either trichloroethylene alone (TCE Alone) or clean air (Controls).

Trichloroethylene vapour was generated at a target concentration of 3000 ppm for 18 hrs/day, 5 days/week, Monday through Friday from 1400 hr in the afternoon until 0800 hr the following morning. Generation was accomplished by using a dynamic flow system in which nitrogen gas was sparged through the solvent fluid at 41oC and the saturated gas was injected into the air supply system serving the exposure chamber (air flow: 36 m 3 /hr). The TCE concentration inside the exposure chamber was automatically sampled three times per hour and analysed using a microprocessor-controlled gas chromatograph system. Daily records indicated that the concentrations of TCE inside the exposure chambers remained within 10 % of the intended values throughout exposure.

Noise was generated at a target level of 95 dBA (dBA: measured according to the "A" scale) or 95.5 dB SPL (sound pressure level re 10 -12 W/m 2 ), by means of an IC digital white noise generator (Motorola MM5837) bandfiltered between 1 and 30 kHz. After amplification by a commercial audio amplifier (AKAI, AM-17), the signal was fed to 8 piezo-ceramic tweeters (Motorola L054) located 45 cm above the cages inside the chambers. The resulting sound field was measured at different spots within each cage with a sound level meter (B&K Model 2204) fitted with a ½ inch condenser microphone (B&K Model 4133) which has a flat response up to 40 kHz. The results revealed a uniform noise level for each cage with the highest and lowest levels measured in the cages being 95 and 93 dBA, respectively. The frequency spectrum of the noise is depicted in [Figure 1]. It was measured with the sound level meter switched to the linear mode (SPL: sound pressure level relative to 20 µPa) and extended with a switchable octave filter set (B&K Model 1613). The centre frequencies of the octave filter were 31.5 Hz, 64 Hz, 125 Hz, 250 Hz, 500 Hz, 1 kHz, 2 kHz, 4 kHz, 8 kHz, 16 kHz or 31.5 kHz. Although the noise below 1 kHz produced by the ventilation system is appreciable, it is in a frequency region where auditory sensitivity of the rat is low (Kelly and Masterton, 1977).

Reflex Modification Testing

Reflex-modification testing was conducted using an eight-unit acoustic startle system as described previously (Jaspers et al, 1993). Each unit consisted of a wire-mesh cage (14x7x7 cm 3 ) mounted on a force transducer assembly equipped with strain gauges (Kyowa, Tokyo, Japan, Model KFC-5C1-11) to detect changes in vertical force. Each test cage was located in a separate sound-attenuating chamber. The noise level inside the test chambers was approximately 30 dBA. All acoustic stimuli were presented using a piezo-ceramic tweeter (Motorola, 3.5", Model L052A) suspended from the ceiling of each box. The generation of stimuli and the registration of responses were computer­controlled using laboratory-developed software and interfaces.

The startle-eliciting stimulus (S2) consisted of a 40 ms, 110 dB (re 20 µPa), 1-20 kHz band-pass filtered burst of white noise with a linear rise/decay time of 2.5 ms. A 40 ms Hanning­shaped tone (i.e., a tone having the waveform described by the function A = 1/2 {1-cos(2 t/T)} where A = amplitude, t = time within the interval [0,T] and A outside [0,T] = 0) of 4, 8, 16, 20, 24 or 32 kHz presented 100 ms before the onset of S2 served as the prepulse stimulus (S1). At each test session, auditory thresholds for two different tone frequencies were assessed by presenting prepulse stimuli at 13 different intensities at increments of 6 dB up to a maximum intensity of 69, 64, 62, 53, 48 and 48 dB (re 20 µPa) for the frequencies mentioned above, respectively. At a test session, all prepulse conditions were generated in 25 blocks of 32 trials with each block consisting of one trial at each of the 13 S1 intensities for each of the two prepulse frequencies and 6 blank trials in which S1 was absent. The presentation of the trials within each block was counterbalanced in a semi-random order. The intertrial interval was 15 s. Testing a cohort of 16 animals with three pairs of tone frequencies was performed in 3 morning and 3 afternoon sessions on three consecutive days (Wednesday through Friday). Half of the rats from each group of a cohort was tested in morning sessions and the other half in afternoon sessions.

Startle responses were sampled at a 1 kHz rate for 100 ms starting at the onset of S2 and subsequently stored on disk. In order to determine the average force exerted by the weight of the animal, samples taken during the first 10 ms were averaged for each trial. The amplitude of the startle response was defined as the maximum peak force exerted 13 to 40 ms following the onset of the startle stimulus (S2) relative to the average force exerted within the first 10 ms.

