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Year : 2006  |  Volume : 8  |  Issue : 32  |  Page : 114-133
Effects of industrial solvents on hearing and balance: A review

School of Audiology, UCL Ear Institute, University College London, London, United Kingdom

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  Abstract 

Industrial hearing loss has generally been associated with noise exposure, but there is a growing awareness that industrial solvents can have an adverse effect on the auditory and vestibular systems in man. Both animal experiments and human studies point to an ototoxic effect of industrial solvents, as well as some central auditory and vestibular disturbances.
This review examines the research from the last four decades in an attempt to get an overview of the available evidence.
Research shows that industrial solvents are ototoxic in rats. The majority of the solvents studied cause a loss of auditory sensitivity in the mid-frequencies in rats, affecting outer hair cells in the order OHC 3 > OHC 2 > OHC 1 . Inner hair cells are generally unaffected. Spiral ganglion cells are most vulnerable to trichloroethylene. Simultaneous exposure to solvents and noise results in a synergistic effect; the pattern of trauma mirrors that due to solvent exposure rather than noise, but is more enhanced. There is a critical level when synergy occurs.
The effects of solvents on the vestibular system are neurotoxic and influence the vestibulo-oculomotor system in both animals and humans; humans also present with problems in postural sway.
There is a strong suggestion from human studies that solvents are ototoxic in man, but findings show that both the peripheral and central auditory pathways can be affected. Hearing losses can be in the high frequency region or can affect a wider range of frequencies. Hearing loss and balance disturbances can occur at levels below permitted levels of exposure.
The synergistic effect of combined exposure to solvents and noise has also been noted in humans, resulting in greater hearing losses than would be expected from exposure to noise and solvents alone.
The findings from both human and animal studies indicate that exposure to industrial solvents or to industrial solvents and noise can have an adverse effect on hearing and balance. The implications for industry and hearing conservation are far reaching.

Keywords: Balance, carbon disulfide, hearing loss, industrial solvents, noise, styrene, TCE, toluene, xylene

How to cite this article:
Hodgkinson L, Prasher D. Effects of industrial solvents on hearing and balance: A review. Noise Health 2006;8:114-33

How to cite this URL:
Hodgkinson L, Prasher D. Effects of industrial solvents on hearing and balance: A review. Noise Health [serial online] 2006 [cited 2019 Oct 17];8:114-33. Available from: http://www.noiseandhealth.org/text.asp?2006/8/32/114/33952
The ototoxic effects of industrial solvents on workers' hearing and balance have been reported for only a relatively short time, [1],[2] in their long history of industrial use.

Numerous animal experiments and field studies have highlighted the ototoxic effects; yet whilst the risk of exposure to high levels of noise is well understood, the risk of exposure to industrial chemicals remains less well defined.

According to Prasher et al., [3] there are currently around 30 million people in Europe exposed to working environments where the level of noise is hazardous to hearing, with an additional 10 million working in environments where they are exposed to hazardous chemicals, which include industrial solvents. Many of these workers are exposed to both hazards, which could have a dramatic effect on hearing and balance that would not be expected from exposure to occupational noise alone.

Solvents used in industry that are known to affect hearing and balance are toluene, styrene, carbon disulfide, trichloroethylene and xylene. [3] The neurotoxic effects of such chemicals on exposed workers can be acute - in the form of narcosis, central nervous system (CNS) depression, respiratory arrest, unconsciousness and even death. [4] The evidence for chronic effects points to peripheral neuropathy and mild toxic encephalopathy in solvent-exposed workers. [4]

Epidemiological studies have shown that impaired memory, emotional instability, dizziness, nausea and impaired reaction time are some of the side effects of solvent exposure.


  Toluene Top


Toluene is one of the most extensively researched of the industrial solvents. Toluene is an aromatic hydrocarbon (C6H5CH3). It is a noncorrosive, volatile liquid with an aromatic odor. Worldwide production is estimated to be 10 million tonnes and stems from two main sources: the catalytic conversion of petroleum and by-product of the coke industry. [5],[6]

Toluene is most frequently used for the manufacture of paints, other chemicals, thinners, adhesives, rubber; and in rotogravure printing and leather tanning. Toxicity from toluene can occur from accidental or deliberate inhalation of fumes, ingestion or absorption through the skin.

Toluene affects the central nervous system primarily. Acute exposure to high doses can provoke euphoria and excitability, which is followed by a depressant response. Long-term exposure can lead to impaired memory and concentration levels, emotional disturbance and impaired reaction times. Balance disturbances and damage to the cerebellum have also been reported among toluene abusers. [7]

Occupational exposure limits (OELs) for toluene

Occupational exposure limits (OELs) for toluene vary between 35 parts per million (ppm) in Denmark to 100 ppm in Poland and the USA. According to the National Institute for Occupational Safety and Health (NIOSH), the recommended exposure limit (REL) is 100 ppm as an 8-hour time-weighted average (TWA) with a 10-minute ceiling of 200 ppm. According to the former Occupational Safety and Health Administration (OSHA), the standard for toluene was 200 ppm as an 8-hour TWA limit; but in 1989, it proposed the acceptable exposure level to be 100 ppm with 150 ppm as a short-term exposure limit (STEL). This limit was expected to prevent adverse effects on the peripheral and central nervous system and the reproductive system. However, evidence suggesting that adverse effects occur at or below these exposure concentrations has led NIOSH to review these recommendations. [8] The American Conference of Governmental Industrial Hygienists (ACGIH) has a TWA of 50 ppm. Toluene levels of 2,000 ppm are considered dangerous to life and health.

Hippuric acid, a metabolite of toluene, is a biological marker for toluene and can be measured in urine.

Animal experiments: The effects of toluene on the auditory system

The ototoxic effects of toluene were first noted when weaning male Fischer rats exposed to 1,400 ppm or 1,200 ppm toluene, 14 h/day, 7 days/week, for 5 weeks [9] demonstrated a slightly impaired hearing loss at 8 kHz, which was markedly impaired at 12 kHz and above. No hearing loss was noted at 4 kHz. Although Pryor et al. described these findings as a high-frequency hearing, no testing was done beyond 20 kHz. In later studies, [10] this frequency area for the rat is described as the mid-frequency range.

The above findings prompted further research regarding the hazards of exposure to, and abuse of, toluene. Electrophysiological testing of these rats 2.5 months following exposure [11] revealed auditory brainstem responses (ABR) consistent with a sensori-neural hearing loss. These were deemed the first results indicating ototoxic effects of toluene on experimental animals.

Electrophysiological and behavioral audiometry [12] on weaning or young adult male Fischer rats exposed to 1200 ppm toluene, 14 h/day, 7 days/week, for 5 weeks confirmed what Pryor et al. describe as a high-frequency hearing deficit, with a peak at 16 kHz, which was more pronounced in the younger rats. Missing and/or damaged hair cells were also found in the basal turn of the cochlea of the younger rats during preliminary morphological examination (the only part of the cochlea investigated, in a nonquantified study). Subsequent experiments showed that high exposure levels of 1,000 ppm for 14 h/day for 2 weeks were ototoxic, but lower levels of 400 and 700 ppm had no effect after a period of 16 weeks. [13] The morphological effects on the cochlea of these levels of exposure, however, were not investigated. Pryor and Howard [14] pointed out that noise emanating from the inhalation system in previous experiments was not the major factor in toluene-induced hearing loss. Using a non-inhalation route of exposure also resulted in hearing losses in the frequency range 8-20 kHz in male Fischer rats injected with 1.5 or 1.7 g/kg of toluene for a period of a week. Possible interactions between noise and toluene exposure required investigating.

Sullivan et al., [15] attempted to relate histological data to electrophysiological data. In this experiment, Sprague-Dawley rats were gavaged with daily doses of 0.5 ml and 1.0 ml toluene per kg body weight for 21 days consecutively. ABR thresholds were elevated for toluene-treated rats typically in the frequency regions 2-8 kHz, described by Sullivan et al., [15] as mid-frequency regions. Outer hair cell (OHC) loss occurred in the middle and basal turn of the cochlea. The greatest loss was seen in the third row and became progressively less moving to the second and first rows of OHCs.

The ototoxic effects of toluene noted by Sullivan et al., [15] are in contrast to those seen with other ototoxins such as aminoglycosides (broad spectrum antibiotics), where the first row of OHCs are the primary target with damage progressing to the second and third row of OHCs. The basal turn of the cochlea is preferentially affected by aminoglycosides, with damage spreading apically with increasing dosage in a linear fashion.

The suggested auditory effects of toluene exposure [9] have been correlated by further animal experiments which have taken a more detailed approach.

Studies using male Sprague-Dawley rats exposed to toluene by inhalation, 1,400 ppm, 16 h/day for 8 days, [16],[17] support the interpretation that OHCs are progressively affected by toluene exposure in the rat. A tendency towards lowered distortion product otoacoustic emission (DPOAE) amplitudes (a sensitive means of assessing the integrity of the auditory periphery) and elevated ABRs was noted 3 days after the start of exposure. Statistically significant lowered DPOAE amplitudes and elevated ABR thresholds were noted after 5 days of exposure. Four days post-exposure, DPOAEs were very much reduced, with ABR thresholds elevated by around 40 dB across the 1.6-20 kHz frequency range, with maximal hearing loss between 6.3 and 12.5 kHz. The DPOAE results point to OHCs being mainly affected by toluene exposure, reflecting cochlear damage, which increases with time of exposure in the rat.

