Download Epidemiological review: some risk factors of hearing loss

GUIDELINE FOR DIAGNOSING OCCUPATIONAL
NOISE-INDUCED HEARING LOSS
PART 2
Epidemiological review: some risk factors of hearing loss
Zhi-ling Zhang
September 2010
Research Unit
Governance, Policy and Research
Accident Compensation Corporation
Wellington, New Zealand
Important Note
This review summarises information on the epidemiological evidence for some risk
factors of hearing loss including noise-induced hearing loss. It is not intended to replace
clinical judgement, or be used as a clinical protocol. A reasonable attempt has been
made to find and review papers relevant to the focus of this report. It does not claim to
be exhaustive. This document has been prepared by staff of ACC’s Research Unit. The
content does not necessarily represent the official view of ACC or represent ACC policy.
ii
Executive summary
Background
Noise-induced hearing loss (NIHL) appears to be a significant occupational disease in many
countries. The effects of noise exposure on hearing have been well documented and widely
recognised. However, many exposures other than noise may also contribute to developing
hearing loss. Some of these factors, for example occupational exposure to solvents, may have
been ignored previously and require more attention in the future.
Search strategy
A range of bibliographic databases were searched for published epidemiological studies that
investigated the relationship between some selected risk factors (age, smoking, genetic factors,
organic solvents and carbon monoxide) and hearing loss in humans. Some experimental
studies in animals were also searched if there was a lack of studies in humans.
Main findings and implications
Age
All related studies included in this review show that age is strongly associated with hearing
loss.
Evidence that supports a synergistic effect of ageing and noise exposure appears to be very
weak. Compared with those without historical noise exposure, older adults previously
exposed to occupational noise do not have a higher rate of threshold changes or even have a
lower rate of the changes. These findings support that noise exposure in working age is very
unlikely to be an attribute of hearing deterioration in older people who are no longer exposed
to noise. In other words, previous noise exposure is very unlikely to cause older people to be
more prone to age-related hearing loss, even though hearing loss caused by the previous noise
exposure will still exist.
An additive effect model of ageing and noise exposure on hearing loss is much more
acceptable than the assumption of synergistic effect. Nevertheless, the model is not always in
iii
agreement with some data from available studies. An additive effect model with modification
is considered to be the best approach available.
Recommendation
The impact of ageing has to be considered in the diagnosis of noise-induced hearing loss.
Hearing deterioration (threshold changes) after people leave occupational noise exposure
cannot be attributed to occupational noise exposure.
Exit audiograms (for those leaving employment or a noise-exposed job) appear to be critical
in assessing the maximum amount of occupation-attributable hearing loss in the individual.
However, any historical records of hearing tests can be relevant and helpful and should be
tracked and considered for hearing impairment assessment.
When assessing older patients with significant hearing impairment and historically exposed to
a high level of occupational noise, caution is needed to avoid potential “over-adjustment” of
age-related hearing loss, especially in cases where historical records of hearing tests are not
available.
In terms of research on noise-induced hearing loss, age should be considered as an important
confounder and needs to be adjusted or controlled.
Smoking
Smoking can be considered a risk factor for hearing loss.
However, all included studies have significant weaknesses in methodology, especially in the
measurement of noise exposure and in controlling the exposure as a relevant confounder.
Even though most included studies indicate that smoking is associated with hearing loss, more
well-designed studies with appropriate controls on relevant confounders are needed.
Recommendation
Patients with noise-induced hearing loss can be advised to stop smoking to prevent related
adverse health effects including possible further hearing impairment. In some studies
reviewed, ex-smokers had a lower risk of hearing impairment than current smokers or an
iv
insignificant risk when compared with non-smokers. For long-term heavy smokers, it is
possible that smoking could cause hearing loss.
Genetic factors
Genetic studies on noise-induced hearing loss appear to be at an early stage. Numbers of the
studies on individual genes or single nucleotide polymorphisms (SNPs) are still limited. Six
of the ten studies found are based on two sample sets in Sweden and Poland.
It is noted that some genetic mutations are associated with susceptibility to noise-induced
hearing loss. However, some of these findings are based on analysis of relatively large
numbers of the genetic markers (e.g. SNPs). It is possible that some of the findings are false
positive associations rather than true associations. Further studies are needed to test these
associations in different sample sets so that true associations can be established.
Based on odds ratios reported in these studies, and the sampling methodology used (e.g. the
most susceptible versus most resistant), available studies appear to suggest that genetic
markers currently investigated are not strong risk factors for noise-induced hearing loss.
The contribution of genetic factors to noise-induced hearing loss also depends on the
frequency of related genetic markers in the local population, which appears to be unclear at
this stage.
Potential combination effects of different related genes remain unexplored at this stage. The
studies included in this review only investigate the effect of individual genes.
Recommendation
The implication of the results from these available genetic studies on the diagnosis and
management of noise-induced hearing loss appears to be limited. Clinical applications of
these studies have not been developed.
v
Organic solvents
Based on the studies reviewed, exposure to solvents appears to be a risk factor for hearing
impairment. Styrene at relatively low exposure levels is associated with hearing impairment
in the workplace at a low level of noise exposure. Some studies found that there was a
potential synergistic effect of combined exposure to solvents (styrene and toluene) and noise.
The effect indicates that the combined noise and solvent exposure could potentially lead to a
greater risk of hearing loss than exposure to solvents and noise alone. According to available
studies, some solvents are associated with hearing impairments at low (0.5, 1 and 2 kHz, for
toluene and carbon disulphide) or high frequencies (6-8 kHz, for styrene) which are not
typically seen in noise-induced hearing loss at working age.
However, most of these study results are based on cross-sectional study design. More cohort
studies are obviously needed to further demonstrate and quantify the causal relationship
between solvent exposure and hearing loss. The relationship appears to be relevant to clinical
assessment.
Recommendation
Information in relation to solvent exposure needs to be collected in hearing loss assessments,
especially for workers from related industries (e.g. yacht building). Input from occupational
health professionals may be needed in some cases. Currently, clinical tools or guidelines to
assess hearing impairment in association with solvent exposure in the workplace are lacking.
Surveillance data of hearing tests in the workers exposed to solvents can be critical in the
assessment.
It is worth mentioning that some of these solvents are also present in the cases of substance
abuse (e.g. inhalation of solvent-based propellants). Cases of hearing loss caused by the
substance abuse have been reported previously. Related information and medical history need
to be asked and considered in hearing loss assessment.
Risk control to reduce solvent exposures may need to be considered in the programmes to
prevent noise-induced hearing loss in the workplace. Internationally, there is currently an
absence of guidelines or criteria to determine solvent-related hearing loss.
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Carbon monoxide
The findings from animal studies and human case reports are different. No hearing
impairment was found in animal studies even with a significantly high concentration exposure
of carbon monoxide (up to 1,500 ppm). However, human cases of hearing loss were reported
after carbon monoxide poisoning. Exposure levels of carbon monoxide are not available in the
accidental poisoning reports. It is reasonable to assume that the poisoning levels are higher
than the exposure levels in most workplaces.
Based on the case reports, carbon monoxide poisoning-related hearing loss could be described
as bilateral sensorineural impairment and is at least partly reversible. It is unclear whether the
hearing loss is related to the potential ototoxicity and/or neurotoxicity of carbon monoxide.
There is only a very limited number of epidemiological studies on occupational exposure to
carbon monoxide and hearing impairment in the working population are available. There
appears to be a need for more studies in the future. The risk of hearing loss in association with
long-term occupational exposure to carbon monoxide in the working environment, and the
possible interaction between the exposure, noise and other risk factors, remains unclear.
Recommendation
A patient’s medical history of carbon monoxide poisoning should be investigated and
recorded during the diagnosis of noise-induced hearing loss. Audiometric testing results after
the poisoning need to be considered in the assessment if they are available.
Applications of the evidence to assessment
Compared with the use of the findings from epidemiological studies on risk factors for
prevention, it is relatively difficult to use the findings for clinical assessment on individual
patients. Effects of the risk factors are assessed at population or group level in
epidemiological studies, so there are limitations in generalising the findings for an individual.
Moreover, the exposure “dose” of the risk factors (apart from age) for an individual is usually
unclear and difficult to obtain quantitatively. Exposure to multiple risk factors also makes the
assessment much more difficult. As mentioned previously, there is also a lack of high quality
cohort studies for some risk factors reviewed.
vii
Based on recent available research evidence on most of the risk factors reviewed, it is very
difficult to develop clinical tools to quantitatively determine how much of an individual’s
hearing loss is caused by smoking and how much is caused by solvents. Internationally, there
is currently an absence of such clinical tools. In short, it is difficult to use the findings in a
“quantitative approach” in the clinical assessment in most cases.
However, these limitations do not hinder the findings being used in a “qualitative approach”
in a clinical assessment. For example, if hearing impairment in a yacht building worker does
not match with the level of noise exposed, information in relation to other risk factors (e.g.
exposure to styrene, smoking and other non-occupational related exposure) should be
considered when interpreting the hearing impairment. It would be very useful if historical
audiometric records for the worker were available.
Practically, noise exposure needs to be considered as the highest risk factor for occupational
hearing loss at present. However, exposure to other risk factors (e.g. solvents) should not be
ignored.
Limitations
It should be noted that the risk factors of hearing loss are not limited to those reviewed in this
report. A number of other risk factors have been reported in the literature. They include
gender, socio-economic status, heavy metals, medications, cardiovascular disorders and other
medical conditions. These factors are not included in this review primarily because of time
constraints; users should be aware of this limitation and seek other related information when it
is needed.
viii
Acknowledgements
The draft of this review was circulated to several internal and external experts for peer review,
including:

