Hearing loss is the most common occupational disease in the United States with noise serving as the presumed causative agent in most instances; noise is identified as a prominent factor in approximately 10 million individuals in the United States with hearing impairments. Despite the characterization of noise exposures that yield temporary and permanent threshold shifts and partial elucidation of mechanisms that are responsible for noise-induced hearing loss (NIHL), there remain significant knowledge gaps concerning factors causing NIHL. One such knowledge gap concerns potentiation of NIHL by simultaneous exposure to chemical agents. We have pursued investigation of the exposure conditions that facilitate the potentiation of NIHL by carbon monoxide. The selection of these specific agents is predicated upon the ubiquitous nature of exposure to chemical asphyxiants and a preliminary understanding of the mechanisms by which chemical asphyxiants disrupt hearing. Our data indicate that the potentiation of NIHL by carbon monoxide increases as a function of carbon monoxide concentration at levels of 500 ppm and above, but that the extent of potentiation shows a nonlinear relationship to total noise energy with the greatest potentiation shown at moderate noise exposures that produce limited permanent threshold shifts. Further, the potentiation of NIHL by carbon monoxide appears to saturate as noise severity is increased such that at the most severe conditions used, the effects of carbon monoxide on NIHL are obscured totally by the noise effect. Finally, the data presented demonstrate that carbon monoxide is able to impair the recovery of NIHL that normally occurs when periods of silence are interspersed within noise exposure.
Keywords: potentiation of noise induced hearing loss, carbon monoxide, chemical asphyxiants, noise
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Fechter LD, Chen GD, Rao D. Characterising conditions that favour potentiation of noise induced hearing loss by chemical asphyxiants. Noise Health 2000;3:11-21
Noise induced hearing loss is recognized as the most common occupational disease in the United States (NIOSH, 1996) with approximately 30 million workers exposed to potentially hazardous noise levels in the workplace (Franks et al., 1996). Formal standards have been adopted for preventing noise induced hearing loss in the Hearing Conservation Amendment (46 Fed. Reg. 4078, 1981) to the US Occupational Safety and Health Act of 1970 (PL 91-596). For non-impact noise, the OSHA permissible exposure level is 90dBA Leq based upon an 8 hr average with a 5 dB trade off when duration of noise is doubled. However, occupational hearing loss from noise remains a significant problem not only in the United States, but throughout the world.
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Fechter LD, Chen GD, Rao D. Characterising conditions that favour potentiation of noise induced hearing loss by chemical asphyxiants. Noise Health [serial online] 2000 [cited 2020 Aug 3];3:11-21. Available from: http://www.noiseandhealth.org/text.asp?2000/3/9/11/31774
There are many different reasons why occupational noise exposure still produces hearing loss at permissible exposure levels. These include problems of accurate noise characterization, problems in equating noise exposures of varying time durations using the "equal-energy principle" (selection of an appropriate relationship between duration and intensity of exposure), and significant individual (and idiopathic) differences in susceptibility that might relate to genetic factors and to unrecognized environmental factors. Research published over the past 10 years shows, clearly, that a number of common environmental contaminants can produce hearing loss both in laboratory animals (e.g. Crofton, 1994; Campo, 1997; Johnson, 1988) and also in working populations (Morata et al., 1993, 1994, 1997 a,b). Moreover, simultaneous exposure to certain environmental contaminants can increase greatly susceptibility to noise induced hearing loss. Since noise is rarely the sole potentially adverse agent present in the workplace, it is critical to determine the characteristics of exposure that favor enhancement of noise induced hearing loss by chemical contaminants.
The importance of this area is underscored by laboratory investigations demonstrating the potentiation of NIHL by carbon monoxide exposure in rats (Young et al., 1987; Fechter et al., 1988; Fechter, 1989) and by epidemiological studies identifying interactions between solvent exposure and noise in the workplace (Morata et al. 1993; 1997 a,b).
The research presented here evaluates conditions favoring potentiation of noise induced hearing loss by the chemical asphyxiant carbon monoxide in pigmented rats. The rationale for studying this agent reflects the frequency with which chemical asphyxiants are present along with noise in the work environment, a good understanding of the mechanisms by which carbon monoxide affects neuronal tissue in general and the cochlear in particular (Fechter et al., 1987; Liu and Fechter, 1995; Fechter et al,. 1997), and early data that demonstrate potentiation of noise-induced hearing loss by carbon monoxide (Young et al, 1987; Fechter et al, 1988).