Minimal damage to the third row of OHCs in the middle turn of the cochlea was seen after 5 days of exposure. Ototoxic effects were noted after 3 days of exposure at levels of exposure similar to those studied by Pryor et al., [13] but the rats used were younger and possibly more sensitive to the effects.

With more prolonged exposure and post-exposure, damage had spread to all three rows of OHCs in the upper, middle and part of the basal turn of the cochlea, with some inner hair cell (IHC) loss in the 4 kHz area in (n = 2) animals. The pattern of damage to OHCs is similar to that reported by Sullivan et al, [15] but the reports disagree on toluene-induced lesions in the cochlea, (Sullivan - low-mid frequency area of the organ of Corti ; Johnson and Canlon - mid-high frequency area of the organ of Corti). [15],[16],[17] These differences may be attributed to a number of different causes such as concentration and duration of exposure, different species of rat and gavage in the case of Sullivan as opposed to inhalation in the case of Johnson and Canlon. Both studies suggest that the ototoxic effects of toluene act in a nonlinear fashion.

The studies by Johnson and Canlon [16],[17] suggest that damage progresses after the end of toluene exposure, similar to the effects of both noise exposure and aminoglycoside exposure. The concentration levels of toluene (1,400 ppm) used for these experiments are much higher than levels permitted in the working environment in Europe or the USA but were chosen because they were known to produce a considerable loss of auditory sensitivity in the rat [9],[13] without causing any apparent effects on the general condition of the rat.

In the previous studies noted, auditory testing in rats has been mainly within the 2-20 kHz range. Whilst hearing losses have been described as 'high frequency' in the 8-20 kHz range [9] and as 'mid-frequency range' for 2-8 kHz, [15] the fact that the rat has a hearing range of 0.25-80 kHz has led to a questioning of these descriptions, with hearing losses previously named 'high frequency' being now referred to as 'mid-frequency.' [18],[19],[20]

A study comparing the effects of a number of different solvents suggests evidence of a solvent-induced selective mid-frequency (8-24 kHz) hearing loss in rats exposed to concentrations in the 1,000-4,000 ppm range. [21] This would suggest a distinctive mechanism of action which would take into account the nonlinear nature of cochlear damage caused by solvent exposure in rats. However, the results from the study by Crofton et al., [21] were obtained using behavioral audiometry, and no morphological examinations of the cochlea were noted.

As a result of their findings, Crofton et al., suggest that the monitoring of high-frequency hearing thresholds in humans may not be the most effective and/or sensitive means of measuring auditory dysfunction resulting from exposure to industrial solvents.

Differences in findings regarding frequency location of toluene-induced hearing loss motivated Campo et al., [22] to clarify the results of previous studies. Groups of adult male pigmented rats were exposed to concentrations of toluene of 1,000 ppm, 1,250 ppm, 1,500 ppm, 1,750 ppm and 2,000 ppm respectively for 6 h/day, 5 days/week, over a period of 4 weeks. Electrophysiological data (inferior colliculus potentials - ICPs) showed that toluene concentrations of 1,500-2,000 ppm produced significant auditory threshold shifts [Table - 1].

No significant threshold shift was noted at 32 kHz or below 6 kHz, whatever the dose. These results are indicative of no high-frequency hearing loss in the rat, with the low-frequency regions also being spared.

Histological data showed that toluene has a toxic effect on the cochlea. Generally, as noted by Sullivan et al., [15] the most significant hair cell loss occurred in the third row of OHCs, with the second row less damaged and the first row least damaged. IHCs were relatively well preserved. Interestingly toluene exposure resulted in two peaks of damage, one at approximately 4 kHz (the mid-apical turn of the rat cochlea) and the second in the 16-22 kHz range (the middle turn). More damage was noted in the 4 kHz region than at 16-20 kHz region for all toluene concentrates, but only a weak threshold shift was noted in this area. There was no obvious difference in OHC loss between cochleograms for 1,750 ppm and 2,000 ppm.

The inconsistencies between the functional and structural results at 4 kHz can have a number of explanations, including anatomical structure of the rat cochlea, sensitivity of the tests at different frequencies and the plasticity of the response properties of the inferior colliculus. [22],[23] However, it is clear from this study that evoked potentials from the central auditory pathway do not mirror structural changes within the cochlea; therefore, audiometric thresholds following toluene-induced hearing loss need to be studied with caution in terms of frequency localization.

Findings by Lataye et al., [23] measuring acute compound action potentials (CAP) on adult Long-Evans rats exposed to 1,750 ppm toluene 6 h/day, 5 days/week, for 4 weeks not only showed a significant auditory deficit of 20.8 dB at 16 kHz but also approximately 12 dB at 3, 4 and 5 kHz, correlated by histological findings and with the histological findings of a previous study by Campo et al. [22] Again, anatomical differences within the rat cochlea and inferior colliculus may explain the different results using ABR [22] and CAP. [23] The greatest number of afferent nerves (3,000) is positioned halfway between the base and apex of the rat cochlea, with only 800 at the apical turn. The number of neural tissues exhibiting evoked neural activity is 3-4 times higher in the inferior colliculus for high frequencies than for low frequencies; thus CAP may be a more sensitive means of testing the low-frequency regions.

The results of the study by Lataye et al., [23] suggest that toluene-induced hearing loss can occur over a broader range of frequencies than previously reported.

In an attempt to determine the route of solvent intoxication, namely, toluene and styrene, in the rat cochlea, Campo et al., [24] found traces of toluene and styrene in the blood, brain, auditory nerve and cochlea of exposed male Long-Evans rats following 10 h of exposure over 2 days to 1,750 ppm toluene or styrene. No traces of the solvents were found in the cerebral spinal fluids (CSF) or inner ear liquids (IEL). These results, along with the well-documented pattern of damage to outer hair cells, led Campo et al., [24] to propose that the most likely preferential route for intoxication is via blood from the stria vascularis or spiral prominence diffusing through the outer sulcus, thus reaching Hensen's cells which are in close connection with Deiters' cells located under the OHCs.

The mechanism of action for toluene is less known, but physical or chemical reactions in the hair cells are suspected. In vitro studies [25] indicate that toluene exposure leads to an increase in intracellular calcium levels, thereby disrupting the motility of the hair cells, which in turn affects sensitivity to sound.

The ototoxic effects of toluene and other solvents have been found to be species dependant. [26],[27],[28],[29],[30] Guinea pigs do not appear to be affected by styrene or ethyl benzene inhalation, nor does there appear to be a synergistic effect between noise and styrene on the guinea pigs' auditory function. Chinchillas are markedly less sensitive to the effects of solvent exposure than rats and mice. Guinea pigs have been noted to exhibit a temporary sensitivity to toluene, [27] even at low levels of exposure - 500 ppm (threshold limit value in some countries is 100 ppm) - but these results were not confirmed in a later study. [30] These variations in susceptibility could be due to differences in levels in uptake of solvents between species, differences in solvent metabolism between species or morphological differences in OHC structures.

Animal experiments: The effects of toluene on the vestibular system.

The effect of toluene and other industrial solvents on the vestibular system in experimental animals is less well documented than the effects on the auditory system, but studies point to neurotoxic effects rather than ototoxic effects - that is, the end organs of balance are not affected.

Studies have pointed to similarities in action of solvents producing different results, with the conclusion that solvents influence the vestibulo-oculomotor system, but by different mechanisms. [31],[32] It was suggested by Odkvist et al., [31] that positional nystagmus elicited by solvents is caused in vestibular subcortical pathways either by facilitation or by blocking inhibition, i.e., acting on the cerebellum. Tham et al., [33] also suggested that solvent exposure results in excitation or depression of the vestibulo-ocular reflex (VOR) by interacting with the central pathways in the reticular formation and the cerebellum, the effect being related to the blood levels of the solvents. Toluene was noted to have an excitatory effect.

Short-term exposure to toluene (1,500 ppm 50 min) resulted in exposed rats exhibiting longer nystagmus reaction time to rotary acceleration with increased gain. The mean slow phase velocity was lower for exposed rats at higher stimulation velocities. Optokinetic nystagmus after-nystagmus (OKNAN) and optokinetic nystagmus after-after nystagmus (OKAAN) were significantly prolonged, likely due to loss of normal cerebellar activity. [34] Decreased gain in optokinetic nystagmus is also consistent with cerebellar damage.

Results of a study by Nylen et al., [35] looking at long-term exposure to toluene (1,000 ppm, 21 h/day, for 6 or 11 weeks) in rats tested 1 month after 6 or 11 weeks' exposure indicated that long-term exposure to toluene causes a long-lasting, possibly permanent, lesion within the vestibulo-cerebellum, with no effects on the peripheral vestibular or visual function.

Animal experiments: Interaction between noise and toluene.

One of the more critical aspects of industrial exposure to toluene concerns interaction with noise. Barregard and Axelsson [36] suggested a possible ototraumatic interaction between noise and solvents when in a small case study, four shipyard spray painters exposed to both noise and solvents presented with more pronounced sensori-neural hearing losses (SNHL) than would be expected from noise exposure alone. The study was expanded to look at an additional 30 shipyard workers but no obvious cluster of inexplicable SNHL could be found.

In a follow-up of a 20-year longitudinal study of employees at a timber-processing firm, Bergstrom and Nystrom [37] found what they described as a remarkably large proportion of workers in the chemical division with a hearing loss: 5-8% of workers with a history of exposure to noise levels of 95-100 dBA compared with 23% of workers in the chemical division exposed to noise levels of 80-90 dBA.

