Home Email this page Print this page Bookmark this page Decrease font size Default font size Increase font size
Noise & Health  
 CURRENT ISSUE    PAST ISSUES    AHEAD OF PRINT    SEARCH   GET E-ALERTS    
 
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Email Alert *
Add to My List *
* Registration required (free)  
 


 
   Abstract
  Introduction
  Methods
  Results
  Discussion
  Conclusions
  Acknowledgments
   References
   Article Figures
   Article Tables
 

 Article Access Statistics
    Viewed6649    
    Printed284    
    Emailed11    
    PDF Downloaded22    
    Comments [Add]    
    Cited by others 4    

Recommend this journal

 


 
  Table of Contents    
ARTICLE  
Year : 2011  |  Volume : 13  |  Issue : 55  |  Page : 392-401
The efficacy of N-acetylcysteine to protect the human cochlea from subclinical hearing loss caused by impulse noise: A controlled trial

1 Department of Clinical Science, Intervention and Technology, Division of Ear, Nose and Throat Diseases, Unit of Technical and Experimental Audiology, Karolinska Institutet, Stockholm, Sweden
2 Department of Clinical Science, Intervention and Technology, Division of Ear, Nose and Throat Diseases, Karolinska Institutet and Department of Audiology, Karolinska University Hospital, Stockholm, Sweden

Click here for correspondence address and email
Date of Web Publication28-Nov-2011
 
  Abstract 

In military outdoor shooting training, with safety measures enforced, the risk of a permanent, noise-induced hearing loss is very small. But urban warfare training performed indoors, with reflections from walls, might increase the risk. A question is whether antioxidants can reduce the negative effects of noise on human hearing as it does on research animals. Hearing tests were performed on a control group of 23 military officers before and after a shooting session in a bunker-like room. The experiments were repeated on another group of 11 officers with peroral adminstration of N-acetyl­cysteine (NAC), directly after the shooting. The measurements performed were tone thresholds; transient-evoked otoacoustic emissions, with and without contralateral noise; and psycho­acoustical modulation transfer function (PMTF), thresholds for brief tones in modulated noise. Effects from shooting on hearing thresholds were small, but threshold behavior supports use of NAC treatment. On the PMTF, shooting without NAC gave strong effects. Those effects were like those from continuous noise, which means that strict safety measures should be enforced. The most striking finding was that the non-linearity of the cochlea, that was strongly reduced in the group without NAC, as manifested by the PMTF-results, was practically unchanged in the NAC-group throughout the study. NAC treatment directly after shooting in a bunkerlike room seems to give some protection of the cochlea.

Keywords: Hearing loss, impulse noise, military, N-acetylsysteine, protection

How to cite this article:
Lindblad AC, Rosenhall U, Olofsson Å, Hagerman B. The efficacy of N-acetylcysteine to protect the human cochlea from subclinical hearing loss caused by impulse noise: A controlled trial. Noise Health 2011;13:392-401

How to cite this URL:
Lindblad AC, Rosenhall U, Olofsson Å, Hagerman B. The efficacy of N-acetylcysteine to protect the human cochlea from subclinical hearing loss caused by impulse noise: A controlled trial. Noise Health [serial online] 2011 [cited 2018 Oct 19];13:392-401. Available from: http://www.noiseandhealth.org/text.asp?2011/13/55/392/90293

  Introduction Top


Exposure to excessive noise is one of the most common causes of hearing loss and tinnitus. It has been estimated that 16% of late-onset hearing loss in adults worldwide (9% in Western Europe) is due to occupational noise. [1] Research on animal models has in detail described the mechanisms causing noise-induced hearing loss (NIHL). Exposure to noise causes metabolic oxidative stress and the production of reactive oxygen species (ROS) resulting in cochlear injury. [2],[3] Free radical formation induces both necrotic and apoptotic cell death in the organ of Corti, affecting both outer and inner hair cells and marginal cells in the stria vascularis.

Experimental hearing research has developed biochemical models to prevent or even treat NIHL. The method that is most promising for human use is to deactivate free radicals with antioxidants. [4] A number of agents with antioxidant properties, and with very low toxicity, are available for this purpose. Vitamins A, C, and E are free radical scavengers, and the combination is highly effective to reduce both hearing loss and cochlear cell death. [5] Delivered alone, each of these agents does not reliably reduce NIHL. In some studies an adjuvant (magnesium or salicylate) was reported to be needed to elicit the protective effect of antioxidants. [5],[6]

N-acetylcysteine (NAC) is the antioxidant agent that has been most thoroughly investigated regarding NIHL-protection. NAC has been tested in animal models, and has been shown to provide hearing protection in several studies. [7],[8],[9],[10],[11],[12] In these studies NAC administered before noise exposure is effective to reduce hearing loss and to protect the hair cells. There is, however, no total agreement of the protective effect of NAC. In two animal studies NAC did not reduce the trauma produced by exposure to continous broadband noise, [13],[14] 105 dB SPL, 8 h/d, 5 days and 104 dB SPL, 1 h, respectively.

In most investigations the otoprotective effects of antioxidants have been studied as a preventive measure before noise exposure. However, Kopke et al. also examined the effect of NAC and salicylate administered immediately following noise exposure, and they reported a small but significant reduction in permanent threshold shift, but not in hair cell loss. [7] Choi et al. gave combinations of otoprotective drugs, including NAC to chinchillas after a prolonged exposure to noise. [15] They reported a positive effect of the combination treatment. Lorito et al. studied the protective effects of three different NAC-administrations before and after exposure to noise on albino rats. [16] All administrations, including the one given after the exposure, reduced NIHL significantly.