Dr Robert Dobie, Professor, University of Texas, San Antonio, USA

Dr Pierre Campo, Institut National de Recherche et de Sécurité, France

Dr Peter Larking, Senior Research Advisor, Research Unit, ACC, Wellington

Anne Greville, Audiology Advisor, ACC, Wellington

Dr Margaret Macky, Director, Workwise, ACC, Wellington.
The author is grateful for their comments on the draft report and for the provision of
information. The conclusions in this final report are the views expressed by the author.
The author also thanks Helen Brodie and Beth Tillier of ACC Information Services for their
help in obtaining related materials used in this report, Sheryl Calvert for her assistance in
editing and proof reading, and Emma Roache for preliminary literature searching.
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Contents
Title Page.................................................................................................................................... i
Executive Summary ................................................................................................................iii
Acknowledgements.................................................................................................................. ix
List of Tables........................................................................................................................... xii
List of Figures ........................................................................................................................xiii
1. Introduction .......................................................................................................................... 1
2. Objectives.............................................................................................................................. 1
3. Methodology ......................................................................................................................... 2
3.1 Criteria for selecting studies for this review................................................................ 2
3.2 Search strategies and information sources .................................................................. 2
3.3 Methods of the review .................................................................................................... 3
4. Results ................................................................................................................................... 4
4.1 Age ................................................................................................................................... 4
4.1.1 Background ......................................................................................................... 4
4.1.2 Studies identified................................................................................................. 5
4.1.3 Evidence and implications ................................................................................ 16
4.2 Smoking......................................................................................................................... 19
4.2.1 Background ....................................................................................................... 19
4.2.2 Studies identified............................................................................................... 19
4.2.3 Evidence and implications ................................................................................ 29
4.3 Genetic factors .............................................................................................................. 30
4.3.1 Background ....................................................................................................... 30
4.3.2 Studies identified............................................................................................... 30
4.3.3 Evidence and implications ................................................................................ 39
4.4 Organic solvents ........................................................................................................... 40
4.4.1 Background ....................................................................................................... 40
4.4.2 Studies identified............................................................................................... 40
4.4.3 Evidence and implications ................................................................................ 53
4.5 Carbon monoxide (CO) ............................................................................................... 55
4.5.1 Background ....................................................................................................... 55
4.5.2 Studies identified............................................................................................... 55
4.5.3 Evidence and implications ................................................................................ 57
5. Discussion............................................................................................................................ 58
5.1 Methodological quality ................................................................................................ 58
5.2 Implications of findings ............................................................................................... 59
x
5.3 Limitations .................................................................................................................... 62
6. Conclusions ......................................................................................................................... 63
References ............................................................................................................................... 66
Appendix: Literature search strategy .................................................................................. 74
xi
List of Tables
Table 1: Summary of the studies on ageing and noise-induced hearing loss............................. 8
Table 2: Summary of the studies on the co-effect of ageing and noise on hearing loss .......... 13
Table 3: Summary of the cohort studies on the association of smoking and hearing loss....... 20
Table 4: Summary of the case control studies on the association of smoking and hearing loss
.................................................................................................................................................. 23
Table 5: Summary of the cross-sectional studies on the association of smoking and hearing
loss............................................................................................................................................ 26
Table 6: Summary of the studies on the association of genetic factors in relation to antioxidant
systems or oxidative stress and hearing loss ............................................................................ 32
Table 7: Summary of studies on the association of genetic factors in relation to the potassium
recycling pathway and hearing loss ......................................................................................... 34
Table 8: Summary of studies on the association of genetic factors in relation to heat-shock
proteins and hearing loss .......................................................................................................... 36
Table 9: Summary of the studies on the association of other genetic factors and hearing loss37
Table 10: Summary of the studies on the association of toluene and hearing loss .................. 41
Table 11: Summary of the studies on the association of styrene and hearing loss .................. 45
Table 12: Summary of the studies on the association of a mixture of solvents and hearing loss
.................................................................................................................................................. 49
Table 13: Summary of the studies on the association of carbon disulphide and hearing loss . 52
xii
List of Figures
Figure 1: Changes in hearing thresholds (smoothed curve) between baseline and 10-year
measures, Beaver Dam study ..................................................................................................... 7
Figure 2: Rate of changes in hearing thresholds between those with and without noise
exposure history, MUSC study ................................................................................................ 10
xiii
1. Introduction
Noise-induced hearing loss (NIHL) is a significant occupational disease in many countries. In
Europe it is “the most prominent and most recognised occupational disease in the Member
States of the European Union” and ranked as the fourth most common occupational disease
after musculoskeletal diseases, skin disease and respiratory diseases in 20011-3. On average,
the cost of noise-induced hearing loss accounted for 10.3% of total compensation for
occupational disease in six European countries in the period between 1999 and 20014. In
Washington state, in the USA, the number of compensation claims for hearing loss increased
12 times from 1984 to 1998. In 1998, the annual incidence reached 2.6 claims per 1,000
workers for the entire workforce in the state. In the most affected industry (logging), the
incidence reached as high as 70 claims per 1,000 workers5. In New Zealand, the number of
noise-induced hearing loss claims covered by the Accident Compensation Corporation (ACC)
increased from 4,200 cases in 1995 to 12,500 cases in 2003, and related medical costs
(hearing aids, treatment and assessment) in 2003 were about five times higher than the costs
in 1995.
The effects of noise exposure on hearing have been well documented and widely recognised.
However, many exposures other than noise may also contribute to developing hearing loss.
Some of these factors (e.g. occupational exposure to solvents) may have been ignored
previously and require more attention in the management of noise-induced hearing loss1,2,6.
This report summarises the findings from an epidemiological review on available studies of
selected risk factors of hearing loss. Other relevant risk factors (e.g. medication,
cardiovascular disease and heavy metal) are not included in this review because of time
constraints.
2. Objectives
The aims of this work are to assess epidemiological evidence of selected risk factors of
hearing impairment, provide information to understand the complexity of developing noiseinduced hearing loss, and finally to discuss the implications for the management of noise-
1
induced hearing loss (e.g. prevention, diagnosis and research). The factors under investigation
include age, smoking, genetic markers, organic solvents and carbon monoxide exposure.
3. Methodology
3.1 Criteria for selecting studies for this review
Types of studies
Epidemiological studies that investigate the relationship between the risk factors and hearing
impairment on humans are considered in this review. Most of the included studies are based
on working populations, but some studies on ageing and smoking are population or
community based. All types of study design for observational studies including cohort studies,
case control studies, cross-sectional studies and case reports are included.
Some experimental studies in animals are also used owing to the lack of human studies in
some areas. Results from animal studies are usually taken into consideration in the
determination of occupational risk factors (e.g. toxicity of occupational chemicals) when
relevant human studies are unavailable.
Types of participants
Both male and female participants who were exposed to the factors under study and with
outcomes on hearing impairment are included. No limitation on age is used in this review.
Types of outcomes
The studies are included if at least one of the following three categories of outcome measure
is reported:

audiometric tests including pure-tone audiometry, high-frequency audiometry and
otoacoustic emission

self-reported hearing impairment

hearing loss diagnosed by criteria or guidelines.
3.2 Search strategies and information sources
2
A search strategy for different bibliographic databases was developed (Appendix 1). The
literature was searched up to July 2009.
The databases included in the literature search are MEDLINE, MEDLINE Daily Update,
EMBASE, CDSR, ACP Journal Club, DARE, CCTR, CLCMR, CLHTA and CLEED.
A secondary hand search of citations of systematic reviews and other relevant reports was
also conducted.
3.3 Methods of the review
This review uses the method reported by Hayden et al7 in 2006 for the evaluation of the
quality of prognosis studies. The method covers six areas of a study, including:

study participation

study attrition

exposure assessment

confounding measurement and control

outcome measurement

analysis.
In addition to these components, dose-response relationship between exposure and outcome
was also considered in the quality assessment of the studies included, as relevant evidence in
interpreting causal relationship8.
After quality assessment, studies with relatively poor quality were still included in this review.
However, by a subjective approach, more weight was given to the studies with relatively high
quality when making conclusions and synthesising evidence for the risk factors under
discussion.
Human data are given priority over animal data in this review.
3
4. Results
4.1 Age
4.1.1 Background
Ageing affects many parts of the auditory system. Histopathological studies report that
degeneration of the auditory system begins early in life and continues insidiously throughout
life9,10. Epidemiological studies have supported a clear trend of an annual decline in hearing
ability11,12. Hearing deterioration may become more rapid for both men and women after the
fourth decade13. In the United States, less than 10% of the burden of adult hearing loss is
considered to be the result of occupational noise exposure; most of the rest is considered to be
age-related14.
Differing patterns of age-related hearing loss are observed in different studies. Some report a
significantly greater decline in the high frequencies than the low frequencies; others report a
similar deterioration over the entire frequency range10.
The impact of the ageing process on hearing loss among those with historical noise exposure
or noise-induced hearing loss is a relevant area in hearing loss assessment. For many older
people with historical noise exposure, the major sources of the hearing loss appear to be the
effects of the noise exposure and ageing15,16. Questions in relation to the co-effects of these
two factors on hearing loss are particularly interesting for exploration. For example, does the
impact of the ageing process differentiate between those with historical noise exposure and
those without? Is there a synergistic effect of ageing and noise exposure on hearing loss? If
there is no synergistic effect observed, then the effects of the factors can be considered as
additive, which indicates that hearing loss caused by occupational noise is unlikely to
deteriorate after the exposure stops15,16.
4
4.1.2 Studies identified
The impact of ageing on noise-induced hearing loss has not been systematically assessed in
this report since the topic will be covered in another report. The following studies were found
to have age as an independent variable in analysis and therefore are included in this section.
Studies investigating the impact of ageing on hearing loss
Compared with a younger age group of 18-29 years old, data from the Danish Work
Environment Cohort Study shows that older age groups had significantly greater self-reported
hearing loss. The results were adjusted by occupational noise, height and smoking and
stratified by gender in a multiple logistic regression model17.
In the study reported on by Starck et al18, age accounted for about 26% of the variation of
sensory hearing loss for forest workers and 48% for shipyard workers, based on a linear
regression model. The authors state that age was the most important single risk factor for the
population studied18.
In the genetic study reported by Rabinowitz et al19, age was found to be significantly
associated with hearing loss in the linear regression, accounting for 27% of variation of
hearing loss in high frequencies (3, 4 and 6 kHz) and 11% of low frequencies (0.5, 1 and 2
kHz).
Pedersen et al20 report on hearing loss in two unscreened cohorts in Gothenburg, Sweden.
Hearing tests were carried out at ages 70, 75, 79 and 81 in one cohort (F01 cohort) and at ages
70 and 75 in another cohort (F06 cohort). The study found that hearing thresholds deteriorated
in all frequencies for both genders over the years. It was found that the hearing loss was most
pronounced at higher frequencies for both genders. For F01 cohort, the decrease in hearing
threshold in men between the ages of 70 and 81 was more pronounced at 2 kHz (27 dB) than
at 4 and 8 kHz (15 and 20dB respectively). The average hearing loss in women increased at a
constant rate between the ages of 70 and 79 (15 dB). The study was conducted in an area with
heavy mechanical industries. Previous exposure to occupational noise was not taken into
account. Some of these findings are likely to be associated with existing hearing loss caused
by occupational noise. A later published paper16 based on the same cohorts reveals the
5
differences in hearing loss between those exposed and those not exposed to occupational
noise (see Table 2).
Another cohort study on unscreened older adults over a 10-year period was carried out in
Beaver Dam, Wisconsin. At the beginning (1993-95) of the study, 3,753 older adults (ranging
from 48 to 92 years old, with a mean age of 68.3 years) participated in the study12; 56% of
them were occupationally exposed to noise. A five-year follow-up examination was
conducted from 1998 to 2000, with 2,800 participants21. A 10-year follow-up examination
was carried out from 2003 to 2005, with 2, 395 participants22.
At the baseline (1993-95) of the study, prevalence of hearing loss was significantly associated
with age (see Table 2). It was found that for every five years of age, the risk of hearing loss
increased by almost 90%12.
At the five-year follow-up (1998-2000), incidence of hearing loss (new cases of hearing loss
in the period) significantly increased with age. The increase was observed in both males and
females21.
At the 10-year follow-up (2003-05), analysis of auditory thresholds showed that22:

continuing decline in hearing ability (increase in hearing threshold) occurred with
advancing age at all frequencies

for younger age groups (50-60 years old, as defined at the baseline), the increase in
thresholds was greatest at higher frequencies (3-8 kHz)

