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|Year : 2005
: 7 | Issue : 28 | Page
|Combined effects of noise and gentamicin on hearing in the guinea pig
F Bombard, P Campo, R Lataye
Institut National de Recherche et de Sécurité, Vandoeuvre, France
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The last ten years, the use of gentamicin has increased due to antibiotic resistance among bacterial pathogens. One of the side effects of gentamicin is its toxicity on hearing. Several authors had even pointed out synergistic effects of gentamicin and noise on hearing. It was therefore reasonable to think that the damaging effects of noise could be emphasized by a gentamicin treatment of the subjects. In order to test the applicability of the Leq8h for estimating the hazard of noise on animals treated with a non-ototoxic dose of gentamicin (40 mg/kg for 8 days), two experiments were carried out with guinea pigs. The animals were exposed to octave band noises centered at 8 kHz and treated with gentamicin either simultaneously or sequentially with regard to the noise exposure. Two noise exposures having different acoustic energy, respectively Leq8h = 85 dB and 98.8 dB SPL, were tested. The auditory function of the guinea pigs was tested by recording auditory-evoked potentials. The electrophysiological findings were completed by histological data. The gentamicin treatment tested in the current studies did not cause any auditory permanent threshold shift neither cochlear disruptions, although the treatment could be considered as approximately ten times the therapeutic dose used in human. The auditory deficit induced by the mixed exposures to noise and gentamicin did not worsen the noise effect alone in our experimental conditions. As a result, the European value recommended for noise exposure (Leq8h=85 dB) seems to be robust enough to protect gentamicin-treated workers.
Keywords: noise, gentamicin, ototoxicity, combined exposure, animal
|How to cite this article:|
Bombard F, Campo P, Lataye R. Combined effects of noise and gentamicin on hearing in the guinea pig. Noise Health 2005;7:29-39
| Introduction|| |
Workers are continuously exposed to a wide variety of chemical, biological and physical agents which can be considered as stressors encountered both in and out of the workplace. Mixed exposures may produce acute or chronic effects or a combination of acute and chronic effects, with or without latency. Discovered in the 1940s, the aminoglycoside antibiotics were the long-sought remedy for tuberculosis and other serious bacterial infections. In spite of their nephrotoxic and ototoxic side effects, they are currently receiving renewed attention in industrial countries because of the increasing concerns regarding antibiotic resistance (Allen et al., 1999). The pathology of gentamicin-induced hearing loss (GIHL) is similar for guinea pigs and humans. The primary effect in the cochlea is a destruction of the outer hair cells (OHCs), beginning in the base and progressing to the apex, which leads from high to low-frequency deficits (Garezt et al., 1994; Forge and Shacht, 2000). Gentamicin produces varying degrees of ototoxicity depending on dose level, dosage time and inter-individual variability, but the rationale for the present investigation was not to assess the ototoxic effects induced by gentamicin. Actually, GIHL has been extensively studied in guinea pigs (Govaerts et al., 1990). As a result, we considered the ototoxic effects for granted and focused on the determination of a non-ototoxic dose of gentamicin in guinea pigs. To achieve this purpose, the effects of four different doses 40, 60, 80 and 100 mg/kg for 8 days were tested on hearing in an unpublished pilot study. While the ototoxic effects of the concentrations of 80 and 100 mg/kg were really obvious, the effects obtained with 60 mg/kg were less convincing. Only the lowest concentration was undoubtedly non-ototoxic, so a concentration of 40 mg/kg was chosen for the combined (noise and gentamicin) investigations. As far as this concentration is concerned, it is worth mentioning that such a treatment corresponds to ten times the prescribed pharmaceutical treatment required for humans (BIAM: Alfandari, 2004).
Taking a safety factor having a value of ten is a common approach for risk assessment of ototoxicants (Slikker et al., 1996) and this value is not exaggerated since risk assessors can occasionally go up to 100 (Ecetoc, 1995). Due to the persistence of gentamicin in the endolymphatic canal: 15 days according to Tran Ba Huy et al. (1983), 30 days according to Forge and Schacht (2000), or even 11 months according to Aran et al. (1999), depending on the species and the doses, we were also worried about the duration of the cochlear resistance to noise of a subject, which was previously treated with a non-ototoxic gentamicin dose. Collins (1988) found a synergistic effect between gentamicin (50mg/kg for 10 days) and noise which was an 8 kHz pure tone emitted at 116 dB for 60 minutes. But, in our opinion, such an intensity for a pure tone was really unrealistic. As a result, the question of a potentiated interaction between a non-ototoxic gentamicin dose and a permissible wide band noise was therefore raised in terms of occupational safety. Because the European noise legislation is based on the notion of Leq8h used as a damage-risk criterion (Directive 2003 : L4238), the applicability of the Leq8h for estimating the hazard of a noise having a permissible acoustic energy (Leq8h=85 dB) on animals treated with a non-ototoxic dose of gentamicin was questioned in this study.