The results of three different experiments are reported here. In experiment 1 we investigated the effect of carbon monoxide concentration on noise induced hearing loss. The objective was to determine a function relating carbon monoxide concentration to potentiation of noise induced hearing loss so that prediction of the carbon monoxide concentration having the lowest adverse effect on hearing could be made. This process of risk assessment is critical in establishing a reference dose that can be considered "safe" for human exposure.
In the second experiment, the role of noise severity was evaluated in subjects exposed to a single concentration of carbon monoxide in order to determine how the potentiation of noise induced hearing loss changes as noise exposure becomes more severe. The objective here was parallel to that addressed in the first experiment, but focused on the role of noise intensity and duration in determining the potentiating effects of carbon monoxide.
Finally, in the third experiment, the role of silence or rest periods in noise was evaluated in order to determine whether the potentiation of noise induced hearing loss by carbon monoxide would abate if noise were removed. Moreover, cochlear tissue was collected for histopathological evaluation.
The basic experimental design employed a minimum of four treatment groups consisting of noise exposure alone, carbon monoxide exposure alone, combined exposure to noise + carbon monoxide, and a control condition that entailed no exposure to noise or to carbon monoxide. Four weeks following the exposure of subjects within a controlled environment, cochlear function was assessed using electrophysiological methods.
| Methods|| |
Subjects: Long-Evans male pigmented rats 2-3 months of age were employed for all experiments. The subjects were housed with free access to food and water in their home cages. Background sound levels in the colony room were below 50 dB (A), temperature was maintained at 20 ± 1° C. and lights were on from 0630 to 1830. All exposures and testing were performed during the daytime.
Exposure procedure: Subjects were assigned randomly to treatment groups that received noise only, carbon monoxide only, noise + carbon monoxide simultaneously, or air and noise levels < 40 dB(A). Exposures were conducted in a reverberant 50 L glass cylinder equipped with stereo speakers for delivering sound, a Quest 1" microphone and sound level meter for monitoring sound, and a carbon monoxide monitor for measuring the chamber gas concentration. The subjects were placed within small wire cloth enclosures (15 x 13 x 11 cm) within the chamber. They were conscious and free to move within the enclosures.
Noise exposure: Broadband noise was generated by a function-generator (Stanford Research System, Model DS335 and bandpass filtered (Frequency Devices, 9002) to provide an octave band noise with centre frequency of 13.6kHz. The roll-off for the filter system was 48 dB/octave. The noise was amplified by a power amplifier (SAE 2200) and delivered to two tweeters (Vifa D25AG-05-06, 709) in the exposure chamber. The animal cages were located under the speakers with a vertical distance (to cage floor) of about 18 cm. Noise intensity was measured with a Quest sound level meter using a linear weighting. The noise level varied less than 2 dB within the space accessible to the subjects. The background noise levels in the colony room and in the exposure chamber when noise was not added are provided using an A weighting in order to remove building vibration from the apparent noise level. Sound levels used for noise exposures were selected in order to produce metabolic demand on the cochlear predominantly rather than traumatic injury.
Carbon monoxide exposure: Air exchange rate in the exposure chamber was 8.5 L 3 /min (approximately one air change every five minutes), which was monitored by a Top Trak 821-1-PS mass flow meter. Carbon monoxide gas was delivered into the chamber and the carbon monoxide level in the chamber was monitored by an Industrial Scientific sensor and controller. The carbon monoxide concentration in the exposure chamber reached the desired level within about 1 hour of exposure onset. Previous studies showed that carboxyhaemoglobin concentrations approached steady state within 30 min of exposure onset (Chen and Fechter, 1999). Carbon monoxide exposure began for the appropriate subjects 90 min prior to the onset of noise to permit equilibration of carboxyhaemoglobin. The noise exposure durations varied between 2 and 8 hr; carbon monoxide or air exposure time varied, therefore, between 3.5 and 9.5 hr.
Characterization of the carbon monoxide dose response for noise induced hearing loss: Groups of six subjects each were exposed for 8hr to noise (100 dB octave band noise centered at 13.6 kHz) + carbon monoxide (300, 500, 700, 1200 and 1500 ppm), to noise alone, to the highest concentration of carbon monoxide alone, or a control exposure in the chamber without noise and carbon monoxide present. Auditory thresholds were assessed four weeks later.
Alteration of noise severity: Groups of six subjects each were exposed to 1200 ppm carbon monoxide alone or in combination with exposure to octave band noise centered at 13.6 kHz for 2 hr (95 and 100 dB) or for 4 hr (100 dB). Noise control groups that did not receive the carbon monoxide exposure were also employed as was an unexposed control group. Auditory thresholds were assessed four weeks later.