for older age groups (70-89 years old, as defined at the baseline), the increase in
thresholds was greatest at lower frequencies (0.5-2 kHz).
In the following graph the authors of the study provide more detailed information on the
changes in thresholds22.
6
Figure 1: Changes in hearing thresholds (smoothed curve) between baseline and 10-year
measures, Beaver Dam study
Source: Wiley TL, et al. Changes in hearing thresholds over 10 years in older adults. Journal of the American
Academy of Audiology 2008;19(4):287 (Figure 2, A in the original paper). The figure is based on
data from all participants (male and female), 2,130 participants and 4,201 ears
Brant and Fozard report changes in hearing thresholds in 813 adult males (20-95 years,
mostly white-collar workers) in the Baltimore Longitudinal Study of Ageing (BLSA)23.
Changes in hearing thresholds occurred in all age groups during the 15-year follow-up period.
The study observed that hearing loss in the males 70 years and older was greatest at the
highest frequencies. However, in terms of the change in hearing thresholds over the time
period, the change rates for lower frequencies (0.5-2 kHz) were greater than the higher
frequencies after age 70 years. This finding is similar to that reported from the Beaver Dam
study22. The authors conclude that the rate of change for the older males is faster in the
speech-range frequencies 0.5-2 kHz than in the higher frequencies, since their hearing has
already diminished at the high frequencies23.
The study reported by Davis et al24 also shows that people who are over 55 years old have
more than three times the deterioration rate per decade than those under 55 years old at
middle frequency (measured by the average of 0.5, 1, 2 and 4 kHz).
The characteristics of these studies are briefly summarised in Table 1.
7
Table 1: Summary of the studies on ageing and noise-induced hearing loss
Study
design
Study
population
Study
group
Comparison
group
Confounders
controlled
Results
Notes
Burr et al,
200517
Based on
Danish Work
Environment
Cohort Study,
7,221 workers
aged 18-59
years without
hearing injury.
Subgroup
analysis was
conducted in
4,766 workers
of Nordic
origin.
Age groups
Age group:
Males:
Self-reported
data
30-39 yrs
40-49 yrs
50-59 yrs
18-29 yrs
Occupational
noise, height and
smoking stratified
by gender
Cohort study
Starck et al,
18
1999
Crosssectional study
Rabinowitz et
al, 200219
Crosssectional study
30-39 yrs: OR=1.62 (1.12-2.34)
40-49 yrs: OR=2.78 (1.95-3.99)
50-59 yrs: OR=3.60 (2.42-5.36)
Five-year
incidece of
hearing loss
Females:
30-39 yrs: OR=2.19 (1.38-3.45)
40-49 yrs: OR=2.74 (1.75-4.30)
50-59 yrs: OR=3.36 (2.04-5.56)
199 forestry
workers and
shipyard
platers who
used noisy
hand-held
power tools in
their regular
work
Unsure, probably
not in the linear
regression
By linear regression, age accounted
for 26% of hearing loss in forestry
workers and 48% in shipyard
workers.
77 volunteer
workers who
were exposed
to noise above
85 dB(A),
male and
female, aged
19-66 yrs; 58
workers
included in the
final analysis
Not in linear
regression
Linear regression:
Audiometric high frequency average
Age: coefficients=0.55, R2=0.27,
P=0.0001
Audiometric low frequency average
Age: coefficients=0.17, R2=0.11,
P=0.01
Age was
associated with
hearing loss in
three noise
exposure strata.
Audiometric
hearing
threshold levels
at 0.5, 1 and 2
kHz were
averaged as low
frequency
average; 3, 4 and
6 kHz were
averaged as high
frequency
average.
Note: In the linear regression, R2 for
age was higher than the value for
years of reported noise exposure.
Pedersen et al,
198920
Cohort study
Two cohorts of
elderly persons
in Gothenburg,
Sweden. Those
in F01 cohort
were born in
1901-02 (376
subjects at age
70); those in
F06 cohort
were born in
1906-07 (297
subjects at age
70). For F01
cohort, hearing
thresholds
were tested at
ages 70, 75, 79
and 81; for
F06 cohort,
test was
conducted at
ages 70 and
75.
Ages and
gender
None
F01 cohort:
Hearing loss was most pronounced at
higher frequencies from the baseline.
Threshold deterioration for men was
less dramatic at 4 and 8 kHz than at 2
kHz. Threshold deterioration for
women appeared to be more even
from 2 to 8 kHz.
F06 cohort:
Deterioration in hearing thresholds
was observed in both men and
women.
8
Noise exposure
and other risk
factors were not
taken into
account.
Unscreened
study subjects
Loss of followup
Study
design
Study
population
Study
group
Cruickshanks
et al, 1998,
200312,21
Populationbased study,
with 3,753
participants at
baseline
(1993-95),
average age
65.8 years (4892 years)
Age groups
Cohort study
(Beaver Dam
study)
Comparison
group
Confounders
controlled
48-59 yrs
60-69 yrs
70-79 yrs
80-92 yrs
Results
Notes
Prevalence at baseline (based on
3,556 participants, males and
females, %)
Incident case:
pure-tone
average of
thresholds at 0.5,
1, 2 and 4 kHz,
>25 dB, and
without hearing
loss at baseline.
48-59 yrs
60-69 yrs
70-79 yrs
80-92 yrs
Three
notch
categories
Five-year incidence (based on 1,576
participants, male and female, %)
48-59 yrs
60-69 yrs
70-79 yrs
80-92 yrs
Brant and
Fozard, 199023
Cohort study
(Baltimore
study)
Volunteers in
the Baltimore
Longitudinal
Study of
Ageing; 813
males aged 2095 years who
had hearing
tests at least
twice between
1968 and 1987
20.6
43.8
66.0
90.0
Age groups
Five-year
incidence of
hearing loss
11.6 (9.5-13.8)
23.1 (19.3-26.9)
49.0 (41.4-54.6)
95.5 (88.9-100)
Change in hearing threshold during
15 years of follow-up:
The rate of change in the lower
frequencies is about four times
greater after age 50 than before (1.4
vs 0.3-0.4 dB per year).
Exposure to
noise was not
assessed.
Most
participants were
white-collar
workers.
The rate of change for 8 kHz
increased in a linear fashion over the
entire adult age span. The rate of loss
for 3 kHz had a similar trend but at
higher rates than the speech
frequencies up to age 70.
The rates of change for the speech
frequencies and 3 kHz were greater
than for 8 kHz.
Davis et al,
199024
405 adults
aged 41-65
years in UK
with 2-4.5 year
follow-up
Age groups
8.8 dB (left ears) and 8.5 dB (right
ears) deterioration per decade for
those over 55 years old, compared
with 2.6 dB and 2.5 dB per decade
for those under 55 years old
Cohort study
There was no change in average
hearing levels for occupational
group, or sex.
Relatively short
period of followup
Relatively young
study
participants –
some of them
may still be
exposed to
occupational
noise
Age is also reported as a significant risk factor in the included studies that investigate the
association between solvent exposure and hearing loss. In the logistic regression analyses
reported by Schaper et al25, Morata et al26,27 and Sliwinska-Kowalska et al28,29, age was found
to be significantly associated with hearing loss after adjustment for noise and solvent
exposure. Gender28 and ear infection25,27 are also controlled in the analyses in some of these
studies.
9
In the multiple linear regression analyses reported by Sass-Kortsak et al30 and SliwinskaKowalska et al31, age is found to be a significant risk factor for hearing loss in all frequencies
measured, after adjustment for noise exposure and solvent exposure.
Studies investigating the co-effect of ageing and noise exposure on hearing
loss
The cohort study of presbyacusis at the Medical University of South Carolina (MUSC)32
found that pure-tone thresholds increase with age. The average rate of changes in thresholds
was 0.7 dB per year at 0.25 kHz, increasing gradually to 1.2 dB per year at 8 kHz and 1.23 dB
per year at 12 kHz. There were different patterns of threshold changes for males and females.
In this study, 74 of the 188 subjects reported a positive noise exposure history (mainly
occupational noise exposure). However, there was no significant difference in threshold
change between those with and without noise exposure history at 1-2 kHz. Interestingly,
subjects with a positive noise exposure history showed slightly lower rates of change than
those without the exposure (females at 2 kHz, males at 6-8 kHz; see Figure 2).
Figure 2: Rate of changes in hearing thresholds between those with and without noise
exposure history, MUSC study
10
Source: Lee FS, et al. Longitudinal study of pure-tone thresholds in older persons. Ear and Hearing
2005;26(1):7 (Figure 8 in the original paper)
In the Framingham study, 203 older males are classified into three notch groups according to
pure-tone thresholds in the 3-6 kHz region at baseline (E15). During the 15-year follow-up,
the threshold shift was found to be significantly higher in those with a large notch (N2)
compared with those with a small notch (N1) or absence of a notch (N0) at 2 kHz. The
authors assume the notched thresholds at the baseline are the result of noise exposure and
therefore suggest that the effect of the noise exposure on pure-tone thresholds would continue
long after the noise exposure had stopped33. However, the noise exposure is not directly
assessed in this study. The audiometric notches presented may not be a good indicator of
historical noise exposure. A recent study34 shows that audiometric notches can occur in the
absence of a positive noise exposure history. Depending on the methods used to define the
notches, up to 33% of those with the notch did not report occupational noise exposure, and up
to 13.6% did not report any history of noise exposure. In addition, it is unclear whether the
11
study subjects were exposed to noise during the follow-up period. The bias caused by
“regression to mean” could also contribute to the findings in this study35.
Macrae reports hearing threshold changes among war veterans over time (about 8-15 years)36.
According to historical records (“initial audiogram”), the veterans had normal hearing for
their age at 1 kHz and considerable hearing loss (20 dB or more) at 4 kHz, which was caused
by acoustic trauma or other wartime noise exposure. A hearing test was conducted for those
without conductive hearing loss or acoustic disorders and with an adequate time interval
(years) from the historical testing. Some veterans exposed to “noxious levels of industrial
noise since the time of initial audiogram” were excluded from the study. Hearing threshold
changes over the years were observed, based on the differences between the results of the test
and the historical records. The observed hearing threshold changes were compared with
predictions based on the presbyacusis equations reported by Spoor37. The author found that
the observed threshold changes were similar to the predictions for these veterans with existing
hearing loss. The author concludes that “the results support the hypothesis that presbyacusis
and noise-induced hearing loss are independent and additive at 4 kHz”36.
Rosenhall et al16 report hearing loss in two cohorts in Gothenburg, Sweden, an industrial city
with heavy mechanical industries including automobile manufacture and shipyards. Hearing
thresholds were tested at ages 70, 75 and 79 in one of the cohorts (F01 cohort). Compared
with those who were not exposed to occupational noise, male participants exposed to noise
for 15 years or more generally had poor hearing at ages 70 and 75. However, the differences
became less apparent at age 79. The authors consider that “presbyacusis eventually catches up
with NIHL”16. There were no significant differences in thresholds between women who were
not exposed to noise and those who had been exposed to noise for 15 years or more. The
authors consider it could be a result of the low level of noise exposure in women or gender
differences regarding susceptibility16.
Changes in hearing thresholds between ages 70 and 79 are not directly reported. However,
according to the median pure-tone thresholds reported in the paper (Table 3 in the original
report16), male participants exposed to noise appeared to have less threshold change (5.4 dB,
from 65.6 to 71 dB) than those without noise exposure (11.8 dB, from 53.8 to 65.6 dB) at 4
kHz16. At 2 kHz, the threshold change in noise-exposed participants was 17.5 dB (from 32.5
12
to 50.0 dB) compared with a change of 19.9 dB (from 23.4 to 43.3 dB) among those without
noise exposure.
The characteristics of the above studies are briefly summarised in Table 2.
Table 2: Summary of the studies on the co-effect of ageing and noise on hearing loss
Study
design
Study
population
Study
group
Lee et al,
200532
188 older
adults
recruited
through
advertisements
and subject
referral.
Average age
68 years (6081 years) at
baseline;
hearing
threshold
followed up
within 3-11.5
years
Age
groups:
Study
design
Study
population
Study
group
Gates et al,
1,662 older
adults from
Framingham
study; aged
63-95 years,
with average
age 73 years
Age
groups:
Cohort study
33,38,39
Cohort study
Comparison
group
Confounders
controlled
60-64 yrs
65-69 yrs
>=70 yrs
Comparison
group
Confounders
controlled
60-64 yrs
65-69 yrs
70-74 yrs
75-79 yrs
…
Results
Notes
The rate of average change in puretone thresholds ranged from 0.7 dB
per year at 0.25 kHz to 1.23 dB per
year at 12 kHz.
History of noise
exposure was
collected by
questionnaire.
Females >=70 yrs had significantly
faster rate of change at 0.25-3 kHz
and slower rate of change at 10 and
11 kHz than females in younger age
groups. Males >= 70 had a faster rate
of change at 6 kHz than males in the
younger age groups.
The slope of a
linear regression
was used to
calculate the rate
of change in
pure-tone
thresholds.
No difference in change of threshold
for those with or without historical
noise exposure (see Figure 2)
Extended high
frequencies (918 kHz)
included
Results
Notes
At the baseline (1983-85), “a
generalised worsening of thresholds
with increasing age is apparent at all
frequencies but particularly in the
high frequencies”.
Exposure to
noise was not
directly
assessed.
At six-year follow-up (1978-79 to
1983-85): amount of threshold
change was greatest in the higher
frequencies (2 kHz and above) and
least in the lower frequencies (1 kHz
and below). Age had a significant
main effect on the average threshold
change at lower frequencies (2 kHz
and below) but not for higher
frequencies (4, 6 and 8 kHz).
It is unclear
whether subjects
were exposed to
noise during the
follow-up.
At the 15-year follow-up, the change
in age-adjusted pure-tone threshold
varied significantly by notch
category.
Macrae, 197136
Case series
About 240 war
veterans who
received
audiogram
testing
(retesting), out
of approx. 360
None, apart from
the criteria used
for exclusion
13
About 160 were included in the final
analysis. Observed hearing threshold
changes were compared with the
changes calculated from presbyacusis
equations (reported by Spoor) over
time.
Excluded and
included cases
were not clearly
reported.
No statistical
analysis was
patients who
had normal
hearing for
their age at 1
kHz, and
hearing loss at
4 kHz at initial
testing
Rosenhall et
al, 199016
Cohort study
Two cohorts of
elderly persons
in Gothenburg,
Sweden. Those
in F01 cohort
were born in
1901-02; those
in F06 cohort
were born in
1906-07. For
F01 cohort,
hearing
thresholds
were tested at
ages 70, 75
and 79; for
F06 cohort, the
test was only
conducted only
at age 70.
Age,
persons
exposed to
occupation
-al noise
for 15
years or
more
Nonoccupational
noise exposure
Gender
It was found that the threshold level
at both 1 kHz and 4 kHz had
increased by approximately the
amounts predicted by the
presbyacusis equations. The author
therefore concludes that the results
support the hypothesis that
presbyacusis and noise-induced
hearing loss are independent and
additive at 4 kHz.
used to test the
differences
between the
observed and
predicted
changes.
For males in both cohorts, persons
exposed to noise had poorer hearing
than those who were not exposed at
frequencies 250 Hz to 8 kHz. At age
70, the differences were about 10 dB
in the F01 cohort and 10-15 dB in the
F06 cohort. However, at age 79 (F01
cohort), the differences were less
pronounced. At this age there were
no significant differences in hearing
acuity between noise-exposed men
and men without exposure.
Noise exposure
was assessed by
years of
exposure only.
There was no difference between
women exposed to noise and women
who were not exposed.
For those with occupational noise
exposure, the men had significantly
poorer high frequency hearing than
the women.
Other risk
factors were not
taken into
account.
No statistical
analysis was
reported in
testing the
differences
between the
noise-exposed
and non-exposed
group.
Hearing
threshold
changes were
not directly
reported and
compared.
Loss of followup
Rosler conducted a comprehensive review on the progression of hearing deterioration during
long-term exposure to noise40. The review includes 11 selected studies on noise-induced
hearing loss in different industry settings at times when an ear protection programme was
“virtually unknown or only seldom used”, between the 1950s and 1970s. Noise exposure level
in most of these studies was about 100 dB SPL or more, including both continuous and
impulsive noise. The main findings of the review are:

At 1 kHz, the average total hearing loss (due to noise exposure and ageing) in the
studies showed a continuous, slow increase with about the same gradient (about 5-6 dB
per 10 years) during the whole exposure time up to 40 years.