The risk for military personnel to get permanent NIHL as a result of shooting within the ordinary training programme in the Swedish Armed Forces (SAF) is regarded to be very small, provided that the safety instructions are enforced. However, in military services the noise levels are often extreme, and in some situations there can be doubts if level-dependent ear-muffs provide enough attenuation for all subjects. A pronounced exposure to noise occurs during shooting in urban warfare training. These training sessions are performed indoors in bunker-like rooms. The acoustical properties in these spaces are extremely poor. The noise levels are enhanced and the noise character is changed by reflections of the sound by the concrete walls. Urban warfare training has been considered to be a health problem with increased risk for NIHL by the Health Authorities of the SAF. This and other acoustic hazards have enforced the need for a treatment programme to be applied directly after an acoustic accident. Antioxidants offer such an opportunity.

The purpose of the investigation was to study how an antioxidant, NAC, can prevent discrete cochlear physiological functions being affected if the drug is administered directly after extreme noise exposure in military personnel.


  Methods Top


The design was a prospective comparative study with concurrent controls. The investigation was commissioned by the SAF who commissioned two separate studies:

  1. A study of the possible adverse effects on the hearing during urban warfare training; and after finding such effects
  2. A study of possible protective effect of an antioxidant (NAC) in conjuncture with urban warfare.


Thus two similar experiments were performed, one with Swedish safety measures enforced and without treatments (control group), and one with the same safety measures and NAC-treatment (NAC group).

Subjects

The control group consisted of 23 military officers in the Swedish Army. The age of the test subjects ranged from 22 to 50, median 29, mean 31, s.d. 7 years. Two of the officers were women.

The NAC group consisted of 11 officers of whom six participated in both parts of the experiment. Five of those who participated in both experiments had apparent effects of the noise exposure in the first experiment, one of the six showed only minor effects. The subjects in the NAC group were younger: Range 21-37 years of age, median 26, mean 27 and s.d. 4 years.

The audiograms before shooting, measured according to the next paragraph, are shown in [Figure 1]. Interindividual standard deviations for these mean thresholds, varied between 5.3 and 11.2 dB in the control group, and between 5.8 and 13.8 dB in the NAC group. The range of the thresholds at the high frequencies were −13 to +34 dB in the control group and −13 to +38 dB in the NAC group. See further under Results.
Figure 1: Mean tone thresholds in the morning before shooting for the control group (N=23, dashed lines) and for the NAC group (N=11, solid lines). Circles = right ear, crosses = left ear. Inter-individual standard deviations for the thresholds, varied between 5.3 and 11.2 dB in the control group, and between 5.8 and 13.8 dB in the NAC group

Click here to view


Noise condition

During urban warfare training two rounds of blank ammunition, with 20 shots in each, were fired within 2 min from an automatic gun, Ksp-58, in a bunker used for this type of training. Two people were in the bunker at the same time - the right-handed shooter, with exact placement and shooting direction indicated on the floor, and a companion placed close by on his/her right side. This means that they had the weapon between them. Both were wearing their standard level-dependent ear-muffs. These conditions were exactly the same for both groups.

In the control condition sound pressure levels were registered by a reference microphone placed on a stand about 2 m from the weapon in the bunker, in the companion's left ear canal and in the shooter's right ear canal by three miniature microphones. The maximum sound pressure levels were 164-166 dB SPL at the reference microphone and 135-154 dB SPL in the ear canal under the hearing protectors (mean 137 dB, range 135-141 dB SPL, except for one subject with ill-fitting hearing protectors, 154 dB SPL). The variation in these levels did not show any significant relation to the results in the hearing tests. They are not further reported here.

Drug application

The NAC treatment consisted of acetylcysteine, 200 mg, (Tika). Four tablets were taken, all of them after exposure: The first tablet, dissolved in half a glass of water, was taken directly after exposure, a second tablet 1 h later, a third one at breakfast the next day, and the fourth and last one an hour later.

Hearing tests

Tone thresholds with fixed frequency Békésy technique - audiogram

Tone thresholds for left and right ears separately were measured with pure tones at 1000, 1500, 2000, 3000, 4000, 6000 and 8000 Hz.

A pulsating tone is presented. The duration is 275 ms, including attack- and release times, and with a 175 ms long interval between pulses. The level of the tone is increased by 2.8 dB/s until the subject detects the tone and starts pressing the button. The level of the tone decreases with the same speed until the button is released again, etc. Thus a zigzag pattern is formed around the threshold level. The turning-points are registered by the computer. The measurement is concluded after 10 turning points. The first two turning points are not used in the calculation. The threshold is calculated as the mean value of the medians of the remaining upper and lower turning points with a resolution of 1 dB. These parameters should give a high threshold resolution with a standard deviation of repeated measures not exceeding 1.8 dB. [17]

Psychoacoustical modulation transfer function

The psychoacoustical modulation transfer function (PMTF)-test reflects the ability of an ear to follow the natural, slow intensity modulation of speech. This modulation is caused by syllables, words and intonation. An ear with a lesion has a decreased capacity to detect for example soft sounds after loud sounds.