The aim of the present investigation, carried out with guinea pigs, was to test the applicability of the Leq8h as a damage-risk criterion, when the animals were exposed to noise and treated with a non-ototoxic dose of gentamicin (40 mg/kg for 8 days) either simultaneously or sequentially. Two different noise exposures were tested. The first noise exposure was an octave band noise centered at 8 kHz having a permissible Leq8h of 85 dB SPL, whereas the second one had the same spectrum but a Leq8h of 98.8 dB SPL. The auditory function was tested by recording evoked potentials by using two different techniques. The recording electrode was either implanted into the inferior colliculus or placed on the round window. The first approach was used with the first mixed exposure (40 mg/kg + Leq8h = 85 dB). It allowed to follow up the auditory thresholds during and after the exposure. The second technique which is more efficient in terms of frequency discrimination, was used with the noise exposure having the highest intensity (40 mg/kg + Leq8h = 98.8 dB). The totality of the electrophysiological findings was completed by counting the hair cells along the organ of Corti and by scanning electron microscopic analysis of the stereocilia.
| Materials and methods|| |
A total of 89 (32 in the chronic study and 57 in the acute study ) albinos male guinea pigs (300350 g) provided by Charles Rivers Laboratories was used in this study. Food and tap water was given ad libitum. In animal facilities, the temperature was 21 ± 2 °C with 55 ± 10% of hygrometry and a 12:12 light-dark cycle. The investigators adhered to the Guide for Care and Use of laboratory Animals, as promulgated by the French Conseil d'Etat through Decret No. 87-848 published in the French Journal Official on 20 October 1987 and modified by the Decret 2001-464 published in the French Journal Official on 29 may 2001.
| Audiometry|| |
Half an hour prior to the surgical anaesthesia, atropine sulphate and levomepromazine (0.15 and 12.5 mg/kg) were given to animals by i.p. injection to minimize stress and respiratory distress. Deep anaesthesia was induced by injection of a mixture of ketamine and xylazine (45 and 5 mg/kg). During the anaesthesia, the core temperature of the animals was maintained at 38°C using a heating pad control system. Otoscopic examination was carried out to verify that the tympanic membranes were free from obstruction, infection or other abnormalities.
Implantation into the right inferior colliculus
Animals were placed in a stereotaxic table with special ear bars to prevent damage to the eardrums. The left ear bar was perforated to leave the external meatus free for acoustic stimulation. The bregma used as stereotaxic reference landmark was exposed. The accurate coordinates for the central nucleus of the right inferior colliculus, obtained from previous measures collected in the laboratory, were -10 mm from bregma on the anteroposterior axis and -0.18 mm on the lateral axis. A tungsten microelectrode covered with Teflon was implanted into the inferior colliculus, whereas a platinum reference electrode was inserted onto the vertex of the animals above the olfactory bulbs. Both electrodes were fastened to a transistor socket and fixed with dental cement to the skull. Such an implantation allowed the recording of the auditory-evoked potentials for 3 months and was considered as a chronic technique.
Implantation on round window
After a retroauricular incision, the otic capsule was exposed by cutting through the connective tissue and the neck musculature. The tip of the recording electrode (platinum wire insulated) was inserted through a guide hole under visual control. When the electrode tip was on the edge of the round window, the electrode was anchored onto the otic capsule with dental cement. As previously, the reference electrode was inserted onto the vertex of the animals above the olfactory bulbs. The measuring and reference electrodes were fastened to a transistor socket and fixed with dental cement to the skull. This acute technique, which is more efficient in terms of frequency discrimination, allowed to record auditory-evoked potentials right after the implantation.