At 2 kHz, the increase in total hearing loss was clearly more rapid during the first 1012 years of noise exposure, with an average gradient of about 20 dB per 10 years. After
the first 12 years of noise exposure, the increase in hearing loss continued, but with a
lower gradient of about 7-11 dB per 10 years up to 40-45 years of exposure.
14

At 4 kHz, the total hearing loss increase during the first 10-12 years of noise exposure
was extremely steep. The increase was, on average, 35-40 dB during the first decade.
After the first 12 years of exposure, the increase in total hearing loss continued up to 40
years of noise exposure, but with a significantly lower gradient of 8.5 dB per decade.
This value indicates that the total effect of noise and ageing had become about the
same or even smaller than that expected from normal ageing effect alone. The median
gradient of the curve for normal ageing in males is about 10 dB per decade in the range
of 40-60 years40.

Hearing deterioration began in the frequency range of 4-6 kHz. During the first 5-10
years the deterioration differed significantly in size between the different studies,
depending on the frequency character, level and temporal pattern of the noise exposure.
However, after long-lasting noise exposure for 30-40 years, the studies showed similar
results in the high frequency range from 3 to 8 kHz: the total median hearing loss had
generally increased to about the same level of 60-70 dB.

At age around 50 years or more, it was observed in several studies that the increase in
the total median hearing loss was relatively small in the range 2-8 kHz, in spite of
continued exposure to noise. The increase was even smaller than the median effect of
normal ageing estimated by the ISO 1999 (1990) database A. When the median value
from ISO 1999 was used for “age consideration”, a clear “reverse” of hearing loss was
found in these studies. This appears to be invalid since the reverse of hearing loss
implies that noise-induced hearing loss would improve after the age.