The threshold of a brief tone, 4 ms, is measured in a 100% sinusoidally intensity-modulated octave-band noise. Separate thresholds are measured with the tone at the peaks and in the valleys of the noise. To prevent listening to sounds outside the octave-band, a faint, periodic, broadband masking noise is added. The measurements were performed at 4000 Hz, with a modulation frequency of 10 Hz and at the noise levels 25 to 95 dB SPL, in steps of 10 dB. The threshold of the brief tone was first measured without noise. The left ear of each subject was tested, since this ear is more sensitive to noise than the right one. [18]

The thresholds are determined with the same Békésy-technique as described earlier. The standard deviation for repeated measurements is about 2 dB for peak and valley thresholds. Further details about the method can be found in Lindblad et al.[19] Experiments with quinine, which causes a transitory hearing loss, have shown that PMTF is a sensitive test of the function of the outer hair cells (unpublished data). Thus PMTF-measurements have proved valuable for testing high quality hearing, as required for example from sonar operators. [20]

The principal difference between normal-hearing and sensorineurally hearing-impaired ears is shown in [Figure 2].
Figure 2: PMTF thresholds at 2 kHz as a function of noise level for one normal-hearing subject (circles) and one sensorineurally impaired subject (triangles). Peak thresholds have filled symbols and valley thresholds have open symbols. The threshold for the brief tone without noise was 24 and 71 dB SPL for the two subjects, respectively

Click here to view


When plotting the thresholds relative to the noise level as a function of the level of the modulated noise you find that normal-hearing subjects have a maximum around 55 dB SPL on the peak-threshold-curve and at an about 10 dB higher noise level on the valley-threshold-curve. A sensorineural hearing loss decreases the height of the maxima and moves them toward higher sound pressure levels. [21] Note that the shape of the curve is the most important feature, not the individual data points. The values at the local maxima of the peak- and valley-threshold curves have been used in statistical analyses and so have the respective noise levels (x-values) of these maxima.

In our research about susceptibility to noise induced hearing loss we have found that results from conscripts with basically continuous noise exposure are similar to results from people with sensori­neural hearing loss. Those who have been subjected to shooting incidents with unprotected ears - with impulse noise of not too extreme levels - develop in a contrary way. An example of an accidental impulse noise exposure is shown in [Figure 3], which shows the test results of a conscript at the beginning of military service and and after the accident. The maxima, both on the peak-threshold-curve and the valley-threshold-curve, move toward 45 dB SPL - and they become extremely high. Note the need of an extended scale in the figure!
Figure 3: "Hyper-PMTF" at 4 kHz. Peak (filled symbols) and valley (open symbols) thresholds before (circles), and some time after (squares) a shooting incident

Click here to view


Transient-evoked otoacoustic emissions

Transient-evoked otoacoustic emissions (TEOAEs) were measured. A contralateral noise was applied to test the function also of the efferent system controlling the outer hair cells. The software used for these measurements is developed at our unit.

Clicks with the duration of 80 μs were repeated with a frequency of 50 Hz. The measurement was performed in a non-linear mode to enhance those components in the response, which have a non-linear dependence of the stimulus level, and to suppress the linear components. To accomplish this the polarity of every fourth click is reversed and the sound pressure level is increased by a factor of 3. The acoustical responses from 1000 clicks are averaged, after removal of the primary click by windowing-technique. The stimulus level is specified as so called peak equivalent sound pressure level. TEOAEs at 75 and 85 dB peSPL with and without contralateral masking consisting of 70 dB broadband noise were used in the control condition. In the NAC condition only 85 dB peSPL was used. The RMS-value for the broadband response (the response that is correlated to the clicks), over the interval of measurement, is used as a variable in the analyses as well as the RMS-values in 1000 Hz-bands. Also the uncorrelated response is analysed in 1000 Hz-bands.

In another of our projects the same type of effects as for the PMTF-results appeared for the TEOAEs. Those who were subjected to continuous noise (in tanks or army orchestra) showed decreasing TEOAEs, similar to those from a sensorineural hearing loss, whilst those exposed to more impulse sounds (in armed personal carriers with an unusual number of shooting incidents or moments without hearing protectors when leaving the carrier) showed stronger TEOAE responses and intensified chaotic activity which might result from less efferent control of still vigorous outer hair cells.

Experimental paradigm

During each day of shooting six people (i.e., three pairs) were exposed. The test subjects were numbered consecutively. A subject with an odd number was a shooter. The subject with the next, even, number was the companion in the pair. For the control group hearing tests were scheduled and performed in a house about 100 m from the bunker on the day preceeding the shooting training and on the day of shooting. When we tested the first subjects we found that PMTF-results were affected at the measurement about 4 hours after shooting. Therefore we asked them to come back for an additional test the next day. With time it was apparent that the PMTF was affected for several subjects. As a result PMTF-measurements were added on the next day for them, and for some subjects also about a week later. For the NAC group test occasions on the next day and 1 week later were scheduled from the start. The test subjects were instructed to avoid noise exposure 24 h before the test. It was not possible to prolong the absence from regular shooting training. Therefore further follow-up measurements could not be made.