The sequence of exposure to noise and toluene can have an effect on the degree of auditory dysfunction in the rat. [38],[39] ABR responses in male Sprague-Dawley rats exposed to noise (100 Leq, 10 h/day, 7 or 5 days/week, 4 weeks) and toluene (100 ppm, 16 h/day, 7 or 5 days/week, 2 weeks) were more elevated when toluene exposure was followed by noise exposure than in the reverse sequence. Toluene followed by noise resulted in a synergistic reaction between the two agents, i.e., threshold shifts exceeded the summated loss caused by noise and toluene alone, particularly at 3.15 and 6.3 kHz, even though the exposure duration was shorter (5 days). The results from the reverse sequence showed an additive reaction between the two agents. In both cases, exposure to both agents resulted in a more severe loss of auditory sensitivity than exposure to each agent alone.

An experiment on male Long-Evans rats exposed to toluene (2,000 ppm, 6 h/day, 5 days/week, 4 weeks) and noise (92 dBSPL) by Lataye and Campo [40] set out to look at the effects of simultaneous exposure to noise and toluene. The results indicated permanent threshold shifts greater than the summated losses of noise and toluene alone across the entire frequency range (2-32 kHz) in comparison to 3.15 and 6.3 kHz noted by Johnson et al. [38]

It is difficult to compare the results of the experiments due to different testing parameters. However, both clearly indicate a synergistic effect of noise and toluene on the auditory function in rats. The occupational impact of this is discussed later.

Histological data [40] indicates that the pattern of damage from simultaneous noise and toluene exposure is similar to that of toluene alone but more pronounced, i.e., OHC 3 > OHC 2 > OHC 1 [Table - 2],[Table - 3]. This is a different pattern from that seen in NIHL , where OHC 1 > IHC > OHC 2 > OHC 3 . This would suggest that the chemical process induced by toluene exposure is compounded by noise exposure and the damage caused by simultaneous exposure to both agents does not involve a new ototraumatic mechanism.


  Styrene Top


Styrene is another industrial solvent that has been extensively researched. [41] Styrene is an aromatic hydrocarbon with a chemical structure of C 8 H 8 or C 6 H 5 CH=CH 2 . It is a colorless to yellow, volatile, viscous liquid widely used in industry in the production of plastics, paints, resins, synthetic rubber and insulation. It has a characteristic pungent odour.

Styrene can be absorbed in the body either through inhalation or absorption through the skin. Short-term exposure to styrene can cause irritation to the eyes, skin and respiratory tract and possible lowering of consciousness. Long-term or repeated exposure can lead to skin sensitization, asthma and effects on the central nervous system, including weakness, unsteadiness, slowing of reaction time and vestibulomotor dysfunction at exposure limits of around 50 ppm. Styrene is also known to have ototoxic effects. [5],[6]

Occupational exposure limits for styrene

Occupational exposure limits for styrene vary between 20 ppm in Sweden and 100 ppm in the UK and USA. NIOSH has a recommended exposure limit of 50 ppm as an 8-hour time-weighted average (TWA) with a short-term exposure limit (STEL) of 100 ppm. OSHA has a permissible exposure limit (PEL) of 100 ppm as an 8-hour TWA limit with a ceiling of 200 ppm, and 150 ppm as a short-term exposure limit (STEL). The American Conference of Governmental Industrial Hygienists (ACGIH) recommends a TWA of 30 ppm. [42]

Mandelic acid, a metabolite of styrene, is a biological marker for styrene and can be measured in urine.

Animal experiments: The effects of styrene on the auditory system

The ototoxic effects of styrene were clearly demonstrated by Pryor et al., [43] when weaning male Fischer rats were exposed to 800, 1,000 and 1,200 ppm daily, 14 h/day, 6 weeks for mixed xylenes and 3 weeks for styrene. ABR and behavioral audiometry results demonstrated a more potent effect of the two solvents compared to toluene ranging from 2-20 kHz (the highest frequency tested).

Results of ABR and histological data from young male rats exposed to styrene (800 ppm, 14h/day, 5 days/week for 3 weeks) also indicated the ototoxic effects of styrene (Yano et al., 1992). ABRs were minimally affected at 4 kHz, more severely affected at 8 and 16 kHz and to a lesser extent at 30 kHz, indicating a mid-frequency hearing loss in the rat. A loss of OHCs occurred in the basal and lower middle turn of the cochlea. The pattern of OHC loss matched that found with toluene, i.e., OHC 3 > OHC 2 > OHC 1 . Some IHC loss was noted in the regions of extensive OHC loss.

At this stage of investigations into styrene, ototoxicity similarities can be seen between the effects of toluene and styrene exposure. However, with lower levels of concentration over shorter duration periods, styrene is seen to have a more damaging effect over a wider range of frequencies in the rat cochlea.

The effects of styrene were noted at 8 and 16 kHz by Crofton et al. [21] on rats exposed to styrene (1,600 ppm, 8h/day for 5days) using behavioral audiometry. Whilst this is consistent with previous findings at these two frequencies, the lack of effect seen at higher and lower frequencies could be due to the different exposure regimes and test parameters; also, behavioral audiometry may not be the most sensitive means of testing solvent ototoxicity.

As with toluene, Campo et al., [24] found traces of styrene in the blood, brain, auditory nerve and cochlea of exposed male Long-Evans rats following 10 h of exposure over 2 days to 1,750 ppm styrene whilst investigating toluene and styrene intoxication route in the rat cochlea. No traces of the solvents were found in the cerebral spinal fluids (CSF) or inner ear liquids (IEL). However, the uptake of styrene was significantly higher than that of toluene, in both the blood and tissue regardless of the tissue examined. The preferential route of intoxication for styrene proposed by Campo et al., [24] is thought to be the same as for toluene. Lataye et al., [44] proposed a second route of intoxication for styrene. With higher concentrations of styrene, damage was also noted in the spiral ganglion cells (SPG), predominantly in the middle and mid-basal turn of the cochlea along with damage to OHCs.

A comparison of toluene-induced and styrene-induced hearing losses [45] clearly demonstrates significant auditory threshold shifts as a function of the concentration of both solvents. For toluene, the peak threshold shift occurred at 16-20 kHz; for styrene, it occurred at 12-16 kHz and at 4 kHz and 32 kHz. Unlike the experiment by Yano et al., [18] no threshold shift was noted at 4 kHz and 30 kHz at styrene exposure levels of 850 ppm. Both styrene exposure and toluene exposure result in the same pattern of damage to OHCs, peaking at 4 kHz and 20 kHz. However, styrene is more potent than toluene - for example, 2,000 ppm toluene resulted in 22.5 dB permanent threshold shift (PTS) at 16 kHz, whilst a 20 dB and 35 dB PTS was obtained with styrene 850 ppm (a 2.4 times lower dosage than toluene) and 1,500 ppm respectively. Styrene concentration of 1,000 ppm and above causes auditory threshold shifts in the rat at mid, mid-low and high frequencies - i.e., styrene is frequency independent at high concentrations. [45]

A combination of exposure to both inhaled styrene (750 ppm, 5 days/week, 4 weeks) and ethanol gavaged (4 g/kg) resulted in greater permanent threshold shifts than those induced by styrene alone, ethanol having resulted in no change in thresholds. Histological data also revealed greater OHC losses in the combined group. [40]

A more detailed look at the mechanisms of the effect of styrene on OHCs led to the conclusion that Hensen's cells and Deiters' cells are the real target of styrene, which then go on to cause the death of OHCs. [46] One week after exposure to styrene (1,000 ppm, 6h/day, 5 days/week), light microscopy showed partial loss of cytoplasm in Hensen's cells. After 2 weeks of exposure, cytoplasm in Deiters' cell was abnormal, the expansion of the supporting cells obliterated the spaces of Nuel, OHC 3 was missing and the base of OHC 2 was no longer well delineated. Campo et al., [46] suggest that 'the disturbances of supporting cells could generate an excessive ion build-up beneath the OHCs causing dramatic metabolic changes of the sensory cells. In fact, the OHCs could be poisoned in this way.'

The above-mentioned study also indicated that 1 week of styrene exposure (1,000 ppm) caused as much permanent threshold shift (PTS) as 2, 3 or 4 weeks of exposure. In addition, the threshold shift did not peak after 1 week's exposure but increased up to 15 dB by 6 weeks post-exposure. Thus trauma continued after exposure ceased. This process was also noted by Crofton and Zhao [47] in a study of the ototoxic effects of trichloroethylene (TCE). These effects are clearly far reaching from the occupational viewpoint.

Animal experiments: The effects of styrene on the vestibular system

Rabbits exposed to styrene demonstrated positional nystagmus, indicating vestibular disturbances. The incidence of the positional nystagmus correlated well with the blood level of the solvent. [48]

In animal experiments looking at the effects of solvent exposure on the vestibular system, rabbits were given an intravenous infusion of styrene or xylene or trichloroethylene (TCE) or methylchloroform. Positional nystagmus was elicited when styrene blood concentration reached 40 ppm, xylene and TCE blood concentrations reached 30 ppm and methylchloroform blood concentration reached 75 ppm. The fast phase of nystagmus was left beating in the right lateral position and right beating in the left lateral position. Cats given either styrene or TCE showed no signs of nystagmus in the lateral positions but exhibited vertical downbeat nystagmus in the prone position with TCE. Styrene had both an inhibiting (with high doses) and facilitating (with low doses) effect on optokinetic nystagmus (OKN). Larsby et al., [34] suggested two possible sites of action - the first directly on the cerebellum and the second on the oculomotor system or reticular formation. An important finding of this paper was the degree of potentiation between simultaneous doses of styrene and TCE.