At the start of each test session, animals were placed in the test cages and allowed to acclimatise to the test surroundings for 10 min prior to the presentation of the first trial. Animals were tested for the first time in the second week after arrival with a reduced number of blocks to habituate them to being tested and these data were not analysed. Auditory threshold determinations were carried out in two pretests conducted at 2 and 3 weeks prior to exposure. Following the three week exposure period, testing was conducted one and two weeks post­exposure.

Data Analysis

Auditory thresholds for each frequency tested were obtained using a two-segmented line model to determine the highest prepulse tone intensity that did not induce inhibition of the startle response (Crofton 1992). The results from the two pre-tests, and likewise those of the two post­tests, were averaged to obtain an estimate of pre­exposure and post-exposure auditory thresholds. In 4 out of the 768 auditory threshold determinations conducted, the computer program could not fit the two-segmented line model to the data and no threshold could be determined for that rat at that frequency for that particular test. In those cases, the pre- or post­exposure threshold was based on one rather than two test sessions. Pre-exposure thresholds and auditory threshold shifts, i.e., the difference between the average post-exposure and average pre-exposure thresholds, were analysed using a multivariate analysis of variance with one grouping factor utilising Wilks lambda. In the case of a significant multivariate main effect, the data were subsequently analysed using one-way ANOVAs conducted at each frequency. Further, post-hoc testing consisted of Tukey's studentised range test to determine which groups differed from the control group and whether the TCE and Noise group was significantly different from either the TCE Alone or Noise Alone groups.

Control startle amplitudes (startle trials without prepulse) were averaged over the pre-exposure data and analysed using a one way ANOVA, followed by Dunnett's test in the case of significant effects. Post-exposure data were treated likewise. Body weight changes were analysed using a one-way ANOVA conducted at each time point followed by Dunnett's test in the case of significant effects. A significance level of 0.05 was used for all tests.


Body weight

There were no significant differences among the groups in body weight measured in the three weeks prior to exposure. By the end of the three week exposure period TCE exposure produced a significant 15 % decrease in body weight in both the TCE Alone and TCE and Noise groups. Although weight gain in the Noise Alone group was somewhat less than that of Controls beginning at the start of the experiment, these differences did not reach statistical significance. Following the termination of exposure, body weights for both groups exposed to TCE increased and there were no significant differences in weight by the third post-exposure week.

Auditory sensitivity

[Figure 2] shows the pre-exposure thresholds averaged over the two measurements. The results of a MANOVA indicated that there were no significant threshold differences between the groups (Wilks lambda: F(18,65.54)=1.09; p=0.38).

Mean threshold shifts, i.e. the difference between the average post-exposure thresholds and the average pre-exposure thresholds are depicted in [Figure 3]. Grouping had a significant multivariate effect on the auditory threshold shifts (Wilks lambda: F(18/65.54)=6.14; p Control startle amplitudes

No significant differences in control startle amplitudes were found before exposure. After exposure, a just significant overall effect of exposure was found (F(3,28)=2.97, p=0.049). However, post-hoc testing failed to identify a single group difference between exposed and control groups. Amplitudes in the TCE Alone group were within 1 % of the Controls and the approximately 30 % increase in amplitude in the Noise Alone group and in the TCE and Noise group in comparison with the Controls was not sufficient to reach significance in the Dunnett post-hoc test.


In the present study hearing loss has been evaluated with reflex-modification audiometry based on acoustic startle reflexes. Since the startle eliciting pulse is derived from wide band noise, including the frequencies that are affected, decreased startle amplitudes might conceivably interfere with the assessment of auditory thresholds. The converse has been demonstrated, however (Crofton et al, 1991; Fechter and Young, 1983). In addition, loud sounds are about equally loud for normal hearing persons and persons with limited hearing deficits (loudness recruitment). The startle amplitude data for non­prepulse trials of the animals exposed to TCE alone are consistent with this view: the startle amplitude is not diminished although appreciable hearing loss is present. In the Noise Alone group as well as in the combined exposure group startle amplitude was even somewhat increased, a finding which may be due to more central effects of extended noise exposure.

Hearing loss in the Noise Alone group was maximal in the mid-frequency range while lower and higher frequencies were spared. The pattern of hearing loss in the 8-24 kHz range in rats due to high frequency wide band noise is analogous to that reported in humans for hearing loss in the 3-5 kHz range resulting from wide band noise (Kryter, 1985; Salvi et al, 1995; Henderson and Hamernik, 1995). Upon further exposure hearing loss extends to both higher and lower frequencies. Because maximum sensitivity of hearing in the rat is at a higher frequency compared to humans, partly because of the higher resonance frequency of the external auditory meatus (Henderson and Hamernik, 1995), maximum vulnerability can also be expected at a higher frequency. In addition, it has been found that maximum hearing loss due to exposure to narrow band noise is induced at a higher frequency than the frequency of the noise by about ½ to 1 octave (Davis et al, 1950). Thus, in spite of full noise energy being present at 4 kHz, no effect of exposure to noise alone at this frequency could have been expected. Likewise, because full noise power is present at 16 kHz, the lack of an effect of exposure to noise alone at 32 kHz reflects less vulnerability at this frequency.