Interrupted noise exposure: Six subjects per group received two hr of noise exposure and noise + carbon monoxide exposure. However, the noise was scheduled differently creating three groups that experienced different one-hour rest periods of silence interspersed in the noise see [Table - 1]. Groups of subjects received noise exposures of 60, 40 and 30 min followed by 60 min quiet. These cycles were repeated, until all subjects had acquired a total of 120 min noise exposure. Total exposure times (noise + rest periods) varied from 3-5 hr providing noise-on periods (noise duty cycles) of 66%, 50% and 40%. Because of the long equilibration and wash out time for carbon monoxide, carbon monoxide concentrations were held steady for the full exposure duration in those subjects assigned to the carbon monoxide + noise and carbon monoxide groups.
Assessment of cochlear function: At four weeks following exposure, the subjects were anesthetized with xylazine (13 mg/kg, i.m.) and ketamine (87 mg/kg, i.m.). Body temperature was monitored for all subjects and maintained at 39oC using a dc heating unit built into the surgical table. The temperature of the cochlea was also maintained using a low voltage lamp. The auditory bulla was opened via a ventrolateral approach to allow the placement of a silver wire electrode onto the round window. A silver chloride reference electrode was placed into the neck muscle. The CAP signals generated in response to sound presentation were amplified 1000x with a Grass A.C. preamplifier (Model P15). The band-pass frequency for CAP was 0.1-1.0 kHz. The sound level necessary to generate a visually detectable CAP response on a digital oscilloscope (approximate response amplitude of 1µV) was identified. The CAP response was not averaged digitally.
Pure tones for eliciting CAP were generated by a SR530 lock-in amplifier (Stanford Research Systems, Inc.) and the tone phase was alternated to reduce the influence of CM on the CAP. The tone intensity was controlled by a programmable attenuator and the output of the attenuators was amplified by a high voltage amplifier and then delivered to the sound transducer in the rat's external auditory meatus. Auditory thresholds were determined for tones of 2, 4, 6, 8, 12, 16, 20, 24, 30, 35 and 40 kHz using tone bursts of 10 msec duration with a rise/fall time of 1.0 msec.
Since auditory thresholds for frequencies below 12kHz were unaffected by noise alone or noise in combination with CO, risk analyses designed to assess the lowest CO exposure level that potentiated the effects of noise were restricted to three frequencies of noise contained in the octave band (12, 16, 20 kHz) and three frequencies above that octave band (24, 30, and 35 kHz). The repetition rate of the tone bursts was 9.7 times/sec. Sound levels at all the testing frequencies were calibrated with a probe microphone located near the eardrum.
Histopathology: At the conclusion of physiological assessment, the cochlea were harvested from a sample of subjects in the intermittent noise study in order to provide tissue for assessment of hair cell loss using a surface preparation. The subjects were decapitated while anesthetized following CAP recording. Cochleae were removed and the round and oval windows were opened and the apex of the cochlea was drilled open. Each cochlea was perfused with succinyl dehydrogenase incubative solution (0.05 M sodium succinate, 0.05 M phosphate buffer and 0.05% TetraNitro Blue TetraZolium) gently using a fine pipette placed over the round window and then immersed in the solution for one hour (37°C). Then the cochlea was fixed with 10% formalin for at least 2 days. After fixation, the cochlea was decalcified in 10% EDTA solution (EthyleneDiamine Tetraacetic Acid) for 3 days or longer. Cochlea microdissection and preparation of slides was performed under a microscope.
The effects of treatment are evaluated by subtracting the mean threshold level of the control subjects (those receiving air and quiet ) from the threshold levels of the various experimental treatment groups. The data were initially analysed using a split-plot ANOVA in which treatment was a between subjects variable and frequency was evaluated as a within subject variable. For risk assessment relating carbon monoxide dose with threshold shift, linear regression analysis was used in order to identify a benchmark dose level. The correlation between CO exposure concentration and extent of potentiation are calculated based upon data obtained from each subject.