Animal experiments: Interaction between noise and styrene

As previously stated, guinea pigs do not appear to be affected by styrene. Fechter et al., [26] administered styrene by injection or inhalation (500 ppm/7h) with no obvious deleterious effects on hearing. The addition of 95 dB broadband noise resulted in a noise-induced hearing loss (NIHL), but there was no enhancement of NIHL by styrene.

In the rat, the pattern of trauma for simultaneous exposure to styrene and noise is very similar to that of toluene and noise. In a group of experiments, [30] adult Long-Evans rats exposed to noise at 97 dBSPL, 6 h/day, 5 days/week for 4 weeks, presented with an NIHL in the frequency range 8-20 kHz with a peak loss near 12 kHz. Styrene exposure (750 ppm, 6 h/day, 5 days/week for 4 weeks) resulted in hearing loss in the narrower frequency range of 16-20 kHz. Simultaneous exposure to noise and styrene led to hearing loss in the frequency range 8-20 kHz with a peak loss at 12 kHz. Simultaneous exposure to noise and styrene also resulted in significantly greater permanent threshold shifts compared to those caused by either noise or styrene alone. A significant synergy appears between the two agents at 6-12 kHz, with affects being additive at the other frequencies.

The order of trauma for simultaneous exposure group followed that for styrene. OHC 3 was more severely affected than OHC 2 , which in turn was more severely affected than OHC 1 but more pronounced. This is a different pattern from that seen in NIHL, where OHC 1 > IHC > OHC 2 > OHC 3 . Splayed stereocilia were observed on IHCs at the most damaged frequency area, 8-20 kHz for noise exposure and simultaneous noise and styrene exposure [Table - 4],[Table - 5],[Table - 6].

Fechter et al., [26] looked at the effects of styrene, styrene and noise exposure at 1, 2, 4 and 8 kHz (human hearing is usually tested between 125 Hz and 8 kHz), a much narrower frequency range than previously tested, along with lower concentrations of 100, 300 and 600 ppm (100 ppm being the OEL for the UK and USA). Styrene alone at 100 ppm and 300 ppm concentrations did not have an adverse effect on the auditory sensitivity in the rat; 600 ppm styrene resulted in a 1-3 dB PTS at 8 kHz. Simultaneous exposure to styrene (100 ppm and 300 ppm) and noise (100-105 dB) resulted in flat PTS of 5-10 dB across all frequencies tested, while 600 ppm styrene with 100-105 dB noise resulted in more significant PTS across all frequencies, the greatest ranging from 31.4 dB at 2 kHz to 40 dB at 8 kHz. These findings agree with those of Lataye et al [30] in that a synergistic interaction between noise and styrene occurred.


  Carbon disulfide Top


Carbon disulfide (CS 2 ) in its pure form is a colorless liquid with a smell similar to chloroform. The commonest form used in industry is impure and yellowish in color with an unpleasant odor. It is made by combining carbon and sulfur at very high temperatures.

Carbon disulfide evaporates at room temperature and is highly inflammable. It is listed as an extremely hazardous substance.

It has played an important role in industry since the 1800s. It was first recognized as an occupational hazard in the 1840s when cold vulcanization (a strengthening process for rubber) was introduced.

Several incidences of neurotoxicity were noted in a number of countries using the process, and as a result carbon disulfide was eliminated from the process. [49]

Carbon disulfide has many useful properties and was previously used in many extraction processes. Prior to 1985, it was used as a grain fumigant. At present its most important industrial use is in the manufacturing process for rayon and cellophane and as a solvent.

Exposure to carbon disulfide can be through inhalation, ingestion, skin or eye contact; or it can be absorbed through the skin. Acute and chronic forms of poisoning can result from exposure; at very high levels, it can be life threatening because of the effects on the heart and nervous system. The effects of exposure are nonspecific and require a diagnosis based on exposure history, signs or symptoms and exclusion of other diseases.

Occupational exposure limits for carbon disulfide

NIOSH has a recommended exposure limit of 1 ppm as an 8-hour time-weighted average (TWA), with a short-term exposure limit (STEL) of 10 ppm. OSHA has a permissible exposure limit (PEL) of 20 ppm as an 8-hour TWA.

2-thiothiazoladine-4-carboxylic acid is a biological marker for carbon disulfide and can be measured in urine.

Animal experiments: The effects of carbon disulfide on the auditory system

Experiments on Fischer-344 rats exposed to carbon disulfide (172, 286 and 400 mg/kg, 5 days/week, 11 weeks) administered intraperitoneally resulted in ABR latencies in wave V but not in wave I, indicating an effect on conduction within the central auditory pathway. No histological data was reported. [50]

ABR results from Long-Evans rats exposed to carbon disulfide (400 or 800 ppm, 7 h/day, 7 days/week for 11 weeks) were also consistent with a retrocochlear pattern of hearing loss. Inter-peak latency was also prolonged. An additional peripheral loss of a conductive nature was suspected, possibly due to effects on  Eustachian tube More Details function. [51]

No significant effect was noted on pure-tone thresholds in rats exposed to carbon disulfide (500 ppm 6 h/day, 5 days/week for 12 weeks). At this exposure level, severe neuromuscular compromise occurred, highlighting the fact that pure-tone audiometry (PTA) is not sensitive to the early effects of carbon disulfide exposure. [52]

The effects of carbon disulfide on the vestibular system or the effect of simultaneous exposure to noise and carbon disulfide has not been well documented in animals.


  Xylene Top


Xylene, CH 6 H 4 (CH 3 ) 2 , is an aromatic hydrocarbon. It is a colorless liquid with a sweet smell. It is primarily a man-made chemical produced from petroleum and, to a lesser extent, coal.

There are three forms of xylene. Mixed xylene is a mixture of all three and usually contains 6-15% ethylbenzene. It is often found in thinners, paints and varnishes and is used as a solvent in printing, rubber and leather industries. It is also used as a material in the chemical, plastic and synthetic fiber industries. [53]

Xylene can be absorbed in the body either through inhalation or through the skin. Short-term exposure to xylene can cause irritation to the eyes, skin and respiratory tract; breathing difficulties and impaired memory. Long-term or repeated exposure can lead to effects on the nervous system, dizziness and lack of muscle coordination. Xylene is known to be ototoxic.

Occupational exposure limits for xylene

Occupational exposure limits for xylene vary between 35 ppm in Denmark and 100 ppm in the UK, Poland, Japan and USA.

Methylhippuric acid, a metabolite of xylene, is a biological marker for xylene and can be measured in urine.

Animal experiments: The effects of xylene on the auditory system

As previously stated, mixed xylene was found to have marked effect on the hearing sensitivity in exposed rats. [43]

A slight loss of hearing sensitivity was noted 2 days after the end of exposure by Nylen and Hagman [54] in rats exposed to xylene (1,000 ppm, 18 h/day, 7days/week for 61 days). Simultaneous exposure with 1,000 ppm n-hexane resulted in a persistent loss of auditory sensitivity of 7-17 dB.

In experiments looking at the three different forms of xylene ( meta -xylene, ortho -xylene, para -xylene), only para -xylene at 900 and 1,800 ppm was noted to have ototoxic effect. Exposure levels for male Sprague-Dawley rats were 450, 900 and 1,800 ppm, 6 h/day, 6 days/week for 13 weeks. ABR results indicated increased auditory thresholds (35-38 dB) at 2, 4, 8 and 16 kHz in the group exposed to 1,800 ppm xylene. These were still present 8 weeks post-exposure. Histological investigations found moderate and severe loss of outer hair cells for 900 and 1,800 ppm xylene.

The effects of xylene on the vestibular system or the effect of simultaneous exposure to noise and xylene has not been well documented in animals.


  Ethyl benzene Top


Ethyl benzene (C8 H10) is an aromatic hydrocarbon. It is used as a solvent; in the production of styrene; and also in the rubber, plastics and petroleum industries. It is also present in mixed xylene.

Occupational exposure limits for ethyl benzene

The general occupational exposure limit for ethyl benzene is 100 ppm.

Animal experiments: The effects of ethyl benzene on the auditory system

Experiments involving male rats exposed to ethyl benzene (800 ppm, 8 h/day, 5 days) led to the conclusion that ethyl benzene does induce a permanent hearing loss in rats. [55] Evidence from reflex modification audiometry (RMA), CAP and histological data all point to effects similar to toluene and styrene, particularly regarding pattern of outer hair cell loss - OHC 3 > OHC 2 > OHC 1 - with inner hair cells remaining undamaged. [15],[18],[22] OHC loss occurred in the upper basal and lower middle turns (the mid-frequency regions). Prior to this, very little was noted regarding the site of ototoxic action of ethyl benzene.

RMA results show that the frequency range 4-24 kHz was significantly affected by about 25 dB and CAP thresholds increased significantly by 10-30 dB at all frequencies tested. These results point to the ototoxic effects of ethyl benzene being frequency independent at this level of exposure. Experiments by Campo et al., [22] showed increasing doses of toluene leading to an increasing range of frequencies affected; this was also noted by Pryor et al. [43] and Loquet et al. [45] This would suggest that higher doses of styrene and toluene are required to induce comparable effects to that found in this study. These in turn could lead to the conclusion that ethyl benzene is an extremely ototoxic solvent.