Hearing testing was performed in an audiometric room. Guinea-pigs were placed in a restraining device that ensured constant distance (15 cm) and orientation from the left pinna to the speaker (JBL 2405). The generation of the sound stimuli and the signal treatment were performed with a Tucker-Davis technologies apparatus equipped with Biosig software. The acoustic stimuli, 2 cycles for the rise/fall ramp, 4 cycles for the plateau, were filtered clicks and gated sinusoidal stimuli at 2, 4, 8, 10, 12, 16, 20, 24 and 32 kHz.
The acoustic stimuli were emitted at a rate of 20 per second. The analysis window lasted 10 ms and 30 ms for the acute and chronic techniques respectively. After amplification (x2.10 3 ) and filtering between 30 and 3000Hz, the electrophysiological potentials were fed into a signal average (n=260) in order to determine a 14µV amplitude (peak to peak, chronic technique) or a 10µV amplitude (peak to peak, acute technique), which were considered as the threshold value in our respective experimental conditions.
Non-ototoxic gentamicin treatment
Guinea-pigs received a saline solution of gentamicin (40 mg/kg) by a sc injection for 8 consecutive days.
Whatever the experiment, the animals were exposed to a continuous octave band noise centered at 8 kHz (OBN8kHz). The noise spectrum, illustrated in [Figure - 1], was chosen in order to cause hearing loss in a frequency ranges where auditory sensitivity is the highest. They were housed in individual cages with a speaker above the cages. The noise level inside the chambers did not exceed 66 dB SPL for guinea pigs not exposed to noise.
Noise exposure having a Leq8h of 85 dB
The guinea-pigs implanted with an electrode into the inferior colliculus were exposed to a 86.2 dB (± 1 dB) OBN8 kHz for 5 days, 6 hours per day (5d, 6 h/d). As a result, the Leq8h of this exposure was therefore 85 dB.
Noise exposure having a Leq8h of 98.8 dB
The guinea-pigs implanted with an acute electrode on the round window were exposed to a 100 dB (± 1 dB) OBN8 kHz for 6 hours per day, 5 days per week for 4 weeks (6h/d, 5d/w, 4w). The Leq8h of this exposure was 98.8 dB.
| Experimental design|| |
Combined exposure with noise having a Leq8h=85 dB
[Figure - 2] illustrates the experimental design followed in this first experiment. Four groups of eight guinea-pigs were used. The gentamicin group was treated with gentamicin alone, the noise group was exposed to noise alone, and the combined group was simultaneously exposed to noise and treated with gentamicin. One unexposed and untreated group was used as controls. The audiometric thresholds were measured
- one day (d-1) before the beginning of the noise exposure which lasted from d0 to d28,
- one day before the gentamicin treatment which lasted from d0 to d7,
- and at day 39.
The permanent threshold shift (PTS= Audio2 - Audio1) was calculated for each animal as indicated in [Figure - 2].
Combined exposure with noise having a Leq8h=98.8 dB
Fifty seven guinea-pigs were split up in several groups as indicated in [Table - 1].
Whatever the experimental design tested in this experiment [Figure - 3], the implantation of the electrode on the round window was always performed 3 weeks after the end of noise exposure and 7 weeks after the end of treatment for the gentamicin group.
As illustrated in [Figure - 3], three different durations (one, two and three weeks) between the end of the gentamicin treatment and the beginning of the one week-noise exposure were tested.
After the last audiogram, the animals were deeply anaesthetized with a heavy dose of pentobarbital (165mg/kg). The animals were fixed by intracardiac perfusion with 400mL of a mixture of 3% glutaraldehyde, 2% formaldehyde, 1% acrolein and 2.5%, dimethylsulfoxide in a trihydrate solution of sodium cacodylate (0.08M, pH 7.4). After the perfusion, the cochlea were harvested and left in the fixative for 24h. Then the cochleae were postfixed with OsO4 1% in 0.1M cacodylate buffer (pH 7.4) for 1h. For each animal, one cochlea was used for surface preparation, whereas the second was used for scanning electron microscopy.
The cochleae were drilled and dissected in 70% ethanol at room temperature. The organ of Corti was dissected away in five pieces, mounted in glycerin and observed at (400X) using a microscope for counting the hair cells. Cells were counted as present if either the stereocilia, the cuticular plate, or the cell nucleus could be visualized. No attempt was made to assess the degree of possible cellular damage to surviving cells. Data of each row of hair cells were entered in a home-made software and the frequency place map established by Greenwood (1990) was used to superimpose the frequency coordinates on the length coordinates of the organ of Corti. A cochleogram showing the percentage of hair cells loss as a function of distance from the base of the organ of Corti was plotted for each animal.