A test setup with three measuring systems allowed for hearing tests to be performed on three people at a time. The time schedule was adjusted accordingly. The test parameters for each type of test were chosen to make it possible to start new measurements every 15 minutes [Table 1]. The hearing tests directly after the shooting were performed at the same time for both subjects in a pair. After that the odd numbered subjects performed all the other hearing tests 15 minutes earlier in relation to the shooting than the even numbered ones.
Table 1: Test schedule from one shooting day

Click here to view


  1. During the afternoon of the day before the shooting several tests were carried out. Eardrums were inspected and ear canals were checked for wax, tympanometry was performed, tone thresholds were practised on both ears, i.e., audiogram; eartips for TEOAEs for both ears were chosen and emissions measured. Psychoacoustical modulation transfer function, PMTF, on the left ear was measured. These PMTF-results, measured the day before shooting, were used as reference values for the PMTF before shooting.
  2. Reference values for audiogram and left ear TEOAEs were taken the same morning as the shooting, 1.5 hours or less before shooting.
  3. Directly after the shooting, 15 min and 30 min after shooting, two audiograms were taken. On the last shooting day of the control group the second of these audiograms, 30 min after, was replaced by a PMTF-measurement
  4. 1 hour after shooting (audiogram).
  5. 2 hours after shooting (audiogram).
  6. 3 hours after shooting (audiogram; TEOAEs and PMTF on left ear).
  7. Those in the control group, who, at 3 hours after shooting, showed worse audiograms or PMTFs than pre-exposure, were tested again the next day (if possible). There was no time to evaluate if possible changes in otoacoustic emissions after the measurements had come to an end on the shooting days. For all subjects in the NAC group all the types of measurements were performed again during the next day.
  8. If, for a person in the control group, the inspection of results in 7) so implied, further measurements were performed about a week after shooting. In the NAC group everyone was tested again about one week after shooting. Test occasion next week.


Equipment

Three almost identical test systems were used. Each of them consisted of a Tucker-Davis Technologies (System II) module system including signal processor DSP32C, AD/DA-converter and computer controlled amplifiers and attenuators. The TDT-systems were controlled by personal computers. Circumaural earphones, Sennheiser HD 200, were used for the psychoacoustical measurements. Only one of the systems was used for measuring otoacoustic emissions. The probe system used for that was of type ER-10C from Etymotic Research.

Statistical analysis

The program Statistica 9.1 with the module "General linear models" was used for statistical analyses. Details are given under Results. Although six subjects participated in both groups they were treated as different subjects in the statistical analyses. This could give less strength to the analyses but decreased risk of Type I errors.

Ethical approvement

The investigations were commissioned by the SAFs. The regional ethical committee approved the study.


  Results Top


Tone thresholds

An ANOVA was performed with the hearing thresholds as the dependent response variable. Frequency, time after shooting, and ear, were repeated factors, and group (control vs. NAC) was a factor between subjects. This analysis was performed for the measurements from before shooting until, and including, 3 hours after shooting, the last measurement of the control group. The only significant factor was frequency (P<0.00001), where higher mean thresholds at 6 and 8 kHz, 10 and 5 dB HL, respectively, stood out from thresholds, close to 0 dB HL, at other frequencies. Over this time span the factor group was not significant (P=0.609) and the interaction group/time was not significant either (P=0.106). However, in [Figure 4], the NAC group shows a tendency to recovery between 3 hours after the shooting and the next day. Since all the subjects in the NAC group were measured on the next day and next week a separate ANOVA was performed for this group only, with the hearing thresholds at the three frequencies 3, 4, and 6 kHz as dependent response variables and with frequency, ear, and time as repeated factors. The factor time was significant (P=0.007) and the factor frequency (P=0.00001), but no interactions were significant. A Tukey's post-hoc test was performed for the factor time, showing that the result the next day, but not next week, was significantly different from the results 2 hours (P=0.02) and 3 hours (P=0.03) after shooting.
Figure 4: Tone thresholds as a function of time after shooting, averaged over subjects and over the frequencies 3, 4, and 6 kHz for the control group (N=23, dashed lines) and the NAC group (N=11, solid lines). Circles = right ear, crosses = left ear

Click here to view


During the measurements we noticed that after shooting the subjects took longer time for each threshold and there were unusally large intraindividual variations over time. As an indicator of these fluctuations, both toward worse and better thresholds, we therefore calculated the standard deviation (and variance) for each subject and frequency over the six measurements from the test occasion before shooting up to 3 hours after the shooting.

The intraindividual standard deviations in the present study showed the same general frequency dependence as standard deviations for repeated thresholds at conventional audiometry using the same headphone [Figure 5]a. Data for the headphone were taken from an unpublished study of standard deviations for various headphones by one of the authors. However, the fixed-frequency Békésy method, with the parameters used here, has higher accuracy than the conventional audiometry used in the headphone study. Therefore most of the individual standard deviations were slightly smaller in the present study [Figure 5]b.
Figure 5: Standard deviations of repeated thresholds measured with a headphone Sennheiser HDA 200: (a) at conventional audiometry, (b) as "means" of subjects' intra-individual standard deviations over the six measurements in this study (in fact the square roots of the means of the variances), for the control group (N=23, dashed lines) and the NAC group (N=11, solid lines). Circles = right ear, crosses = left ear

Click here to view


For the control group, with noise exposure without treatment, the intraindividual standard deviations for the left ear were larger than for the right ear at 1-6 kHz. A test of equal variances showed that the variances on the two ears were significantly different at 3 and at 4 kHz, P<0.05 (F 97.5 , d.f. = 22), suggesting a temporary effect on threshold stability of the left ear caused by the exposure.