Further experiments by Cappaert et al., exposing rats to ethyl benzene (0, 300, 400 and 550 ppm, 8 h/day, 5 days) indicated a dose-dependent loss of auditory sensitivity, measured using DPOAEs and CAP, following exposure. It was found that 0 and 300 ppm had no effect on auditory sensitivity; 400 ppm affected 12 and 16 kHz by 15 and 16 dB respectively; and 550 ppm affected 8, 12 and 16 kHz by 24, 31 22 dB respectively. Histological data corresponded with a mid-frequency hearing loss. The combined results of the experiments by Cappaert et al [55],[56] and Pryor and Rebert [13] confirm the fact that ethyl benzene is probably one of the most ototoxic organic solvents and yet it has not been extensively examined.

The effects of ethyl benzene on the vestibular system have not been well documented in animals.

Animal experiments: Interaction between noise and ethyl benzene

Some interesting results were noted by Cappaert et al., when studying the simultaneous effects of low levels of ethyl benzene and noise exposure on rats.

Exposure to ethyl benzene (300 and 4,000 ppm, 8 h/day, 5 days) did not result in significant threshold shifts in DPOAE or CAP. This was not the case for 400 ppm in a previous experiment by Cappaert et al., [56] but OHC losses, specifically in the third row, were noted in the mid-frequency regions of the cochlea. The affected region was noted to broaden with increased doses. Noise exposure at 95 dBSPL and 105 dBSPL resulted in minor loss of OHCs in the first row at 105 dBSPL only. Combined exposure did not result in any threshold shifts as measured by DPOAEs or CAP, indicating the absence of synergistic effects at the low levels of exposure. However, morphological data did suggest a synergistic effect between the two agents.


  Trichloroethylene (TCE) Top


Trichloroethylene (TCE) is a colorless, noncorrosive solvent first introduced as a degreaser in Germany during the First World War. It is currently used as a grease remover, dry cleaning agent; and in rug-cleaning solutions, it is found as an ingredient and is used as a spot remover . It is also used in the production of paints, waxes and pesticides. High level exposure to TCE has resulted in decreased visual perception skills and motor skills. [57]

Occupational exposure limits for trichloroethylene

Occupational exposure limits for TCE vary between 25 ppm and 100 ppm. NIOSH has recommended a 2 ppm/60 min ceiling when used as an anesthetic and a 25 ppm TWA for all other exposures. OSHA have a PEL of 100 ppm TWA; ACGIH have a 50 ppm TWA. [57]

Trichloroacetic acid and trichloro pethynol are biological markers for TCE and can be measured in urine.

Animal experiments: The effects of trichloroethylene on the auditory system

Initial experiments on male Long-Evans and Fischer rats exposed to TCE (1,600 or 3,200 ppm for 12 weeks) demonstrated its ototoxic effects. [58] Increased ABR thresholds were noted in what is now termed as the mid-frequencies in rats.

Jaspers et al., [59] noted that rats exposed to TCE (0, 1,500 or 3,000 ppm, 18 h/day, 5 days/week for 3 weeks) exhibited increased hearing thresholds at 20 kHz for the 3,000 ppm group. There was no significant increase at 5 or 35 kHz, indicating a short-term, high-level effect of TCE exposure in the mid-frequency region.

Crofton and Zhao [20],[47] and Crofton et al., [21] also demonstrated, using reflex modification audiometry (RMA), a mid-frequency hearing loss in rats exposed to TCE at 16 kHz, 16 kHz and 8 and 16 kHz respectively .

Whilst the above-mentioned studies on the ototoxic effects of TCE confirm a clear pattern of the frequency range affected, they are unable to determine the site of trauma.

RMA thresholds of rats exposed to TCE (0 or 4,000 ppm, 6 h/day, 5 days) in a study by Lui et al., [25] confirmed previous findings of a mid-frequency hearing loss. [20],[21],[47] Auditory thresholds were elevated by 25 dB at 8 and 16 kHz in rats exposed to TCE. CAP thresholds showed an impairment of 20 dB restricted to 8 and 16 kHz. The cochlear microphonic (CM which appears to arise from the OHCs in the basal most turn of the cochlea) was not affected. CAP data and CM data suggest that TCE affects the IHCs and/or the spiral ganglion cells.

Histological investigations from the experiment did reveal a marked decrease in the number of spiral ganglion cells whilst OHCs were rarely seen to be missing. In a number of sections of the cochlea, the loss of spiral ganglion cells was obvious even though IHCs and OHCs in the same section were intact. Whilst within the experiment it was not possible to quantify hair cell loss, the subjective impression was that spiral ganglion cell decline was consistent in all sections whilst hair cell loss was infrequent. TCE exposure decreased the numbers of spiral ganglion cells by 47% in the lower middle turn and 43% in the upper middle turn of the cochlea. Clearly whilst the region of damage (i.e., a mid-frequency cochlear site of action) caused by TCE is similar to that caused by toluene, styrene, xylene and ethyl benzene, the mechanism of damage is quite different - i.e., toluene, styrene, xylene and ethyl benzene cause damage to outer hair cell; TCE to spiral ganglion cells. The reasons for the two different patterns of morphological damage are not clearly understood.

Animal experiments: The effects of trichloroethylene on the vestibular system

Experiments in this field are quite limited and have been discussed in a previous section.

Animal experiments: Interaction between noise and trichloroethylene

There is relatively little information regarding this field, but an experiment by Muijser et al., [60] points to combined exposure to TCE (3,000 ppm, 18 h/day, 5 days/week, 3 weeks) and noise (95 dBSPL) having a synergistic effect on the auditory sensitivity in rats at 4 kHz and possibly 24 kHz (results at 24 kHz not confirmed statistically). There was no histological data available for this experiment.


  Main findings from the animal experiments Top


There is a considerable amount of evidence from animal studies, using a variety of test parameters [Table - 7],[Table - 8], pointing to the effects of industrial solvent on hearing and balance, the majority of which have been carried out on rodent species. Below are noted a number of important findings.

  • Industrial solvents can be ototoxic, causing a permanent hearing loss in rats.
  • The effects of solvents are species dependent.
  • Rodents are more sensitive to the effects of solvents than guinea pigs and chinchillas and, as with the case of styrene, metabolism in the human is more in line with rodents than guinea pigs. [41]
  • Studies show that the effects of solvents exposure, with the exception of carbon disulfide, are related to cochlear damage.
  • Exposure to solvents causes both functional and structural damage to the cochlea.
  • OHCs are more vulnerable to solvent exposure, with the degree of damage to OHCs being OHC 3 > OHC 2 > OHC 1 - the exceptions being carbon disulfide, for which no histological data was found for this study, and TCE.
  • Spiral ganglion cells are most vulnerable to TCE exposure.
  • The effects of carbon disulfide exposure suggest a retrocochlear pattern of hearing loss.
  • A mid-frequency hearing loss is most widely reported with evidence of a wider spread of frequencies affected and greater threshold shifts with higher concentrations of solvents, i.e., dose dependent.
  • The ototoxic effects of solvents continue after exposure ceases.
  • Styrene and xylene are more potent than toluene, but ethyl benzene is even more potent.
  • There is evidence that combined exposure to solvents and noise has a synergistic effect. This can happen when levels of exposure are below permitted levels.
  • Evidence points to the pattern of trauma from simultaneous exposure to noise and solvents mirroring that of the solvent, but the scale of the trauma is more enhanced.
  • The damage caused by simultaneous noise and solvent exposure does not involve a new ototraumatic mechanism.
  • There is a critical level when synergy occurs. It is important to find out that level for occupational exposure.
  • There is a synergistic effect of some solvents with other solvents, dependent upon their molecular makeup.
  • The preferential intoxication route would appear to be via blood from the stria vascularis or spiral prominence diffusing through the outer sulcus.
  • The effects of solvents on the vestibular system are not as well documented as the effects on hearing.
  • The effects on the vestibular system are neurotoxic, having an effect on the cerebellum.
  • Solvents influence the vestibulo-oculomotor system, different solvents by different mechanisms.
  • There appears to be a synergistic effect of TCE and styrene on the vestibular system.
  • Test parameters vary often, making it difficult to compare results.
  • Toluene and styrene have been more extensively studied for ototoxic effects than other solvents. In comparison, very little is documented on the effects of TCE and xylene.
  • The above findings have far-reaching implications for occupational exposure to industrial solvents. Of greatest interest and concern is the evidence of a synergistic effects from combined exposures to noise and solvents, a factor that has not really been taken into consideration in industry previously and one that is not clearly recognized and understood.


Occupational studies: the effects of toluene on hearing and balance

Groups of workers in a printing factory exposed to high levels of toluene (100-365 ppm) and noise (88-98 dBA), noise alone (88-97 dBA); and a group exposed to a mixture of solvents were tested for hearing function [63] and compared to a control group. The majority of average hearing losses in the groups exposed to solvents were up to 45 dBHL. In the group exposed to both toluene and noise, the prevalence for sensorineural (permanent) hearing loss was 53%. This was statistically higher than for the other groups. The prevalence in the unexposed groups was 8%; in the noise-exposed group, 26%; and the 'mixed solvent'-exposed group, 18%. Of the workers exposed to solvents only, 18% had a high-frequency hearing loss compared to 8% in the unexposed group. The adjusted relative risk for hearing loss in the groups was 4 times greater for workers exposed to noise, 11 times greater for those exposed to noise and toluene and 5 times greater for the group exposed to mixed solvents. Acoustic reflex threshold (ART) measurements pointed to lesions within the central auditory pathway. The indications are that exposure to solvents can cause a hearing loss, and there is a relation between simultaneous exposure to noise and solvents.