These results indicate that at higher ages and hearing loss levels of more than 45-50 dB,
the assumption of additive effects of ageing and noise exposure appears to be “no
longer valid”40.
In the review by Rosler40, the analysis is based on the mean or median of hearing impairment
of occupational groups under investigation in the cross-sectional studies included, rather than
individual audiometric data. Therefore, it is difficult to carry out more detailed statistical
analysis, for example significant testing and confidence interval analysis. Workers
investigated in the original studies appear to have been exposed to a high level of noise
without hearing protection, which may be different from the current working population.
However, the findings of a lower gradient of hearing loss at higher ages or later years of noise
exposure in the review are in line with the results from two cohort studies16,32 that found
15
hearing threshold changes in the elderly with historical noise exposure were smaller than
those without noise exposure.
These findings may indicate that there is a “ceiling effect” in total hearing loss. In terms of
threshold shifts, the sum of the effects of noise exposure, ageing and other factors cannot
exceed a certain level (a “ceiling”, which could correspond to the biological structure of the
auditory system). If hearing loss caused by noise exposure in the early or middle age groups is
significant, then the “space” left for further hearing loss (e.g. effect of ageing) in the older age
groups would be limited. For the hearing frequencies significantly impaired by noise (3-8
kHz), the impact of ageing in the older age groups could depend on the extent of previous
impairment caused by noise. For the hearing frequency (1 kHz) less impaired by noise, there
would be more “space” that can be affected by ageing in the older age groups. This could
explain the low change rate of threshold shifts in the high frequencies, and the high rate in the
low frequencies. Nevertheless, such an explanation needs to be proved by related quantitative
analysis in different frequencies. Corso15 and Rosler40 also consider that after the related
cochlear structure has been damaged or destroyed to a certain degree by noise, the impact of
continuous noise exposure and ageing can only cause a small or undetectable further
deterioration in an audiogram.
4.1.3 Evidence and implications
All related studies included in this review show that age is strongly associated with hearing
loss.
Evidence that supports a synergistic effect of ageing and noise exposure appears to be very
weak. Apart from the study reported by Gates et al33, no study indicates that total hearing loss
observed is greater than the sum of hearing loss attributable to noise exposure and age-related
hearing loss. Compared with those without historical noise exposure, older adults previously
exposed to occupational noise do not have a higher rate of threshold changes or may even
have a lower rate of the changes. These findings support that noise exposure in working age is
very unlikely to be an attribute of hearing deterioration in older people who are no longer
exposed to noise. In other words, previous noise exposure is very unlikely to cause older
people to be more prone to age-related hearing loss, even though hearing loss caused by
previous noise exposure will still exist.
16
An additive effect model of ageing and noise exposure on hearing loss is much more
acceptable than the assumption of synergistic effect. The study reported by Macrae36 supports
the additive effect; nevertheless, it is not always in agreement with some of the data from
available studies. After adjusting age-related hearing loss by using values from the database A
in ISO 1999, Rosler found a “reverse” of hearing loss in groups with higher ages and hearing
loss levels of more than 45-50 dB in several studies40. This finding indicates that the additive
model also has limitations in some situations. Sometimes it could lead to an “overadjustment” as those reported by Rosler40. A possible explanation could be that there is a
“ceiling effect” in total hearing loss. When age-related reference values based on a highly
screened population (e.g. database A in the ISO 1999) are applied to those with significant
noise-induced hearing loss, the theoretical sum of both effects could go over the “ceiling”;
however, the co-effect cannot occur to the extent in real situations because of the limited
“space” under the “ceiling”.
To avoid this limitation of the additive effect model, modification appears needed when the
co-effect is likely to go over the “ceiling”. ISO 1999 designs a modify factor, H*N/120 (H is
the hearing threshold associated with age; N is the actual or potential noise-induced
permanent threshold shift) to be used when H + N >=40 dB41. In principle, the additive effect
model with modification can be considered the best approach available. Some studies support
such an approach35,42.
It is recommended that the impact of ageing be considered in the diagnosis of noise-induced
hearing loss. Hearing deterioration (threshold changes) after people leave occupational noise
exposure cannot be attributed to occupational noise exposure.
Exit audiograms (for those leaving employment or a noise-exposed job) appear to be critical
in assessing the maximum amount of occupation-attributable hearing loss in the individual.
However, any historical records of hearing tests can be relevant and helpful and should be
tracked and considered for hearing impairment assessment.
When assessing older patients with significant hearing impairment and historically exposed to
a high level of occupational noise, caution is needed to avoid potential “over-adjustment” of
17
age-related hearing loss, especially in cases where historical records of hearing tests are not
available.
In terms of research on noise-induced hearing loss, age should be considered an important
confounder and needs to be adjusted or controlled.
18
4.2 Smoking
4.2.1 Background
Many adverse health effects of tobacco smoking, for example cancer and cardiovascular
diseases, have been clearly demonstrated in different types of studies. Tobacco smoking may
also affect hearing through its effects on antioxidative mechanisms, blood supply to the
auditory system and possible ototoxic effects17,43-45. Smoking is more common in some
occupational groups who are also more likely to be exposed to noise, for example industrial
plant operators, building workers and machine operators46.
4.2.2 Studies identified
Fourteen studies that investigated the association between tobacco smoking and hearing loss
are included in this review, including two cohort studies, four case control studies and eight
cross-sectional studies.
Cohort studies
An occupational cohort study of male Japanese office workers47 indicates that smoking is a
risk factor for hearing loss. Compared with never-smokers in the cohort, an increased relative
risk of development of hearing loss at 4 kHz was found in current smokers (>=31
cigarettes/day), those with a cumulative exposure index between 20 and 29.9 pack-years, and
those with more than 40 pack-years. However, the relative risk of developing hearing loss at
low frequency (1 kHz) is not statistically significant. Trend analysis indicates that there is a
dose-response relationship between the smoking exposure dose and hearing impairment at 4
kHz.
An elevated relative risk for ex-smokers was found but this is without statistical significance
(RR=1.70, 0.85-3.40)47.
Another cohort study (the Baltimore Longitudinal Study of Ageing48) reports on the
relationship between smoking and the development of age-related hearing loss in the speech
frequencies. Based on the follow-up of 531 male study subjects with no evidence of noise
exposure hearing loss or other hearing-related disorders, association between cigarette
19
smoking and hearing loss in speech frequencies was found not to be statistically significant.
Age is the only confounder controlled in this study. The paper lacks information on noise
exposure. About 60% of the male study subjects were younger than 50 years old at the start of
the follow-up. Occupational noise exposure could be a relevant confounder and needs to be
considered.
The characteristics of these two studies are briefly summarised in Table 3.
Table 3: Summary of the cohort studies on the association of smoking and noise-induced
hearing loss
Study
design
Study
population
Study
group
Comparison
group
Confounders
controlled
Results
Notes
Nakanishi et
al, 200047
Male Japanese
office workers
aged 30-59
years in May
1994; average
noise levels
were less than
60 dB(A).
Current
smokers and
ex-smokers
Never-smokers
RR adjusted for
age, BMI, alcohol
consumption,
mean blood
pressure, serum
total cholesterol,
high density
lipoprotein
cholesterol,
triglyceride,
glucose and
hematocrit at
study entry
Relative risk (RR) of high
frequency hearing loss (4
kHz)
Hearing
impairment:
loss of 30 dB
at 1 kHz and
40 dB at 4 kHz
Cohort
study,
follow-up
from 1994 to
1999
Ex-smokers:
RR=1.70 (0.85-3.40)
Current smokers:
1-20 cigarettes/day
RR=1.82 (0.92-3.59)
21-30 cigarettes/day
RR=2.00 (0.98-4.08)
>=30 cigarettes/day
RR= 2.20 (1.09-4.42)
RR of high frequency
hearing loss (4 kHz):
Cumulative lifetime
exposure:
0.1-19.9 pack-year:
RR=1.74 (0.67-4.53)
20-29.9 pack-year:
RR=2.27 (1.01-5.11)
30-39.9 pack-year:
RR=1.69 (0.73-3.90)
>=40.0 pack-year:
RR=2.45 (1.28-4.70)
20
Significant
statistical trend
of RRs in
different
exposure
categories for
high frequency
hearing
impairment,
but not for low
frequency
hearing
impairment
No
information
about nonoccupational
noise exposure
Study
design
Study
population
Study
group
Comparison
group
Confounders
controlled
Results
Notes
Brant et al,
199648
1,247 men and
588 women,
representing a
predominantly
white uppermiddle class
group of
communitydwelling male
and female
volunteers
living in
Baltimore–
Washington
metropolitan
area. After
excluding
those with
otologic
disorders and
indication of
NIHL, 531
(303 younger
than 50 years)
men and 310
women entered
the study.
“Moderate”
and “high”
cigarette
smoking
No cigarette
smoking
RR adjusted for
age by four age
strata
Relative risk (RR, male
only):
Hearing loss
was
determined if
average puretone threshold
at 0.5, 1, 2 and
3 kHz >= 30
dB in either
ear.
Cohort
study,
maximum
follow-up
22.8 years in
men and
13.0 in
women
Moderate vs none (p=0.35):
RR=1.38 (0.71-2.70)
Moderate: one
pack or
less/day
Higher vs none (p=0.61):
RR=1.23 (0.56-2.70)
High: more
than one
pack/day
Unclear on
how to classify
the ex-smokers
No
information in
relation to
noise exposure
during the
study period,
especially for
those in the
working age
Case control studies
The relationship between cigarette smoking and hearing loss was investigated in a case
control study based on an occupational group of 2,348 noise-exposed white male workers at
an aerospace company44. In this study, cases and controls are defined in two ways: one is by
hearing loss distribution (the top third versus the lowest third of the distribution); the other by
the criteria of NIOSH 1972 (at least 25 dB average hearing loss of over 1, 2 and 3 kHz
frequency with a 5:1 weighting of the better to poorer ear). Current smoking was found to be
a statistically significant risk factor for hearing loss based on both case definitions. However,
past-smoking was found to be insignificant. A significant trend was found for pack-year
history (total smoking) and present smoking intensity (packs/day)44.
Nondahl et al9 report a case control study nested in a population-based cohort comprising 197
cases of hearing loss and 394 matched controls aged 53-75 years old, who were investigated
for the relationship between smoking exposure and hearing loss. Smoking exposure was
measured by the level of serum cotinine. No significant associations were found between
serum cotinine levels and incident hearing loss in this study.
21
It is worth mentioning that cotinine, a metabolite of nicotine, can be used as the biomarker of
exposure to tobacco smoke from active and/or positive smoking. However, it has a half life of
approximately 16-20 hours and therefore only reflects tobacco smoke exposure within the
past two or three days. In this study, serum cotinine measurement was undertaken at the fiveyear follow-up examination rather than at baseline. Therefore the cotinine level is likely to
reflect a very short-term exposure to smoking rather than a long-term or past exposure. Based