For the NAC group the intraindividual standard deviations for the right ear were the same as for the control group except at 8 kHz. The left ear looked only slightly more influenced by the noise exposure than the right ear. An ANOVA calculated with the individual variances of the hearing thresholds as the dependent response variable, and with frequency, and ear as repeated factors within subjects and group as a factor between subjects showed no significant effect of NAC (P=0.38). However, it is known that the left ear is more vulnerable to noise than the right ear. Therefore a simple t-test of the intraindividual standard deviations for the left ears in the two groups (both groups exposed to noise but with or without NAC) was made and showed an almost significant effect, P=0.06 (one-sided test, unequal variance). That argument speaks in favour of true effects of exposure which are reduced by NAC.

Psychoacoustical modulation transfer function

The generally most worth-while way of analysing the PMTF-results is to use the thresholds at the maxima of the peak- and valley-curves. In this study the maximum peak- and valley-thresholds show interesting results.

A look at the individual results in the control group revealed that for most subjects the maxima were decreasing between the day before the shooting and three hours after exposure, with further decrease in maxima until the next day for several subjects. [Figure 6] shows a few examples. [Figure 7] shows the mean results of the PMTF measurements, performed on the left ear only, for both control and NAC groups. Clear decreases of the maximum peak thresholds are seen from the test occasion before shooting, to the result at the end of the shooting day, 3 hours after shooting. An ANOVA was performed with group (control vs. NAC) as a factor between subjects and with peak-valley and time (before, 3 hours after, next day) as repeated factors within subjects. A subsequent Tukey's post-hoc test was also performed. For the control group both the peak threshold and the valley threshold maxima 3 hours after shooting and the next day were significantly lower than the corresponding values before shooting (P < 0.00013). The NAC group showed no corresponding changes (P>0.8). It can also be noted that in the control condition, on the next day, both peak and valley thresholds were even more affected but the difference from 3 hours after shooting was not significant. In the NAC condition they did not change much after the measurement 3 hours after exposure, possibly because a larger proportion of the subjects had started to recover.
Figure 6: Examples of PMTF peak and valley maximum values over time for three subjects in the control group. (a) Peak thresholds. (b) Valley thresholds. Each symbol indicates the same subject in both parts of the figure

Click here to view
Figure 7: PMTF-results. Mean of left ear maximum peak thresholds (left) and mean of left ear maximum valley thresholds (right) over time for the control group (N = 23, dashed lines), and the NAC group (N = 11, solid lines). Vertical bars show 95% confidence intervals

Click here to view


Transientevoked otoacoustic emissions

An ANOVA was focused on the mid frequency range, 2.5-4.5 kHz, since this frequency range should be most influenced by the exposure. The evoked response in dB SPL was the dependent response variable. Group (control vs. NAC) was a factor between subjects. Repeated factors within subjects were response type (correlated vs. uncorrelated), contralateral noise (off vs. on), and time (before vs. after shooting). Stimulus level was not a factor, since the NAC group was only measured at 85 dB peSPL.

Results regarding the efficacy of the NAC treatment are presented first: The factor time was not significant (P=0.16), but the interaction time/group was just inside the significance limit (P=0.0496) and the interaction response type/time/group was also significant (P=0.028). See [Figure 8]. A Tukey's post hoc test showed that the correlated response in the NAC group was significantly higher 3 hours after the shooting than before. There were a few other interactions that were significant, but without interest for the question of the protective effect of NAC. Among these the factor group was significant (P < 0.0039), with the NAC group having 3.2 dB lower response levels, as a mean, than the control group. This was primarily a result of the low response levels of the NAC group measured, untreated, before shooting. Also the factor response type was significant, with the mean level of the correlated response 3.9 dB above that of the uncorrelated response for these relatively normal hearing test subjects. There were no significant changes in contralateral suppression.
Figure 8: Mean TEOAE results of correlated (left) and uncorrelated (right) signals at 2.5-4.5 kHz, before and 3 h after shooting for the control group (N = 23, dashed lines), and the NAC group (N = 11, solid lines). Vertical bars denote 95% confidence intervals

Click here to view



  Discussion Top


Antioxidants have been used in humans, with reported positive results, in age-related hearing loss, [22],[23] Ménière's disease, [24] sudden hearing loss, [25] and meningitis. [26]

There are animal studies of the effects of NAC as protection from noise induced hearing loss in which significant reduction of permanent cochlear damage has been found. However, they have failed to demonstrate a large beneficial effect of NAC in reducing temporary threshold shifts. [7],[8],[10],[11] Ethical limitations for what can be tested on humans in laboratory experiments reduces the possibilities to study NAC as a protector from temporary effects on hearing. Kramer et al. studied persons attending a discotheque. [27] The attendants were randomly selected to receive either NAC or placebo. There were no significant differences in temporary, noise-induced pure tone shift (TTS), or shift in DPOAE amplitude in the two groups. In the present study neither the NAC-group nor the control group showed any TTS. In the NAC group there was an increase in correlated TEOAE response 3 hours after shooting. However, the main differences observed between the groups existed already before shooting and might be attributed to age difference. The control group included a few older officers with larger total exposure, and therefore worse thresholds, but less frequent shooting exercises lately and higher OAE products.

The most striking discovery was that the non-linearity of the cochlea, expressed by the PMTF-findings, was practically unchanged in the NAC-group throughout the study. In the control group there was a highly significant decrease in non-linearity after the noise exposure and it was still decreasing at least until the next day for several subjects.