Exposure to toluene below 50 ppm was studied in 333 rotogravure-printing workers over a period of 5 years, involving four repeated examinations. [64] The mean lifetime weighted average exposure for toluene and noise was 45 ± 17 ppm + 82 ± 7 dBA respectively for printers and 10 ± 7 ppm + 82 ± 4 dBA respectively for end processors. Exposure at the time of testing for printers was 26 ± 20 ppm + 81 ± 4 dBA; and for end processors, it was 3 ± 3 ppm + 82 ± 4 dBA.

The results of this study did not indicate any significant differences in the effects on the auditory system as a result of the toluene exposure between the two groups. A control group was not included in this study; but as noise exposure in both groups was almost identical, any differences in auditory thresholds between the two groups could be attributed to toluene. However, the effect of noise was significant. It would appear from the data that the exposure levels of toluene were not sufficiently high to induce a hearing loss and that the possible threshold level for developing a hearing loss as a result of exposure to toluene could be above the limit of 50 ppm.

In 1981 Biscaldi et al., [65] carried out some neurophysiological studies on a small group of workers accidentally exposed to toluene. Immediately after the accident, abnormal brain activities and a reduction in vestibular reflexes were present. Six months after the exposure, the vestibular findings were markedly improved but abnormal brain activities were still present.

Small groups of volunteers exposed to a number of different solvents for a period of 1 hour were tested to measure vestibular and oculomotor disturbances. [66] The air concentration values of the solvents varied between 1.3 and 3 times the legal threshold value. Light exercise was performed to increase the intake. The test battery used included electronystagmography (ENG) during sinusoidal oscillation with lights off and fixation, smooth pursuit, OKN, saccades and visual suppression. The group exposed to toluene underwent additional rotatory tests with fixation and visual suppression.

The group exposed to styrene showed increased saccade speed and impaired visual suppression (failure to suppress is usually a sign of cerebellar involvement) and high gain in smooth pursuit during sinusoidal swing with fixation. Other tests were normal. The findings for the group exposed to toluene were not as clear-cut as those for styrene. Styrene is more potent than toluene [18],[43] and the dose for this experiment was 2-3 times the legal threshold value for styrene and 1.3-1.9 times the legal threshold value for toluene. The difference in potency and doses makes the two sets of results difficult to compare. The group of volunteers exposed to TCE showed no significant disturbances in the test battery. This could be explained by the differences in the molecular makeup of aliphatic solvents (TCE) and the aromatic solvents (toluene, styrene).

A group of 11 workers with psycho-organic syndrome (POS) as a result of solvent exposure was also included in the above study. The modern terminology for POS is chronic toxic encephalopathy (CTE). The symptoms of CTE develop slowly. In the initial stages, the symptoms include vertigo, dysequilibrium and nausea. Longstanding symptoms include fatigue, poor concentration, reduction in intellectual capability and dysequilibrium. [67] Out of the 11 workers, 6 had balance abnormalities when walking a line with eyes closed, 7 had pathological spontaneous or positional nystagmus of low amplitude, 6 had pathological visual suppression and 4 had above-normal saccade speed. Out of 9 workers with less exposure to industrial solvents, 2 had abnormal findings in visual suppression and saccade speeds.

Tests on 15 workers exposed to toluene at threshold limit value (TLV) also showed impaired visual suppression and increased saccade speed. [68]

A large-scale survey was undertaken in four cities of China to look at dose-dependant increase of subjective symptoms as a result of exposure to toluene. As many as 1,316 workers exposed to toluene and 769 control subjects took part in the survey. Urine and blood samples were taken to monitor the uptake of toluene.

Results showed an increase in subjective symptoms in the exposed group, which was closely associated with the intensity of exposure levels to toluene; the threshold concentration appeared to be 100 ppm. The subjective symptoms included dizziness, floating feeling and loss of hearing capacity. No diagnostic tests were undertaken and noise levels were not taken into consideration. [69]

Occupational studies: The effects of styrene on hearing and balance

The effects of simultaneous exposure to styrene and noise were examined by Sass-Kortsak et al. [70] in a study of 299 workers in 14 different fiber-reinforced manufacturing plants. Although noise and styrene levels differed between the plants, noise levels generally fell within the 85-90 dBA range and styrene was generally below 50 ppm.

The results of the study indicated minimal effects of styrene on pure-tone thresholds for simultaneous exposure to noise and styrene when noise and styrene lifetime exposures were taken into consideration. Age and noise, however, were positively associated with hearing loss. Exposure to styrene only approached significance for 4 and 6 kHz in the left ear.

More recent studies have looked at the effects of styrene and 'styrene and noise' on hearing. [71],[72] The first study looked at 115 workers in seven factories. In six of the factories, workers were exposed to styrene, toluene and methanol in the production of plastic buttons; in the other factory, workers were exposed to styrene and acetone, producing fiber-reinforced plastic baths. The mean duration of exposure was 9.4 ± 8.9 years. Styrene concentrations varied from 0.1 to 91.6 ppm, outside of the permitted TWA of 50 ppm. Exposure to noise was below 85 dBA.

Conventional audiometry indicated no change as a result of styrene exposure. However, tests to determine the upper limit of hearing of the exposed workers {a test in which the subject listens to a tonal stimuli which can range from 0.5-50 kHz, the upper limit of hearing being the highest frequency the subject can perceive as a tone} revealed evidence that exposure to organic solvents for 5 years or more may cause a reduction in the upper limits of hearing even for workers exposed to low levels of styrene. The results also pointed to the effects of styrene on the upper limits of hearing being dose dependent.

These results would suggest that styrene induces a hearing loss which progresses from higher to lower frequencies in humans and that tests for the upper limit of hearing may be useful diagnostic tools for detecting early ototoxic effects of styrene exposure. This does not correlate with findings of a mid-frequency hearing loss in animals.

As the effects of noise were not taken into consideration in the first study, the second study comprised of three groups according to exposure conditions. The first group was exposed to low levels of styrene (2.9-28.9 ppm), methanol (4.7-34.3 ppm) and 'methanol (9.1-69.7 ppm) and noise (69-76 dBA)'. The second group was exposed to noise (82-86 dBA), and the third was an unexposed control group.

The prevalence of reduction in the upper limit of hearing was higher in the combined group than expected, even when exposures were within the OELs. In conventional audiometry, no significant findings were noted.

A study by Sliwinska-Kowalska et al., [73] also looked at combined exposure to styrene and noise in the plastics industry. The study involved three groups of workers matched by age, gender and personal traits. One group was exposed to styrene and noise, one group was exposed to noise at twice the level of the combined group and one group was exposed to neither styrene nor noise.

Workers in the combined group had a significantly increased average hearing loss at 1-8 kHz compared to the other groups. The risk of hearing loss in the combined group was seven times higher than the nonexposed group and four times higher than the noise-exposed group, suggesting that styrene has an additional adverse effect of noise on hearing.

An extensive audiological test battery was carried out on 313 workers exposed to 'styrene (below recommended values) and noise,' styrene, noise; and unexposed controls. Pure-tone audiometry showed significantly worse thresholds at 2, 3, 4 and 6 kHz for workers exposed to styrene or 'styrene and noise' than the other two groups. The three exposed groups showed significantly poorer results on speech in noise test, but no significant differences between the groups were seen in the interrupted speech test or cortical response audiometry. DPOAE results, though not fully analyzed, do not appear to show any differences between the groups. The results also showed that the amount of mandelic acid in urine was more likely to increase the odds ratio for hearing loss than age or noise exposure. [74]

Human volunteers exposed to styrene showed no indications of positional or spontaneous nystagmus with blood/styrene concentration at 8.5 ppm or less.

Further experiments, correlating with the above results, were carried out on 10 healthy volunteers exposed to styrene for 1 hour. [31] Pulmonary uptake and blood levels were carefully monitored, and the blood/styrene concentration was equivalent to that reached after several hours in a working environment with a styrene concentration level within permitted limits. Eight out of the 10 subjects exhibited disturbed visual suppression. The speed of saccades was significantly enhanced in 8 out of 10 volunteers. There were no significant differences in rotatory and optokinetic nystagmus as a result of the exposure. No spontaneous nystagmus was observed.

Postural control was investigated in 18 workers exposed to styrene for 6-15 years in the plastic boat building industry, where styrene evaporation is considerable; ventilation was poor, but levels were below the permitted levels. Nine painters with a diagnosis of CTE as a result of solvent exposure were also included. These workers were mainly painters with an exposure history varying from 8 to 30 years; exposure levels were unknown. The reference group consisted of 52 workers in the construction industry with no exposure to industrial solvents. [75]

The two exposed groups had significantly larger sway areas with eyes open and closed than the reference group. The two exposed groups also showed significantly reduced ability to suppress vestibular nystagmus compared to the reference group. The correlation between static posturography and otoneurological tests was positive for the group exposed to styrene. These results point to cerebellar involvement.