The results were averaged across each group of animals for comparison between groups.
Scanning electron microscopy
The bony shell was picked off to expose the organ of Corti. The samples were dehydrated in ascending concentrations of ethanol up to 100% and immersed for three minutes in hexamethyldisilazane. Then they were placed in a vacuum drying chamber overnight. The dried specimens were mounted on brass tubs using conductive silver paint and finally sputter-coated with gold. The tissues were viewed on a Jeol 7400 scanning electron microscope.
Two-way ANOVA was run in both studies. The "treatment" was considered as a between subjects factor, whereas the "frequency" was considered as a within-subject factor. The ANOVA allowed an evaluation of either the "treatment" or the "frequency" effect and the "treatment x frequency" interaction. An α level of 0.05 (significant at 95%) was used for the significance of the tests.
| Results|| |
Combined exposure with noise having a Leq8h=85 dB
[Figure - 4] presents the permanent auditory threshold shifts (PTS) obtained with the three exposed groups and compared to the age matched controls. The peak of the PTS amplitude (~12.5 dB) appeared at 10 kHz in the group exposed to noise only, but the differences of amplitudes between PTS values were not large enough to reach the statistical reliability between the four groups [Fgroup(3, 260) = 2.17, p = 0.11] and this statement was true whatever the frequency [F group X frequency (24, 260) = 0.66; p = 0.88]. In fact, the values obtained with the combined group exposed to noise and treated with gentamicin were the lowest, highlighting the lack of effect in these experimental conditions.
[Figure - 5] (A) illustrates the average cochleogram (n=4) or, in other terms, the hair cell loss obtained after the mixed exposure. The lack of hair cells (up to 90%) at the apex of the cochlea was absolutely independent of the experiment conditions and exists even in the control subjects. From a general point of view, [Figure - 5] revealed very small amount of hair cell loss scattered along the organ of Corti. The maximum of hair cells loss was positioned at the vicinity of 11 kHz at the level of the first row of outer hair cells (OHC1), but nothing convincing compared to the control cochleogram [Figure - 5](B). In fact, the cochleogram of the controls [Figure - 5]B and of the combined group [Figure - 5]A are flat for all the rows of hair cells, except at the apical extremity. There is therefore a good agreement between electrophysiological and histological data.
Combined exposure with noise having a Leq8h=98.8 dB
[Figure - 6] shows that noise-induced hearing loss was located in a frequency range from 8 to 16 kHz, with a peak of loss occurring around 10 kHz [F frequency(8, 413) = 12.95, p<0.001]. The maximum of hearing loss was therefore positioned approximately one-half octave above the centre frequency of the exposure (8 kHz). In fact, [Figure - 6] showed significant [F group (5, 413) = 17.88, p<0.001] auditory threshold shifts in the totality of the noise-exposed groups (Noise and GN1, 2, 3) compared to the non-exposed groups (controls and genta). Post hoc analyses (LSD 95%) showed that there was no significant difference between the control and genta groups and between the 4 noise-exposed groups (Noise, GN1, 2, 3).
The average cochleogram relating to all groups were flat for all the rows of hair cells. Because they were not different from those depicted in [Figure - 5], they were not reported. Obviously, the presence or lack of hair cells is not the only parameter of deafness. The stereocilia "condition" is also an important parameter to take into consideration to better understand the different tiers of the acoustic trauma. [Figure - 7] (A,B) shows damaged stereociliae mainly at the level of the first row of OHC in the mid frequency region. The impaired stereociliae were splayed and some of them fused at the extremities of the W shape depicted by the stereociliae.
| Discussion|| |
The European parliament and the council of the European union has recently published in the directive 2003/10/EC on the minimum health and safety requirements regarding the risks related to noise exposure at the workplace. Taking into account scientific progress, the main parameter used as risk predictor is the time weighted average of the noise exposure levels for a nominal eight-hour working day (LEX,8h). In this directive, the upper exposure value requiring an action was LEX,8h = 85 dB(A), but nothing was indicated in case of mixed exposures with an ototoxic agent such as gentamicin for instance. To test the robustness of this value in case of a mixed exposure, the interaction between a non-ototoxic dose of gentamicin and a permissible noise was tested in the current experiments. Because guinea pigs were used as a animal model, the damage-risk criterion was reduced to a Leq8h of a 85 dB SPL value. It would not have made sense to use dB weighted A with guinea pigs.