Effects of NAC treatment were found for all the three types of hearing measurements. The hearing thresholds showed no conventional TTS after noise exposure, with or without NAC. However, we observed an increased threshold variablitity of the left, noise sensitive, ear in the control group after noise exposure, but not in the NAC-group. It is known that the left ear is more vulnerable to e.g., noise than the right ear. [18] This finding speaks in favour of true effects of exposure which are reduced by NAC. Wagner et al. observed increased DPOAE variability (measured 3 times during the first 30 minutes after exposure to noise) during magnetic resonance imageing. [28] Since there were no TTS (hearing thresholds measured only 8 min after exposure) or DPOAE amplitude reduction in their study, the increased variability was interpreted as an indication of very discrete changes in cochlear activity. However, in the present study the hearing thresholds were measured repeatedly, and TEOAEs were measured only once 3 hours after exposure. The variability of thresholds in our study supports Wagner's interpretation, since NAC reduced the threshold variability in the left ear. Articles by Luz and Hodge, [29] Hamernik et al., [30] and Dancer et al. [31] stress the variablity in time course of the recovery depending, among other parameters, on type of noise exposure, species, and individuals exposed. To our knowledge there are no data from humans regarding indoor shooting. We can only speculate, like those authors, that there were individual varieties of metabolic and structural processes going on in the inner ear causing the large intraindividual variation in thresholds. Regulatory systems that overreact or "underreact" may introduce instability.

Numerous studies have shown that exposure to noise, e.g., from weapons or engines, has resulted in amplitude reductions of otoacoustic emissions, TEOAEs and/or DPOAEs, as measured during time spans of days or weeks after impulse noise up to a few years' work in engine rooms. [32],[33],[34] Reduced OAE amplitude levels have been interpreted as an indicator of a risk for future NIHL. [35],[36] The medial olivocochlear (MOC) system has also been studied after exposure to noise. The results are contradictory with reports of no MOC influence, [34],[37] and with signs of such an effect when the MOC function was measured after the exposure. [38] In the present study the NAC group, but not the control group, had a significant increase in correlated TEOAE response 3 hours after exposure (which was also 3 hours after the first NAC tablet), but showed no significant change in contralateral suppression. In another project (not yet published) we found hyperactivity after shooting, which might be interpreted as reduced ipsilateral control of OHC. One interpretation is that also NAC, at some stage, reduces the ipsilateral control of the OHC.

The PMTF group results, but not every subject's results, changed towards the direction of a sensorineural hearing loss caused by continuous noise exposure both with and without NAC [Figure 2]. Without NAC treatment the results continued to deteriorate at least until the measurement the day after exposure. Similar to the hearing thresholds, the reference values of the PMTF (taken the day before exposure) also differed between the groups. This underlines the importance of more balanced groups regarding hearing and possibly age. For future planning it may be kept in mind that for those in the control group, that had an extra PMTF-measurement 20-30 min after exposure, there was no difference from the results before exposure. The effects came later.


  Conclusions Top


The experiments have shown that there were some small, temporary effects on hearing thresholds from shooting 2 times 20 shots in a bare bunker-like room, even with proper hearing protection. The characteristics of the test results, but not the time course of the recovery, indicated exposure from continuous noise-after this exposure to impulse noise in reverberation. The results of the experiment with NAC, in a clinical, low dosage, indicates some protection of the cochlea. This is promising considering the small effects on hearing from the ethically defensible noise exposure, the small and unmatched test groups, and the NAC medication taken only after exposure. Administration of NAC gave some significant changes of the physiology of hearing after exposure. The most striking finding was that the non-linearity of the cochlea, that was strongly reduced in the group without NAC, as manifested by the PMTF-results, was practically unchanged in the NAC-group throughout the study.


  Acknowledgments Top


This project was supported by the Swedish Armed Forces and the University of Michigan, USA. Our sincere thanks to dr. Per-Anders Hellström and captain Michael Millberg for the military arrangements.

 
  References Top

1.Nelson DI, Nelson RY, Concha-Barrientos M, Fingerhut M. The global burden of occupational noise-induced hearing loss. Am J Ind Med 2005;48:446-58.  Back to cited text no. 1
[PUBMED]  [FULLTEXT]  
2.Yamane H, Nakai Y, Takayama M, Konishi K, Iguchi H, Nakagawa T, et al. The emergence of free radicals after acoustic trauma and strial blood flow. Acta Otolaryngol Suppl 1995;519:87-92.  Back to cited text no. 2
[PUBMED]    
3.Ohlemiller KK, Wright JS, Dugan LL. Early elevation of cochlear reactive oxygen species following noise exposure. Audiol Neurootol 1999;4:229-36.  Back to cited text no. 3
[PUBMED]  [FULLTEXT]  
4.Henderson D, McFadden SL, Liu CC, Hight N, Zheng XY. The role of antioxidants in protection from impulse noise. Ann N Y Acad Sci 1999 28;884:368-80.  Back to cited text no. 4
    