In another small study looking at the effects of exposure to styrene on balance and hearing, Moller et al [2] found evidence of central components in both audiometric and vestibular test results amongst 18 workers with long-term exposure to low levels of styrene (25 ppm). Although there was no indication of hearing loss being caused by anything other than noise, 7 of the 18 workers displayed disturbances in the central auditory pathway. The styrene-exposed workers also displayed significantly larger sway areas than the reference group and poorer ability to suppress vestibular nystagmus.

Occupational studies: The effects of carbon disulfide on hearing and balance

Carbon disulfide is thought to have an effect on conduction within the central auditory pathway in rats. [50] There have also been a number of studies looking at the effects of carbon disulfide on hearing and balance in humans.

Morata et al., [76] set out to explore the effects of simultaneous exposure to noise and carbon disulfide on two groups of workers in a rayon factory in Brazil. At the time of the study although permissible standards of exposure existed in Brazil, threshold limits of most hazardous agents were not respected due to pressures for industrial development.

Group A consisted of volunteers who reported no exposure to noise or carbon disulfide prior to working in the factory. Group B were randomly chosen following health examinations which included hearing tests for all workers in the factory; these workers had no exposure to noise or carbon disulfide prior to their current employment. All subjects underwent PTA at least 12 h post last exposure to avoid temporary threshold shifts as a result of industrial noise. Group B underwent balance tests. All subjects were interviewed regarding health and history of noise and carbon disulfide exposure and had PTA.

The PTA results showed a large proportion of workers with a hearing loss (71.7% in group A, 66.7% in group B). Hearing losses were higher than expected for all age groups, suggesting that hearing was not simply attributable to ageing process. Further studies revealed that 12.7% of workers exposed to carbon disulfide had hearing losses affected at both higher and lower frequencies compared with 3.5% of workers exposed to noise alone. The indications are that hearing loss occurs earlier and is more serious among workers exposed to carbon disulfide and noise than among those exposed to noise alone. Hearing losses increased with exposure time to carbon disulfide and noise and could be observed after 3 years of simultaneous exposure.

Balance screening was limited, but the largest group that failed had a hearing loss. Results also showed a marked increase in failures on balance test following 3-5 years of simultaneous exposure to carbon disulfide and noise (3.1%, 0-2 years' exposure; 30.3%, 3-5 years' exposure). These results suggest a possible relationship between hearing loss, balance disturbance and exposure to carbon disulfide.

A group of 80 workers in a viscose fiber spinning mill with clinically observed carbon disulfide poisoning and 40 people exposed to carbon disulfide but without subjective or objective symptoms of carbon disulfide poisoning were studied to assess changes in the auditory system resulting from carbon disulfide exposure. Both groups were of similar age with similar durations of employment. Exposure to carbon disulfide varied in time between 10 and 35 mg/m 3 and to continuous noise ranging from 88 to 92 dBA. A control group of 40 workers had no contact with carbon disulfide but were exposed to similar levels of noise ranging from 86 to 93 dBA. [77]

Bilateral retrocochlear hearing loss associated with central vestibular disturbances was noted in 97.5% of the subjects with clinically observed carbon disulfide poisoning. In the exposed group with no symptoms, 45% had a retrocochlear hearing loss and 32% had a cochlear hearing loss. As many as 22% of those under study had normal hearing. In the control group, cochlear hearing loss typical of acoustic trauma without concomitant vestibular disorders was evident.

The results show a dominating carbon disulfide toxic effect on the hearing system in subjects with clinically observed carbon disulfide poisoning and exposure to noise. Hearing impairment and vestibular disorders that occur are central rather than peripheral. The variabilities in subjects exposed to carbon disulfide and noise are probably due to individual susceptibility to the harmful effects of both agents.

Variabilities in results in individuals exposed to solvents have also been noted by Toppila et al., [78] and Morioka et al. [71],[72] The effects of noise and carbon disulfide exposure were also noted by Chang et al. [79] Approximately 80% of workers exposed to carbon disulfide (1.6-20.1 ppm) and noise (80-91 dBHL) had a hearing loss >25 dBHL compared to 32.4% of workers exposed to noise only (83-90 dBHL) and 23% of workers exposed to lower levels of noise (75-82 dBHL). Workers exposed to carbon disulfide and noise had greater hearing impairment at 0.5, 1 and 2 kHz than the noise-exposed groups; the noise-only group had a stronger effect at 4 kHz, which is characteristic of NIHL.

A dose-response effect was also noted in this study, suggesting that chronic exposure to carbon disulfide >10 ppm should be avoided in order to reduce the toxic effects on hearing in workers.

In a group of 37 patients with chronic carbon disulfide intoxication and complaint of vertigo, 72% were found to have a postural stability disorder. These results correlated with ENG results, which confirmed damage to the central part of the vestibular system due to carbon disulfide intoxication. [80] Occupational studies: the affects of xylene on hearing and balance

Groups of workers in the paint and lacquer industry were studied to assess the risk and incidence of hearing loss as a result of exposure to organic solvents whose main components were xylene and ethyl acetate. Levels of exposure depended on individual work posts. PTA results were compared with those of workers exposed to noise above the threshold limit value and a group exposed to neither noise nor solvents. Hearing loss was found in 30% of workers exposed to solvents, 20% in noise-exposed subjects and 6% in the nonexposed group. The highest PTA thresholds were found in the solvent-exposed group, lower in the noise-exposed group and lowest in the nonexposed group. The relative risk of hearing impairment was also greater in the solvent-exposed group. [81] These findings were confirmed in a larger study of 731 workers in the dockyard, paint and lacquer industries. [81] The study comprised four groups: exposed to 'organic solvents alone (the main component being styrene),' 'organic solvents + noise>80 dBA,' 'noise only >80 dBA' and one group exposed to neither noise nor organic solvents. The highest incidence of hearing loss was found in workers exposed to organic solvents (48%), followed by workers exposed to 'organic solvents + noise (42%),' noise-exposed group (26%) and the control group (17%). The range of frequencies affected in the solvent and 'solvent + noise' group ranged from 3-8 kHz. The frequency affected by noise alone was 4 kHz.

Xylene has been found to have an effect on postural sway in exposed workers. A TWA xylene concentration of 100 ppm with 200 ppm peaks resulted in no observable effects on balance but a TWA of 200 ppm with 400 ppm peaks did. The effects were more noticeable with eyes closed. [82]

Xylene exposure at concentrations of 636 and 1,218 mg/m 3 for 4 h had very little effect on the vestibular system. When given with a single dose of 0.4 and 0.8 g/kg ethyl alcohol, the effects of the lower dose of xylene on body sway were additive, and the higher dose of xylene antagonized the effects of alcohol on positional nystagmus and body sway. Alcohol also significantly increased the uptake of xylene. [83] A dose-related effect of xylene on balance was also noted. [84] Changes in body sway with eyes open/closed correlated closely with xylene/blood concentrations.

Occupational studies: The effects of TCE on balance

One hundred fifty workers in a jet engine section of an air force base were studied primarily for pulmonary effects of metal dusts. The workers were also exposed to chlorinated and fluorinated solvents; hence the effects of solvent exposure were also studied. [85]

The level of exposure to solvents apparently was not measured, but it was known that large amounts of TCE and other chlorinated solvents had been assigned to the airbase. Most workers from within the study came from areas where solvents were used to clean metals. A significant difference was noted in sway speed (balance) with eyes open/closed in the exposed group compared to the nonexposed group.

Occupational studies: The effects of mixed solvents on hearing and balance

Whilst a number of studies have looked at the effects of specific solvents, 'solvents + noise' on hearing and balance, many workers are exposed to a mixture of solvents, often with noise.

Otoneurological findings in workers with CTE due to exposure to organic solvents may have impaired equilibrium and central vestibular disorders, as seen in impaired visual suppression, increased saccade speed, abnormal gain in smooth pursuit and pathological nystagmus. In some cases, balance performance deteriorated 5 years after exposure ceased. [86] Tests of central auditory function such as discrimination of interrupted speech and evoked cortical responses to frequency glides (CRA-delta-f) indicate retrocochlear disorders. PTA thresholds (tests of peripheral hearing function) and speech discrimination tests, on the other hand, often show minimal effects. [67],[75],[86],[87],[88],[89],[90] These studies do not support the assumption that long-term exposure to industrial solvents causes cochlear damage.

Long-term exposure to aliphatic and aromatic solvents and jet fuel was studied in three groups of workers by Odkvist et al. [91] Group A consisted of 16 subjects diagnosed with CTE; group B, 7 subjects with suspected CTE; both groups, with long-term exposure to aliphatic and aromatic solvents. Group C consisted of 8 workers with long-term exposure to jet fuel. Discrimination of interrupted speech and CRA-delta-f produced significant abnormal results in all groups, particularly group A. PTA and speech discrimination results correlated with each other. There was no indication of hearing loss which could not be attributed to age or exposure to noise. ABR and stapedius reflex testing did not show significant abnormalities. Abnormal vestibular findings included positional nystagmus, reduced vestibulo-ocular reflex suppression (VORS) and reduced gain in the smooth pursuit test. Vestibular pathology was highest in group A and lowest in group C.

The Copenhagen male study, [92] based on self assessment, reported that exposure to solvents for 5 years or more resulted in a higher risk of hearing impairment than did nonexposure to solvents in men not exposed to noise. Exposure to noise for 5 years or more resulted in twice the risk of hearing impairment than did exposure to solvents. In men exposed to both noise and solvents, the effect of noise dominated and solvents were not assessed as having an additive effect. Although the relative effect of solvent exposure was assessed as moderate in this study, the attributable risk of a damaging effect from long-term exposure to solvents was considerable.