on this limitation, the association can be interpreted as a cross-sectional relationship even
though the study was designed as a case control study.
Carlsson et al45 investigated the association between genetic factors, smoking, cardiovascular
factors and human noise susceptibility. In this case control study, cases are defined as the
10% most susceptible workers. They are compared with the 10% most resistant workers.
Smoking is correlated with the differences in noise susceptibility in the noise-exposed
population. This study indicates that the susceptible workers are more likely to be smokers. It
found that smokers or ever-smokers (current and former smokers) have an additional risk for
NIHL, compared to those who do not smoke or have never smoked for those with null
genotypes for the GSTM1 (gluitathione-s-transferase M1).
Itoh et al49 report a case control study based on the participants in a health screening
programme in Japan. This study found that current smoking was a significant risk factor for
hearing loss at 4 kHz. The study also showed a dose-response relationship between the
hearing loss and cumulative smoking exposure as measured by the Brinkmann index
(cigarettes smoked per day multiplied by years of smoking).
The characteristics of these case control studies are summarised in Table 4.
22
Table 4: Summary of the case control studies on the association of smoking and noiseinduced hearing loss
Study
design
Study
population
Study
group
Comparison
group
Confounders
controlled
Results
Notes
Barone et al,
198744
2,348 noiseexposed
workers in an
aerospace
company in
the USA, aged
18-59
1. 845 workers
in the top third
of the hearing
loss
distribution (at
3, 4 and 6
kHz)
1. 817 workers in
the lowest third of
the hearing loss
distribution (at 3, 4
and 6 kHz)
Age, noisy hobby,
years worked at
the company, use
of hearing
protection and
history of a past
noisy job
1. Present smokers,
OR=1.39 (P=0.003); eversmokers, OR=1.27 (P=0.02)
The trend in
risk for packyears smoked
was significant
(P=0.007).
Case control
study
2. 242 cases
of hearing loss
(defined by
NIOSH criteria
1972)
Noise
exposure
(TWA) 88.7
dB(A)
Nondahl et
al, 20049
Nested case
control
study;
however,
serum
cotinine
testing was
taken at the
5-year
follow-up
not at the
baseline.
Carlsson et
al, 200745
Case control
study
Communitybased cohort
aged 43-84
years in the
baseline
197 new cases
in a five-year
follow-up
period, aged
53-75 years
2. 968 workers with
the least hearing loss
(non-impaired as
defined by NIOSH
criteria 1972)
2. Present smokers,
beta=0.46789 (P=0.03)
(changing to an OR of
about 1.59); past smokers,
not statistically significant
Noise exposure
(TWA) 89.1 dB(A)
394 matched
controlled subjects
selected from the
cohort aged 53-75
years
Education level
was the only
variable in the
logistic regression
model.
There was no association
between levels of serum
cotinine and hearing loss in
the logistic regression
model.
Stratified by
gender and age
group
Hearing loss:
hearing
thresholds
greater than 25
dB in either
ear at 0.5k,
500, 1k, 2k
and 4k Hz
Problems in
the smoking
exposure
assessment
1,261 noiseexposed
workers at two
paper pulp
mills and one
steel factory in
Sweden; about
1,100 male
workers were
finally
included the
study.
10% most
susceptible
(n=103;
hearing
threshold level
considered)
10% most resistant
(n=112; hearing
threshold level
considered)
23
Stratified analyses
used (age range,
noise exposure
level and exposure
time); C x 26, C x
30, GSTT1 del,
high blood
pressure, heart
disease, white
finger syndrome
controlled
Univariate analysis: the
noise-susceptible group
contained more smokers
than the resistant group
(p=0.05; Fisher’s exact
test).
Effect of present smoking
on NIHL susceptibility is
independent of noise
exposure level; the MantelHaenzel common odds ratio
=2.25 (1.017-4.98;
p=0.045).
Hearing
threshold of
left ear at 3
kHz was used
as a measure
of noise
susceptibility.
Study
design
Study
population
Study
group
Comparison
group
Confounders
controlled
Results
Notes
Itoh et al,
200149
Participants in
an automated
multiphasic
health
screening at
the Aichi
Prefectural
Centre of
Health Care
(APCHC) in
Nagoya, Japan.
Most of the
participants
were office
workers aged
60-80 years.
496 subjects
with bilateral
hearing loss
(hearing
threshold >40
dB at 4 kHz)
2,807 control
subjects (hearing
threshold <=40 dB
at 4 kHz for both
ears) were recruited
from the
participants.
Age, sex,
laboratory testing,
BMI, lung
function.
Exposure to noise
is not mentioned
in the report.
Ex-smokers:
OR=1.22 (0.89-1.76)
Trend analysis
of different
doses of
smoking
exposure was
reported.
Case control
study
Current smokers:
OR=2.10 (1.53-2.89)
<20 cigarettes/day
OR=2.23 (1.49-3.35)
>=20 cigarettes/day
OR=2.01 (1.46-2.87)
Brinkmann index:
0: OR=1
1-399: OR=1.27 (1.122.21):
400-799: OR=1.37 (0.971.93);
>=800: OR=1.76 (1.262.44)
Cross-sectional studies
Mizoue et al50 conducted a cross-sectional study based on 4,624 male steel company workers
in Japan. Hearing loss was defined as >25 dB at 1 kHz or >40 dB at 4 kHz. After control for
age and noise exposure levels, smoking was found to be associated with increased odds of
having high frequency (4 kHz) hearing loss in a dose-response manner. However, smoking
was not associated with low frequency (1 kHz) hearing loss in this study. The “synergistic
index” of 1.16 found in this study indicates that the effect of smoking and occupational noise
on hearing may be additive50.
The study reported on by Burr et al17 is based on the data from the Danish Work Environment
Cohort Study. However, prevalence rather than new cases of hearing loss was collected and
analysed in this study. Therefore the study was conducted in the manner of a cross-sectional
study rather than a cohort study. Hearing loss was assessed by a yes-no question – “Do you
have reduced hearing to such an extent that you feel it is difficult to follow a conversation
between several people without using a hearing aid?” Compared with never-smokers,
statistically significant relative risk of hearing loss was found in male former and current
smokers (>=15 g/day) and female current smokers (<15 g/day).
24
Cocchiarella et al51 report on a cross-sectional study based on 1,092 workers from chemical
divisions of Amoco Corporation. Hearing loss was measured as an average high frequency
hearing threshold (4, 6 and 8 kHz, AVE468), while the smoking status was based on the
information collected from a medical history form. About 22% of the workers had missing or
incorrectly recorded smoking status. Using a general linear model approach, the authors found
that smoking was significantly associated with hearing loss without age adjustment. However,
when age was adjusted, the association became insignificant51.
Two reports by Palmer et al52,53 are based on a postal survey carried out in 1997-98.
Approximately 22,000 adults of working age from the registries of 34 British general
practices and 993 members from the armed services were randomly selected for the survey.
Measurements both of smoking and of hearing loss were based on questionnaires. The
response rate for the survey was about 58%. For all subjects, an elevated prevalence ratio (PR)
of severe hearing loss was found for males but this was without statistical significance52. For
those working for more than five years in noisy jobs, significantly increased PRs of
moderate/severe hearing difficulty were found for former and current smokers and also neversmokers53.
Starck et al18 investigated the effect of smoking on hearing among 199 professional forestry
workers and 171 shipyard workers. Linear regression analysis was used, but related statistical
outcomes of the model are not directly reported in the paper. The authors report that 3.3% of
the variation of hearing loss in shipyard workers could be explained by smoking. One percent
of the variation of hearing loss in forestry workers could be explained by smoking (without
statistical significance)18. The report lacks information on audiometry testing (e.g. frequencies,
definition of hearing loss).
Noorhassim and Rampal54 report a study on 263 residents of a rural village who were not
exposed to noise. Hearing threshold levels were measured at frequencies of 0.5, 1, 2 and 3
kHz. A similar elevated prevalence rate ratio of 1.7 was found for smokers in two age groups
(16-40, and 41 years and older) when compared with non-smokers. Prevalence rate of hearing
loss was also associated with smoking pack-years in a dose-response manner; no statistical
test was conducted for the trend.
25
Cunningham et al55 studied the differences in extra-high-frequency (EHF) auditory sensitivity
at 18 kHz between young smokers and non-smokers (aged 21-35 years old). Smokers had a
lower response rate to EHF stimulus (66%) compared with non-smokers (88%).
In a genetic study reported by Fortunato et al56, smoking was found to be a strong risk factor
for hearing loss (OR=49.49, 5.09-480.66) after age, genetic factors and some biochemical
markers were controlled (see Table 6).
The characteristics of these cross-sectional studies are summarised in Table 5.
Table 5: Summary of the cross-sectional studies on the association of smoking and noiseinduced hearing loss
Study
design
Study
population
Study
group
Comparison
group
Confounders
controlled
Results
Notes
Mizoue et al,
200350
4,624 steel
company
workers; males
aged under 61
years
Current
smokers with
or without
noise exposure
Non-smokers
without noise
exposure
Age, noise
exposure in the
workplace,
drinking
No association was found
for hearing loss at 1 kHz.
Non-occupational
noise exposure
and medical
history e.g. head
injury and acoustic
diseases were not
taken into account
owing to lack of
information.
Non-smokers with noise
exposure PRR=1.77 (1.362.30)
Ex-smokers
excluded;
hearing loss
defined as >25
dB at 1 kHz, or
>40 dB at 4
kHz
Crosssectional
study
Hearing loss at 4kHz:
Smokers without noise
exposure PRR=1.57 (1.311.89)
Smokers with noise
exposure PRR=2.56 (2.123.07)
Dose-response relationship
between cigarettes/day and
hearing loss
Burr et al,
200517
Crosssectional
study
Based on the
Danish Work
Environment
Cohort Study;
7,221 workers
aged 18-59
years without
head injury.
Subgroup
analysis was
conducted in
4,766 workers
of Nordic
origin.
Former and
current
smokers
Never-smokers
Gender, age,
occupational noise
exposure and
height
Males:
Former: OR =1.53 (1.082.19)
Current: <15g/day:
OR=1.60 (1.10-2.33)
Current: >=15g/day:
OR=1.81 (1.32-2.49)
Females:
Former: OR =1.05 (0.711.54)
Current: <15g/day:
OR=0.90 (0.60-1.34)
Current >=15g/day:
OR=1.52 (1.07-2.16)
26
Self-reported
data including
hearing loss
Five-year
incidence of
hearing loss
Study
design
Study
population
Study
group
Comparison
group
Confounders
controlled
Results
Notes
Cocchiarella
et al, 199551
1,092 white
men employed
by three
chemical
divisions of
Amoco
Corporation;
noise exposure
was limited.
Most eight
hours timeweighted
average noise
levels were
less than 90
dB(A).
Ever-smokers
(former and
current
smokers)
Never-smokers
Age
Result was reported as ageadjusted regression
coefficient between
AVE468 and smoking
status:
-2.50 (95% CI: -5.20 to
0.20)
An average
hearing
threshold for
both ears over
4, 6 and 8 kHz
(AVE468) was
created as
outcome
measurement.
699/1,092
workers were
included in the
analysis.
22,194 adults
of working age
randomly
selected from
the registries
of 34 British
general
practices, aged
16-64 years
Ever-smokers
Crosssectional
study
Palmer et al,
200252
Crosssectional
study
Unadjusted regression
coefficient between AVE
and smoking status:
-7.7 (95% CI: -10.7 to -4.7)
Never-smokers
PR was “mutually
adjusted and
adjusted also for
age (in three
bands)”.
Crosssectional
study
21,201 adults
randomly
selected from
the registries
of 34 British
general
practices, aged
16-64 years
By
questionnaire –
58% response
rate
Males
PR =1.3 (0.9-2.1)
Analysis of
smoking was
limited to
those aged 3565 years.
Palmer et al,
200453
Prevalence ratio (PR) of
severe hearing difficulty
(severe difficulty in hearing
or cannot hear at all, and/or
use of hearing aid)
Females
PR =0.9 (0.5-1.4)
Self-reported
former
smokers and
current
smokers
Self-reported neversmokers who had
never worked in a
noisy job
Age
For those who had worked
more than five years in
noisy job:
PR of severe hearing
difficulty:
Hearing
difficulty was
assessed by
question in
questionnaire –
58% response
rate.
Never-smokers: PR=4.6
(2.9-7.1)
Former smokers PR=5.9
(3.9-8.7)
Current smokers PR=5.8
(3.7-8.9)
Starck et al,
199918
Crosssectional
study
199 forestry
workers and
shipyard