5.Le Prell CG, Hughes LF, Miller JM. Free radical scavengers vitamins A, C, and E plus magnesium reduce noise trauma. Free Radic Biol Med 2007;42:1454-63.  Back to cited text no. 5
[PUBMED]  [FULLTEXT]  
6.Coleman J, Huang X, Liu J, Kopke R, Jackson R. Dosing study on the effectiveness of salicylate/N-acetylcysteine for prevention of noise-induced hearing loss. Noise Health 2010;12:159-65.  Back to cited text no. 6
[PUBMED]  Medknow Journal  
7.Kopke RD, Weisskopf PA, Boone JL, Jackson RL, Wester DC, Hoffer ME, et al. Reduction of noise-induced hearing loss using L-NAC and salicylate in the chinchilla. Hear Res 2000;149:138-46.  Back to cited text no. 7
[PUBMED]  [FULLTEXT]  
8.Kopke R, Bielefeld E, Liu J, Zheng J, Jackson R, Henderson D, et al. Prevention of impulse noise-induced hearing loss with antioxidants. Acta Otolaryngol 2005;125:235-43.  Back to cited text no. 8
[PUBMED]    
9.Bielefeld EC, Kopke RD, Jackson RL, Coleman JK, Liu J, Henderson D. Noise protection with N-acetyl-l-cysteine (NAC) using a variety of noise exposures, NAC doses, and routes of administration. Acta Otolaryngol 2007;127:914-9.  Back to cited text no. 9
[PUBMED]  [FULLTEXT]  
10.Ohinata Y, Miller JM, Schacht J. Protection from noise-induced lipid peroxidation and hair cell loss in the cochlea. Brain Res 2003;966:265-73.  Back to cited text no. 10
[PUBMED]  [FULLTEXT]  
11.Duan M, Qiu J, Laurell G, Olofsson A, Counter SA, Borg E. Dose and time-dependent protection of the antioxidant N-L-acetylcysteine against impulse noise trauma. Hear Res 2004;192:1-9.  Back to cited text no. 11
[PUBMED]  [FULLTEXT]  
12.Coleman JK, Kopke RD, Liu J, Ge X, Harper EA, Jones GE, et al. Pharmacological rescue of noise induced hearing loss using N-acetylcysteine and acetyl-L-carnitine. Hear Res 2007;226:104-13.  Back to cited text no. 12
[PUBMED]  [FULLTEXT]  
13.Hamernik RP, Qiu W, Davis B. The effectiveness of N-acetyl-L-cysteine (L-NAC) in the prevention of severe noise-induced hearing loss. Hear Res 2008;239:99-106.  Back to cited text no. 13
[PUBMED]  [FULLTEXT]  
14.Davis RR, Custer DA, Krieg E, Alagramam K. N-Acetyl L-Cysteine does not protect mouse ears from the effects of noise*. J Occup Med Toxicol 2010;5:11.  Back to cited text no. 14
[PUBMED]  [FULLTEXT]  
15.Choi CH, Chen K, Vasquez-Weldon A, Jackson RL, Floyd RA, Kopke RD. Effectiveness of 4-hydroxy phenyl N-tert-butylnitrone (4-OHPBN) alone and in combination with other antioxidant drugs in the treatment of acute acoustic trauma in chinchilla. Free Radic Biol Med 2008;44:1772-84.  Back to cited text no. 15
[PUBMED]  [FULLTEXT]  
16.Lorito G, Giordano P, Petruccelli J, Martini A, Hatzopoulos S. Different strategies in treating noiseinduced hearing loss with N-acetylcysteine. Med Sci Monit 2008;14: BR159-64.  Back to cited text no. 16
[PUBMED]    
17.Berninger E, Karlsson KK. Clinical study of Widex Senso on first-time hearing aid users. Scand Audiol 1999;28:117-25.  Back to cited text no. 17
[PUBMED]    
18.Pirilä T. Left-right asymmetry in the human response to experimental noise exposure. I. Interaural correlation of the temporary threshold shift at 4 kHz frequency. Acta Otolaryngol 1991;111:677-83.  Back to cited text no. 18
    
19.Lindblad AC, Hagerman B, Olofsson Å. Tone thresholds in modulated noise. I. Level dependence and relations to SRT in noise for normal-hearing subjects. Techn. Audiol. report No. 125, Karolinska Institutet, Stockholm; 1992.  Back to cited text no. 19
    
20.Lindblad AC, Hagerman B. Hearing tests for selection of sonar operators. ACUSTICA - Acta acustica 1999;85:870-6.  Back to cited text no. 20
    
21.Lindblad AC, Olofsson Å, Hagerman B. Hearing aid fitting using psychoacoustical modulation transfer functions. In: Beilin J, Jensen GR, editors. Recent developments in hearing instrument technology. Copenhagen: Stougard Jensen; 1993. p. 491-6.  Back to cited text no. 21
    