| Results|| |
The results of the initial study in which the dose of carbon monoxide required to potentiate noise induced hearing loss are portrayed in [Figure - 1]. The plotted data points represent the additional loss in auditory threshold sensitivity shown by subjects exposed to octave band noise at 100 dBLn for 8 hr in combination with carbon monoxide as compared to those subjects that received the noise exposure alone. Loss of threshold sensitivity is averaged across either three high frequencies (24-35 kHz) or three middle frequencies. The latter were frequencies contained in the noise exposure (12-20 kHz). For both high and middle frequencies, threshold sensitivity is progressively more impaired as carbon monoxide concentration increases. Statistical analysis demonstrated a significant elevation in threshold due to carbon monoxide exposure (F 5,35=16.48, p<0.0001) and post hoc analyses demonstrated that carbon monoxide concentrations of 500 ppm and greater were significantly different from control (p<0.05). If regression lines are plotted for each frequency range, an estimate of the carbon monoxide concentration that yields no potentiation of the noise induced hearing loss can be attained. This value is 365 ppm for high frequency tones and 218 for middle frequency tones.
In contrast to the linear increase in potentiation observed when carbon monoxide concentrations are increased in the presence of noise, increasing the total noise energy level (sound intensity or exposure duration) does not have comparable effects on the potentiation of impairment resulting from simultaneous exposure to noise and carbon monoxide see [Figure - 2]. While the average noise induced hearing loss increased under conditions of increasing total noise energy level from 4 ± 2 to 13 ± 2 to 23 ± 2 dB (data not shown), potentiation of noise induced hearing loss by carbon monoxide due to simultaneous exposures follows a non-monotonic response. No significant hearing loss due to noise alone or noise + carbon monoxide was observed under conditions of the mildest noise exposure. At the intermediate level of noise severity (100 dB for 2 hrs), a significant potentiation of noise induced hearing loss by carbon monoxide is observed. However, even further increases in noise severity by increasing duration of the 100 dB noise exposure from 2 to 4 hr during combined exposures did not yield any increase in potentiation. Under the most severe noise exposure used, the loss in threshold sensitivity obtained by noise treatment alone obscures any elevation in noise induced hearing loss resulting from the carbon monoxide treatment. Since hearing loss of at least 60 dB relative to controls can be detected by this method (Chen and Fechter, 1999), it appears that the failure to find additional impairment in auditory threshold among subjects subjected to 100dB octave band noise for 4 hr + carbon monoxide did not reflect merely insensitivity of the method for assessing cochlear function.
Analysis of variance showed a significant interaction between treatment and frequency (F60,350 p<0.0001) as well as significant main effects of treatment (F6,35 =9.892, p<0.0001) and frequency (F10,350=37.044, p<0.0001). Post hoc analysis of the interaction effect showed a significant difference between untreated control subjects and those exposed to noise levels of 100dB for both 2 and 4 hours (p<0.02 and 0.0001 respectively) as well as between untreated controls and those receiving 100dB noise + carbon monoxide for both 2 and 4 hours (p's<0.0001). Significant differences were also found between subjects receiving noise alone for 2 hours and those receiving noise + carbon monoxide for this time interval (p<0.01).
Similar findings can be observed in [Figure - 3] where the effects of carbon monoxide exposure are evaluated under three conditions of interrupted noise. While the auditory threshold impairment averaged between 2-40kHz frequencies increased for those subjects receiving noise alone as the number and duration of rest periods decreased, the loss in threshold observed in the combined exposure groups remained relatively stable for all noise duty cycles. Thus, at least in the presence of constant carbon monoxide exposure, periods of silence did not provide subjects in the combined exposure group with an opportunity for recovery of auditory function. Statistical analysis showed a significant interaction between treatment condition and noise duty cycle (F 2,40= 9.411, p< 0.0004) as well as significant main effects of treatment (F 1,20= 15.490, p < 0.0008) and duty cycles (F 2,40= 14.638, p < 0.0001).
The striking physiological differences observed between noise only and combined exposure can also be observed in the histopathological material exemplified in [Figure - 4]. Comparing the difference in staining of succinyl dehydrogenase as a marker for hair cells, only scattered missing outer hair cells are observed in a section of the basal turn from a subject treated with periods of 30 min noise separated by 60 min of silence. In contrast, a comparable section of the basal turn from a subject receiving combined exposure to the same noise pattern + carbon monoxide shows nearly complete loss of outer hair cells while inner hair cells appear to be intact.