In a pilot study, a 40 mg/kg treatment for 8 days turned out to be non-ototoxic in guinea pigs. By the way, the results presented in [Figure - 4] confirm the harmlessness of such a treatment, since there is no significant difference between the PTS values obtained with the genta and control groups. In addition, [Figure - 4] shows the lack of synergistic effect of the combined exposure carried out with a 86.2 dB-noise for 6 h (Leq8h=85 dB). The lack of risk for four-week period tested was first stated with the electrophysiological data and then confirmed with histological data at the level of the cochlea [Figure - 5]. If the combined effects of gentamicin associated with noise have already been reported in the literature (Collins, 1988 ; Aran and Portmann, 1990), one must admit that either the antibiotic dose or the intensity of the noise tested by the cited authors were somehow unrealistic. For instance, Collins used a treatment of 50 mg/kg for 10 days associated with an 8 kHz pure tone (116 dB) for sixty minutes. The author himself considered the gentamicin treatment as a sub-ototoxic dose and the pure tone having a level of 116 dB can be considered as above the "critical level", which means that the stresses developed within the organ of Corti exceed the elastic limits of the tissues. In such conditions, it is clear that such a noise caused mechanical damages (Hamernik et al., 1993), what is not compatible with occupational exposure conditions. Concerning the experiment performed by Aran et al. (1990), the gentamicin dose was really huge (150 mg/kg). The reader has to keep in mind that 40 mg/kg corresponds to approximately ten times the therapeutic dose in human. In our opinion, if there is a synergistic risk between noise and gentamicin, the conditions required to see such an effect are incompatible with those encountered in industry. The only point which might deserve to be verified concerns the nature of the noise. Indeed, an impulsive noise could be more noxious than a continuous noise having the same acoustic energy.
The second experiment carried out with an OBN centered at 8kHz and emitted at 100 dB was dedicated to test the cochlea sensitivity to a damaging noise (Leq8h=98.8 dB) with animals previously treated with a non-ototoxic dose of gentamicin. As in the previous experiment, the gentamicin treatment (40 mg/kg for 8 days) did not cause any auditory permanent threshold shift neither cochlear disruptions. Even with the use of a technique which was very sensitive to the "health" conditions of the cochlea, we did not find any significant difference between the control and gentamicin groups.
On the contrary, the high-intensity noise severely impaired the guinea pigs hearing, as expected. The peak losses (~ 35 dB) occurred around 10 kHz, or approximately half an octave above the exposure centre frequency. Despite the amplitude of the auditory threshold shifts, the cochleogram were flat, testifying that the major morphological changes mainly concerned the stereocilia (Liberman, 1987 a,b) in the current investigation. These changes were observed at the level of the first row of outer hair cells [Figure - 7]B,c which corresponds to a noise signature (Robertson and Johnstone, 1980), rather than an aminoglycoside-induced damage (Williams et al., 1987). In addition, the cochlear impairment was positioned in the mid-frequency and not the high-frequency region as expected from a gentamicin-induced trauma (Collins, 1988).
Such a noise-induced damage was expected, since the Leq8h was largely superior to the permissible value. More unexpected was the absence of effect due to gentamicin on the noise trauma, whatever the delay (one, two or three-week period) tested between the noise exposure and the gentamicin treatment. Actually, whatever the intensity of the permissible or the high intensity continuous noises, the auditory deficits induced by combined exposures to noise and gentamicin were not greater than those induced by the noises alone.
| Conclusion|| |
A 40mg/kg treatment of gentamicin for 8 days was controlled as non ototoxic in our experimental conditions. In the same way, a continuous noise defined as an octave band noise centered at 8kHz emitted at 86.2 dB for 6 hours per day, 5 days per week, for 4 weeks did not cause any auditory dysfunction nor cochlear impairment. These findings are rather reassuring for human hearing and the policymakers involved in European and French legislations since they used a Lex,8h of 85dB(A) as a risk predictor. Finally, a 40 mg/g treatment for 8 days does not potentiate the continuous noise effects and conversely.
| Acknowledgements|| |
The authors wish to thank C. Barthelemy, S.Veissiere and O. Rastoix (INRS, France) for their technical assistance.
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Source of Support: None, Conflict of Interest: None
[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5], [Figure - 6], [Figure - 7]
[Table - 1]
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