Thirty-three workers with varied levels of exposure to solvents, the variation being both in the type of solvent and length of exposure, underwent a comprehensive battery of audiological tests. Apart from a mild to moderate SNHL found in some subjects (some, typical for noise exposure), peripheral tests were normal in most subjects. Central test, filtered speech and mismatch negativity showed varying degrees of abnormality, which was felt to reflect the differing levels of disease resulting from solvent exposure.

Further studies by Morata et al., [93] specifically focused on occupational hearing loss among 438 refinery workers. The workers were exposed to solvents, which included benzene, toluene, xylene and ethyl benzene; and noise. In the majority of cases, exposure levels were within permitted exposure levels. The results show that for the group of workers with simultaneous exposure to noise and solvents, there was increased prevalence of a high-frequency hearing loss (42-50%). Acoustic reflex decay testing pointed to an element of retrocochlear involvement.

The data suggested that workers exposed to solvents within permitted TWA levels were 2.4 times more likely to develop hearing loss than were nonexposed workers. Workers exposed to solvents and level of noise considered high enough to cause hearing loss were 3 times more likely to develop hearing loss than were nonexposed workers and 1.8 times more likely to develop hearing loss than were workers exposed to lower levels of noise and solvents.

Similar findings were also noted by Sliwinska-Kowalska et al, [94] where the relative risk factor of hearing loss in solvent-exposed workers was significantly increased in exposures to solvents and noise in a wide range of frequencies (2-8 kHz). In groups exposed to solvents and 'solvents and noise,' hearing thresholds at 1-8 kHz were significantly poorer than in the nonexposed group. The poorest thresholds in the 'solvent and noise' group were 2-4 kHz.

In a field study [95] of workers exposed to a mixture of solvents, hearing and vestibular function was assessed in 61 workers and results compared with a control group. Vestibular dysfunction was present in 47.5% of the exposed group and 5% of the control group. A high-frequency SNHL was found in 42% of the exposed group and 5% of the controls, identified using PTA and DPOAEs. The findings corresponded closely with the rate of total exposure to the solvents.

Increased postural sway responses were also noted by Smith et al., [96] in US Air Force personnel exposed to jet fuel. It was also noted in workers in a shoe, sandal and leather factory exposed to n -hexane, xylene and toluene. [97] In this study, where the mean level for n -hexane was 40 ppm, exposed workers demonstrated significantly larger sway than did a control group of nonexposed workers. The pattern of changes in sway in the exposed group suggested that the vestibulocerebellar and spinocerebellar systems were affected by n-hexane. The exposed workers did not exhibit any other specific signs or symptoms of solvent poisoning or neurological disorders. The results of this study would suggest that measurements of postural sway may be sensitive to, and useful for, testing the effects of exposure to solvents on balance.


  Main findings of the occupational studies Top
The occupational effects on hearing and balance as a result of exposure to industrial solvents with and without noise have not been as well studied as the effects on animals. Some of the main findings are listed below:

  • Human studies suggest that solvents are ototoxic.
  • Exposure to industrial solvents can cause permanent hearing loss, both peripheral and central, though results vary.
  • Hearing loss can occur at exposure levels within the permitted OEL.
  • There is evidence of a dose-response relationship between hearing thresholds and levels of exposure.
  • A synergistic effect of combined noise and solvent exposure, even at levels below permitted OELs, has been noted; though results are variable.
  • It is very difficult to separate out the individual effects in combined exposures.
  • Minimal effects are often noted on PTA thresholds.
  • PTA results can indicate a high-frequency loss or a hearing loss which affects a wider range of frequencies.
  • The indications are that hearing loss occurs earlier and is more serious among workers exposed to carbon disulfide and noise.
  • Effects of solvents continue after exposure ceases.
  • Exposure to solvents can result in CNS disturbance.
  • Exposure to solvents can result in balance abnormalities.
  • Exposure to solvents can result in vestibular disturbance. Long-term exposure can cause cerebellar lesions, as indicated by decreased VORS, pathological spontaneous and positional nystagmus, pathological increased saccade speed, abnormal gain in smooth pursuit.
  • Vestibulo-oculomotor testing is valuable in testing CNS lesions in solvent-exposed workers.
  • Study parameters vary often, making it difficult to compare results.



  Discussion Top


The main findings from the animal experiments are very important for human studies; however, extrapolating data from animal experiments to human cases is very complex.

In animal experiments although different test parameters have been used, which make it difficult to compare one set of results with another, the variables are fewer than in human studies. Many additional factors need to be taken into account for humans, which include increasing age, levels of noise exposure throughout a working life, personal traits, health history, exposure history including duration of exposure to solvents, individual susceptibility to solvents and solvent uptake - all which could have an adverse effect on hearing. Of confusing the relationship between exposure and hearing loss if they are not carefully considered in studies.

The majority of results from animal experiments and human studies indicate that exposure to solvents results in a permanent hearing loss. Negative results are few. [13],[63] The hearing loss in rats is a mid-frequency cochlear loss, with the exception of the effects of TCE exposure. In human studies a high-frequency loss is noted, [89] or effects on a wider range of frequencies are noted. [74],[94] Evidences of both cochlear and central elements are noted in human studies. [60],[74],[93],[95],[98],[99]

The effect of industrial solvents on balance has not been extensively studied. However, there do seem to be similarities in the site of action for both animals and humans. In both groups solvents appear to act on the cerebellum, causing pathological nystagmus and effects on the vestibulo-ocular reflex. [32],[48],[62],[75]

Animal experiments have concentrated on individual solvents, with or without noise exposure. Whilst some occupational studies have also looked at the effects of specific solvents with or without noise, the majority of workers are exposed to a mixture or mixtures of solvents and noise that may interact with each other in an additive or synergistic manner. The permutations are numerous, and it is very difficult to monitor and measure their effects. Further, more detailed studies are needed in this area.

Among the combinations of agents, of greatest concern is simultaneous exposure to solvents and noise. There are a number of examples of a synergistic reaction between these two agents in experiments on rats. [10],[30],[39] There is also some evidence in human studies of a synergistic reaction between the two agents. [60],[73],[94] This could have far-reaching implications in the workplace. Exposure levels for each agent may currently be within permitted OELs but can still result in damage to hearing and balance when combined. If the presence of such synergy were confirmed in humans, OELs would need to be revised for both solvents and noise to prevent the occurrence of occupational hearing loss in future.

In both animal and human studies, considerable work is needed to define dose-response relationships and determine any critical level at which damage occurs. These are critical in securing safe levels of exposure for solvents alone and in combination with noise. If hearing losses are developing at levels at or below the current PELs, this would suggest that they are already too high.

Animal experiments point to different levels of susceptibility to solvent exposure between species. Human studies point to different levels of susceptibility between individuals. A better understanding of these differences would help to determine which individuals would be more prone to the adverse effects of solvent exposure.

In many countries, the only agent considered ototraumatic is high-intensity noise. With so many workers exposed to solvents (10 million in Europe alone), it would suggest that a high number of unmet needs regarding hearing conservation exist. Few workers exposed to solvents would be required to have a hearing test, because the level of noise would not be deemed hazardous; so the extent of the problem may go unnoticed. Whilst it is now recommended that workers exposed to solvents have their hearing tested, there are no regulations requiring this to be done on a regular basis.

There are periods during a working life when workers are exposed to very high concentrations for short periods of time. Exposure concentrations in the animal experiments far exceed the TWA for occupational exposure in the majority of experiments. It may be more relevant at this stage for experiments to use exposure levels closer to permitted OELs, taking into consideration the safety factor considered relevant to human exposure. Duration of exposure also needs careful consideration in further experiments; whilst very short in animal experiments, workers are usually exposed for a period of many years.

Balance problems resulting from solvent exposure have been neglected to a large extent; yet evidence suggests it can be a real problem for exposed workers and could potentially be very dangerous. However, research in this field is quite limited, making the need for further studies of paramount importance.

An agreed regular standardized battery of tests sympathetic to both peripheral and central elements of hearing and balance would be an effective means of monitoring the effects of solvent exposure and aiding research purposes. These tests would need to be quick and easy to administer and be acceptable to the workforce.


  Conclusions Top


Hearing loss in industry has generally been assumed to be as a result of age and noise exposure.

There is now clear evidence emerging to suggest that exposure to industrial solvents and 'industrial solvents and noise' has an adverse effect on the hearing and balance function in rats, causing a permanent loss of auditory sensitivity and vestibular disturbances. Whilst the results of human studies can be contradictory in part and study designs often make it difficult to make direct comparisons, there is a clear indication that exposure to solvents can result in a permanent hearing loss and balance disorders in humans, the level of which can be enhanced by interaction with noise.

If confirmed, these results could have far-reaching implications for industry in terms of possible changes needed in working environments to reduce levels of combined exposures to noise and solvents.

If appropriate changes in working practices and exposure protocols are to develop to match changing needs, a solid evidence base regarding the effects of exposure to solvents is critical for the decision makers in industry. Providing that evidence base will require a standardized approach to the assessment of the hazards both in terms of animal experiments and human studies.

 
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Correspondence Address:
Deepak Prasher
School of Audiology, UCL Ear Institute, University College London, London
United Kingdom
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1463-1741.33952

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