Compared to the results found in an earlier study (Jaspers et al, 1993) hearing loss due to exposure to TCE alone in the present experiment was more severe in the 4-5 kHz range. Although the same exposure regimen was employed in both studies, two different strains of Wistar-derived rats from different suppliers were used, which may account for the difference in results. Compared to the findings of other laboratories, the TCE-induced hearing deficit found in the present experiment was also more severe: Crofton and Zhao (1993) found effects at 8 and 16 kHz, but not at 4 or 24 kHz in Long Evans rats exposed to 4000 ppm TCE (no effects at 2000 ppm). Rebert et al (1991) found a minimal effect at 4 kHz and more pronounced effects at 8 and 16 kHz in Long Evans rats exposed to 3200 ppm TCE but 1600 ppm had no effect. In contrast, it was reported in the same paper that 16 kHz was affected in Fischer-344 rats exposed to 2000 ppm. It must be borne in mind, however, that the daily exposure period in the present experiment was longer (18 h/day) than that of Rebert et al (12 h) or Crofton and Zhao (6 h/day), thus limiting the comparability of the results. In addition, the different total duration of the exposure was also different for the different studies, ranging from 5 days (Crofton and Zhao, 1993) to 12 weeks (Rebert et al, 1991). In the experiments of Pryor et al (1983, 1987) in which Fischer-344 rats were exposed to a range of concentrations of toluene, xylenes or styrene, it could be seen that while at the lowest concentration only 12 and 20 kHz were affected, at higher concentrations the affected frequency range was extended to include 8 and 4 kHz. The view that solvent-induced hearing loss starts at mid-frequencies and extents to both lower and higher frequencies with higher exposure levels was illustrated in a recent paper by Campo et al (1997) on toluene-induced hearing loss in rats using electrophysiological and histological methods. It thus seems plausible that also in the case of TCE, exposure to lower concentrations would have restricted the range of frequencies affected.

Since hearing loss at 4 kHz due to exposure to TCE alone was enhanced by simultaneous exposure to noise while exposure to the same level of noise alone did not lead to hearing loss, a clear-cut interactive effect between TCE and noise exposure at 4 kHz was demonstrated. At 8, 16 and 20 kHz hearing loss due to combined exposure was less than the algebraic sum of the decrement due to exposure to TCE alone or noise alone, while at 24 kHz hearing loss due to combined exposure was larger than the sum of the separate effects (although not confirmed statistically). At 32 kHz the exposed groups did not differ from the control group. It is unlikely that hearing in rats is especially sensitive to combined exposures at a single frequency (4 kHz). Exposure to lower levels of TCE and noise would have resulted in less severe effects at higher frequencies due to TCE alone or noise alone (similar to those at 4 kHz in the present experiment), and it is expected that the interactive effect would have included the higher frequencies, similar to the interactive effects of exposure to noise and toluene on hearing in rats found by Lataye and Campo (1997) using a lower effect level of noise (approximately 10dB hearing deficit in the 10-16 kHz range) than in the present study.

A fundamental question which needs to be addressed in future investigations is what approach is most appropriate for differentiating interactive and additive effects on hearing in solvent and noise co-exposures. Existing strategies for evaluating the effects of combined exposures include dose addition and response addition. Dose addition is often employed in cases where the interacting compounds share a common mechanism of action. Because trichloroethylene affects spiral ganglion cells (Fechter et al 1998) rather than the outer hair cells which are the target for most other solvents, a shared mechanism of noise-induced hearing loss (affecting hair cells) and trichloroethylene­induced hearing loss seems improbable. Therefore, interactive effects in the present experiment were assessed by studying response addition (Calabrese, 1991; Poch, 1993). It was possible to demonstrate an interactive effect at 4 kHz due to combined exposure since at this frequency exposure to one factor (noise) did not cause an effect when applied alone. From the point of view of risk assessment, it is relevant whether additional exposure to solvents can accelerate the effects of noise on hearing in workers and whether this is by simple addition or by synergistic interaction is important for developing safe occupational limits. Thus, future experimental studies should concentrate on uncovering hearing loss in the range 8-20 kHz as a result of exposure to noise levels and solvent levels which by itself cause hearing loss at a minimal level.


This work was supported in part by the Directorate General of Labour of the Netherlands Ministry of Social Affairs and Employment. The authors wish to thank J.F. Vermij and F.C.W. Luiten for technical support in conducting the experiments and Ir D.C.J. Poortvliet for the design of a Pascal program for least square estimates of the thresholds.[44]


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