| Discussion|| |
Noise is clearly the predominant environmental hazard to hearing. While exposure standards are important in protecting against noise induced hearing loss, the evaluation of complex exposures for their potential to injure the ear must be undertaken. The data presented here provide an initial understanding of the conditions under which an important class of toxicants, the chemical asphyxiants, can potentiate noise induced hearing loss. The data show a linear relationship between carbon monoxide concentration and extent of potentiation of noise induced hearing loss. Statistically significant elevations in threshold are observed with carbon monoxide exposures of 500 ppm and higher, yet correlational analysis suggests that the theoretical carbon monoxide level at which auditory thresholds might be elevated lies between 200-400 ppm carbon monoxide in rats. How might such exposure conditions relate to human exposure and human health? The predicted threshold levels at which carbon monoxide exposure potentiates noise induced hearing loss far exceed permissible exposure levels for carbon monoxide. In the United States, the Environmental Protection Agency permits ambient exposure levels of 9 ppm averaged over 24 hr and 35 ppm averaged over 1 hr. For work environments, the standards proposed by ACGIH and by OSHA are 50 ppm averaged over an 8 hr work day, with a peak level of 200 ppm. However, a process of risk assessment is critical to determining possible human health consequences. While agencies and scientists differ with regard to the precise manner in which risk characterization determinations are made (e.g. Ohanian et al., 1997), they typically entail laboratory investigations designed to characterize a threshold dose for some toxic agent that produces the smallest recognizable adverse effect. We have done this through a process known as "benchmarking" in which a function is fit to data in order to predict the concentration of a chemical having a known adverse effect (Slikker et al., 1996) such as the elevation of auditory threshold by 1dB. This dose is then modified by safety factors that represent uncertainty concerning differential susceptibility of the study sample compared with the human population with which we are actually concerned. There is an on-going debate about the size of the safety factor that should be accorded on the basis, for example, of species differences, extrapolation from sub-chronic to chronic exposures, and increased sensitivity of particular groups within the population such as the elderly or very young. However, it is fairly common to adopt a safety factor of 10 in setting permissible human exposures based upon laboratory animal data (c.f. Slikker et al., 1996). This "reference dose" then becomes the best estimate of a safe exposure for humans. Based upon our data, we predict a benchmark dose of carbon monoxide for potentiation of noise induced hearing loss of 218 ppm for mid-frequency tone thresholds. When modified to account for possible greater susceptibility of people compared with rats, we obtained a reference dose of 22 ppm. Thus, using currently accepted standards for assessing risk, human carbon monoxide exposures are approximately at or somewhat above the reference dose required to maintain safety from potential of NIHL by carbon monoxide.
Unlike the findings with respect to carbon monoxide, the current data show that the potentiation of noise induced hearing loss by carbon monoxide does not grow with increasing severity of noise exposure. Rather, the potentiating effects of carbon monoxide are apparent with intermediate noise exposures that by themselves result in threshold shifts of approximately 20dB. As expected, permanent threshold shifts attributable to noise alone do increase as noise exposure becomes more severe, but there is no added effect or potentiating effect of carbon monoxide when noise exposure exceeds a specific level; in this instance octave band noise of 100 dBLn for 2 hr.
In this research we have begun to investigate the value of rest periods from noise exposure in evaluating the effects of carbon monoxide on noise induced hearing loss. Note that these initial studies have maintained the carbon monoxide exposure during the periods of silence. Here we find results that are comparable in many respects to our second study in which noise duration was varied; namely, among those subjects exposed to noise only, the magnitude of the auditory impairment increases as the number of rest periods in noise decreases. By contrast, among those subjects exposed to both noise and carbon monoxide, there is no relationship between number of rest periods and extent of noise induced hearing loss; the loss in hearing is flat across all treatment groups. While it might be argued that the data are confounded because the total length of carbon monoxide exposure increases along with the number of rest periods from noise and that carbon monoxide might act to elevate thresholds even as the extra rest periods provide an opportunity for the cochlea to recover, there is no evidence that carbon monoxide exposure alone can produce permanent threshold shifts either from prior studies (Young et al, 1987; Fechter et al, 1988) or from subjects receiving carbon monoxide by itself in the current study.
Finally, the current report provides additional evidence that the potentiation of noise induced hearing loss by carbon monoxide entails impairment of the outer hair cells at least in the basal turn of the cochlea. Whether inner hair cells or spiral ganglion cells are disrupted cannot be answered at this time.
| Acknowledgements|| |
This research was supported in part by NIOSH (OH 03481 ), NIH (ES 08082), and NSF (EPS9550478). The authors are grateful to Misty McWilliams and Paula Meder for their help in preparing this manuscript.
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Laurence D Fechter
Centre for Toxicology, University of Oklahoma Health Sciences Centre, Oklahoma City OK 73190
Source of Support: None, Conflict of Interest: None
[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4]
[Table - 1]