22.Romeo G, Giorgetti M. Therapeutic effects of vitamin A associated with vitamin E in perceptual hearing loss. Acta Vitaminol Enzymol 1985;7:139-43.  Back to cited text no. 22
[PUBMED]    
23.Takumida M, Anniko M. Radical scavengers for elderly patients with age-related hearing loss. Acta Otolaryngol 2009;129:36-44.  Back to cited text no. 23
[PUBMED]  [FULLTEXT]  
24.Takumida M, Anniko M, Ohtani M. Radical scavengers for Meniere's disease after failure of conventional therapy: A pilot study. Acta Otolaryngol 2003;123:697-703.  Back to cited text no. 24
[PUBMED]    
25.Joachims HZ, Segal J, Golz A, Netzer A, Goldenberg D. Antioxidants in treatment of idiopathic sudden hearing loss. Otol Neurotol 2003;24:572-5.  Back to cited text no. 25
[PUBMED]  [FULLTEXT]  
26.Klein M, Koedel U, Pfister HW, Kastenbauer S. Meningitis-associated hearing loss: Protection by adjunctive antioxidant therapy. Ann Neurol 2003;54:451-8.  Back to cited text no. 26
[PUBMED]  [FULLTEXT]  
27.Kramer S, Dreisbach L, Lockwood J, Baldwin K, Kopke R, Scranton S, et al. Efficacy of the antioxidant N-acetylcysteine (NAC) in protecting ears exposed to loud music. J Am Acad Audiol 2006;17:265-78.  Back to cited text no. 27
[PUBMED]    
28.Wagner W, Staud I, Frank G, Dammann F, Plontke S, Plinkert PK. Noise in magnetic resonance imaging: No risk for sensorineural function but increased amplitude variability of otoacoustic emissions. Laryngoscope 2003;113:1216-23.  Back to cited text no. 28
[PUBMED]  [FULLTEXT]  
29.Luz GA, Hodge DC. Recovery from impulse-noise induced TTS in monkeys and men: A descriptive model. J Acoust Soc Am 1971;49:1770-7.  Back to cited text no. 29
[PUBMED]  [FULLTEXT]  
30.Hamernik RP, Ahroon WA, Patterson JA Jr. Threshold recovery functions following impulse noise trauma. J Acoust Soc Am 1988;84:941-50.  Back to cited text no. 30
[PUBMED]  [FULLTEXT]  
31.Dancer A, Grateau P, Cabanis A, Vaillant T, Lafont D. Delayed temporary threshold shift induced by impulse noises (weapon noises) in men. Audiology 1991;30:345-56.  Back to cited text no. 31
[PUBMED]    
32.Balatsouras DG, Tsimpiris N, Korres S, Karapantzos I, Papadimitriou N, Danielidis V. The effect of impulse noise on distortion product otoacoustic emissions. Int J Audiol 2005;44:540-9.  Back to cited text no. 32
[PUBMED]    
33.Marshall L, Lapsley Miller JA, Heller LM, Wolgemuth KS, Hughes LM, et al. Detecting incipient inner-ear damage from impulse noise with otoacoustic emissions. J Acoust Soc Am 2009;125:995-1013.  Back to cited text no. 33
[PUBMED]  [FULLTEXT]  
34.Shupak A, Tal D, Sharoni Z, Oren M, Ravid A, Pratt H. Otoacoustic emissions in early noise-induced hearing loss. Otol Neurotol 2007;28:745-52.  Back to cited text no. 34
[PUBMED]  [FULLTEXT]  
35.Lapsley Miller JA, Marshall L, Heller LM, Hughes LM. Low-level otoacoustic emissions may predict susceptibility to noise-induced hearing loss. J Acoust Soc Am 2006;120:280-96.  Back to cited text no. 35
[PUBMED]  [FULLTEXT]  
36.Job A, Raynal M, Kossowski M, Studler M, Ghernaouti C, Baffioni-Venturi A, et al. Otoacoustic detection of risk of early hearing loss in ears with normal audiograms: A 3-year follow-up study. Hear Res 2009;251:10-6.  Back to cited text no. 36
[PUBMED]  [FULLTEXT]  
37.Muller J, Janssen T. Impact of occupational noise on pure-tone threshold and distortion product otoacoustic emissions after one workday. Hear Res 2008;246:9-22.  Back to cited text no. 37
    
38.Veuillet E, Martin V, Suc B, Vesson JF, Morgon A, Collet L. Otoacoustic emissions and medial olivocochlear suppression during auditory recovery from acoustic trauma in humans. Acta Otolaryngol 2001;121:278-83.  Back to cited text no. 38
[PUBMED]    

Top
Correspondence Address:
Ann-Cathrine Lindblad
Technical Audiology, KI, M45, Karolinska/Huddinge, SE-141 86 Stockholm
Sweden
Login to access the Email id

Source of Support: Grants from Swedish Armed Forces and the University of Michigan, USA, Conflict of Interest: None


DOI: 10.4103/1463-1741.90293

Rights and Permissions


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
 
 
    Tables

  [Table 1]

This article has been cited by
1 Using prophylactic antioxidants to prevent noise-induced hearing damage in young adults: a protocol for a double-blind, randomized controlled trial
Annick Gilles,Berina Ihtijarevic,Kristien Wouters,Paul Van de Heyning
Trials. 2014; 15(1): 110
[Pubmed] | [DOI]
2 Temporary threshold shift after impulse-noise during video game play: Laboratory data
C. Spankovich,S. K. Griffiths,E. Lobariñas,K. E. Morgenstein,S. de la Calle,V. Ledon,D. Guercio,C. G. Le Prell
International Journal of Audiology. 2014; 53(S2): S53
[Pubmed] | [DOI]
3 Digital Music Exposure Reliably Induces Temporary Threshold Shift in Normal-Hearing Human Subjects
Colleen G. Le Prell,Shawna Dell,Brittany Hensley,James W. Hall,Kathleen C. M. Campbell,Patrick J. Antonelli,Glenn E. Green,James M. Miller,Kenneth Guire
Ear and Hearing. 2012; 33(6): e44
[Pubmed] | [DOI]
4 Digital music exposure reliably induces temporary threshold shift in normal-hearing human subjects
Le Prell, C.G. and Dell, S. and Hensley, B. and Hall III, J.W. and Campbel, K.C.M. and Antonelli, P.J. and Green, G.E. and Miller, J.M. and Guire, K.
Ear and Hearing. 2012; 33(6): e44-e58
[Pubmed]



 

Top