platers who
regularly used
noisy handheld power
tools in their
work
Smokers
Non-smokers and
ex-smokers who had
stopped smoking for
10 years
Age
Smoking accounted for
3.3% of the variation of
hearing loss in the shipyard
workers.
Smoking accounted for 1%
in the forestry workers but
without statistical
significance.
27
Authors state
that “smoking
in combination
with
Raynaud’s
syndrome and
elevated
diastolic blood
pressure
potentiates the
hazardous
effect of noise
on hearing”.
No detail of
statistical
analysis for
this statement
is provided in
the paper.
Study
design
Study
population
Study
group
Comparison
group
Confounders
controlled
Results
Notes
Noorhassim
and Rampal,
199854
263 rural
village males
aged 16 years
and older in
Malaysia
Smokers aged
16-40 years
(Group II)
Non-smokers aged
16-40 years (Group
I)
Apart from age
(stratified), other
risk factors or
confounders were
not analysed.
Prevalence rate ratio:
Hearing
impairment:
average
threshold level
at 0.5, 1, 2 and
3 kHz was 25
db and above.
Crosssectional
study
Non smokers
aged 41 years
and older
(Group III)
II/I=1.7
III/I=4.3
IV/I=7.5
IV/III=1.7 (calculated from
data reported)
Smokers aged
41 years and
older (Group
IV)
Prevalence rate (both ears)
by pack-years:
0 pack-years: 11.0%
1-10 pack-years: 13.6%
11-20 pack-years: 25.6%
21 and above: 50%
Cunningham
et al, 198355
Crosssectional
study
25 adult
smokers and
18 smokers
aged 21-35
years
(volunteers?)
Smokers
Non-smokers
None, except for
exclusion criteria
used in the study
All subjects had hearing
thresholds that were better
(lower) than 15 dB in the
range 0.5-8k Hz.
Young age
groups studied;
exposure dose
was not
reported.
At 18 kHz, 88% of the nonsmokers and 66% of the
smokers responded to
stimulus.
Small sample
size
Other study
Dengerink et al57 report on an experimental study of temporary threshold shift (TTS) in 18
students (aged 16-20 years) in Sweden. TTS among smokers and non-smokers was measured
after the study subjects were exposed to physical exercise, noise and a combination of the
exercise and noise exposure. It was observed that smokers experienced less TTS than the nonsmokers. Results of this small sample size study need to be interpreted with caution. Strictly
speaking, smoking is not a controlled exposure/intervention in the study design, and therefore
the differences in TTS cannot be directly attributed to smoking. An appropriate study design
would compare the differences of hearing thresholds pre or post smoking exposure, or in
people exposed to smoking compared with those without. In addition, there is a lack of
background information about the smoking group, for example years of smoking history.
There is also a lack of information on hearing threshold levels at the baseline for both the
study groups which could be helpful when interpreting the differences in TTS. The
association of TTS and permanent threshold shift (PST) appears to be an under-researched
28
area58. TTS may or may not be an appropriate measurement to investigate the impact of
smoking on hearing loss since it will not reflect possible pre-existing hearing impairment.
Smoking should not be considered a protective factor for hearing loss from this study.
4.2.3 Evidence and implications
Smoking can be considered a risk factor for hearing loss. However, all included studies have
significant weaknesses in methodology, especially in the measurement of noise exposure and
in controlling the exposure as a relevant confounder. Even though most included studies
indicate that smoking is associated with hearing loss, more well-designed studies with
appropriate control on relevant confounders are needed.
Practically, it is difficult to assess how much of an individual hearing loss is caused by
smoking at this stage. However, patients with noise-induced hearing loss can be advised to
stop smoking to prevent related adverse health effects including possible further hearing
impairment. In some studies reviewed, ex-smokers had a lower risk of hearing impairment
than current smokers or an insignificant risk when compared with non-smokers. For longterm heavy smokers, it is possible that smoking could cause hearing loss.
29
4.3 Genetic factors
4.3.1 Background
Individual susceptibility or vulnerability to noise, and the degree of hearing loss developed,
varies considerably among people. After the same exposure to noise, some workers can
develop significant hearing loss, while others develop little or no hearing loss59. This
difference reflects that multiple factors contribute to the development of hearing impairment.
In animal studies, it is observed that the genetic factor can influence individual susceptibility
to noise60. Currently, some genetic studies on human noise-induced hearing loss have been
reported and are included in this review.
4.3.2 Studies identified
Genetic factors in relation to antioxidant system or oxidative stress
response
Tissues in cochlea are metabolically active and generate reactive oxygen species (ROS) which
are potentially damaging. Antioxidant systems are present to neutralise these ROS. Some
molecules or enzymes involved in the protective effect include gluitathione-s-transferase
(GST), catalase (CAT), paraoxonases (PONx), glutathione peroxidise (GPX), glutathione
reductase (GSR) and superoxide dismutase (SOD)61,62.
Rabinowitz et al19 analysed hearing status and GST genes in 58 volunteer workers who were
exposed to noise at levels above 85 dB(A). There was no association between GSTT1
(22q11.2) or GSTM1 (1p13.3) and hearing status when it was measured by audiometric
hearing threshold levels at 0.5, 1, 2, 3, 4 and 6 kHz. However, when hearing status was
assessed by otoacoustic emissions (DPOAE values), a protective effect at high frequency
average (F2=3, 4, 4.5 and 5 kHz) was found in the workers with GSTM1. The protective
effect of GSTM1 was present after adjustment for age, race, sex, and years of noise exposure.
GSTT1 did not exhibit a similarly protective effect in this cross-sectional study. The authors
suggest that the GSTM1 null individual might be more susceptible to noise based on this
small sample size study.
30
However, the protective effect could not be confirmed by a case control study reported by
Carlsson et al61. This later study investigated genetic variation between the 10% most
susceptible and 10% most resistant extremes of 1,200 Swedish noise-exposed workers.
Genetic polymorphisms were derived from genes of GSTM1, GSTT1, CAT, SOD, GPX,
GSR and GSTP1. No significant differences were found between susceptible and resistant
groups. This study does not support that genetic variation of antioxidant enzymes play a
major role in the susceptibility to noise-induced hearing loss.
A study reported by Konings et al62 investigated genetic variations (single nucleotide
polymorphisms; SNPs) in the catalase gene (CAT, 11p13) between the 10% most susceptible
and the 10% most resistant individuals in the 1,200 Swedish workers and 4,500 Polish noiseexposed labourers. Twelve SNPs were selected and genotyped. Significant interactions were
observed between noise exposure levels and genotypes of two SNPs (SNP5 and SNP12) in
both the Swedish and Polish samples. This study also found that susceptible workers who
were exposed to low level noise (<85 dB) in Sweden were more likely to carry AG genotype
of SNP5 (indicating a potential damaging effect), while the resistant workers who were
exposed to a high level of noise (>92 dB) were more likely to carry AG genotype (indicating
a potential protective effect). These findings need to be confirmed by further studies.
Fortunato et al56 evaluated the association between the susceptibility to noise-induced hearing
loss and SOD2, PON1 and PON2 polymorphisms in workers exposed to prolonged loud noise
in a case control study. While no association was detected for PON1 (QQ+RR) and PON1
(LL) genotypes, PON2 (SC+CC) genotypes and SOD2 IVS3-23T/G and IVS3-60T/G
polymorphisms, age and smoking were significantly associated with hearing loss. However,
the authors suggest that SOD2 polymorphisms are unlikely to be involved in the development
of hearing loss because of their intron localisation. “They may function, instead, as markers
that are in linkage disequilibrium with other polymorphisms.”56
The characteristics of the above studies are summarised in Table 6.
31
Table 6: Summary of the studies on the association of genetic factors in relation to
antioxidant systems or oxidative stress and noise-induced hearing loss
Study
design
Study
population
Study
group
Rabinowitz
et al, 200219
77 volunteer
workers
exposed to
noise above 85
dB(A); males
and females,
aged 19-66
years
GSTM1 and
GSTT1
status
Crosssectional
study
Comparison
group
Confounders
controlled
Results
Notes
Age, gender, race
and years of noise
exposure
High frequency audiometric average
(standard test, negative coefficient
indicates protective effect):
Audiometric
hearing
threshold levels
at 0.5, 1 and 2
kHz were
averaged as low
frequency
average; 3, 4 and
6 kHz were
averaged as high
frequency
average.
GSTM1: coefficient = -1.3, p=0.6
GSTT1: coefficient = -1.1, p=0.8
High frequency OAE average
(positive coefficient indicates
protective effect):
GSTM1: coefficient=3.1, p=0.01
GSTT1: coefficient=-2.1, p=0.2
The results indicate that GSTM1 null
individuals had lower amplitude of
high frequency otoacoustic emissions
compared with individuals
possessing the gene; therefore
GSTM1 null individuals might be
more susceptible to noise.
For otoacoustic
emissions
(OAEs),
DPOAE values
were calculated
as low frequency
OAE average
(F2=1,500,
2,000 and 2,500
Hz), and high
frequency
average
(F2=3,000,
3,500, 4,000,
4,500 and 5,000
Hz).
Small sample
size
Carlsson et
al, 200561
Case control
study
1,261 noiseexposed
workers at two
paper pulp
mills and one
steel factory in
Sweden; males
only
The most
susceptible
(n=103)
The most
resistant (n=112)
Stratified analysis
by age and noise
exposure level
Null genotype:
GSTM1:
Susceptible group: 51.4% (41.361.6%)
Resistant group: 47.7% (37.8-57.4%)
p=0.68
Majority
(79%) of the
subjects in the
study were
exposed to
noise for 20-30
years.
GSTT1:
Susceptible group: 12.2% (5.219.2%)
Resistant group: 7.5% (2.0-13.0%)
p=0.37
In addition, there were no significant
differences between the groups in 14
SNPs in the genes CAT, SOD,
GPX1, GSR and GSTP1.
32
Swedish
workers: hearing
threshold level
(HTL) of the left
ear at 3 kHz as a
measure of noise
susceptibility
Extreme
sampling (most
susceptible and
most resistant
subjects)
Study
design
Study
population
Study
group
Comparison
group
Confounders
controlled
Results
Notes
Konings et
al, 200762
1,261 noiseexposed
workers at two
paper pulp
mills and one
steel factory in
Sweden
The most
susceptible
(104
Swedish
workers and
347 Polish
workers)
The most
resistant (114
Swedish workers
and 338 Polish
workers)
Age and noise
exposure level
SNP 5 (rs494024), CAT gene:
Swedish
workers: hearing
threshold level
(HTL) of the left
ear at 3 kHz as a
measure of noise
susceptibility;
Polish workers:
mean HTLs of
the left ear at 4
kHz and 6 kHz
were used.
Case control
study
SNP 5 was found to have significant
effects in low noise exposure level
(<85 dB) in the Swedish workers
(p=0.033): susceptible workers are
more likely to carry AG genotype;
however, the resistant workers are
more likely to carry AG genotype at
high level exposure level (>92 dB)
(p=0.057).
Approx. 1,100
male workers
were finally
included in the
study, and
approx. 4,500
male Polish
workers from
different
industries.
SNP 5 was found to have significant
effects in low and high noise
exposure level in the Polish workers
(p=0.031 and 0.022): resistant
workers are more likely to carry AG
genotype in the low noise exposure
level while susceptible workers are
likely to carry the genotype at the
high noise exposure level.
Extreme
sampling (most
susceptible and
most resistant
subjects)
SNP 12 (rs475043):
Non-statistically significant
difference for SNP 12 was found in
the Swedish workers.
SNP 12 was found to have
significant effects in low and high
noise exposure level in the Polish
workers (p=0.022 and 0.022):
resistant workers are more likely to
carry AG genotype in the low noise
exposure level while susceptible
workers are likely to carry the
genotype at high noise exposure
level.
Fortunato et
al, 200456
Case control
study
94 male
workers from
an aircraft
factory,
exposed to
noise level
equivalent to
92.4 dB(A) for
20 years
Hearing loss
(n=63)
Normal hearing
(n=31)
Biochemical
indices
(cholesterol,
glucose and
triglycerides), age,
smoking and
genotypes
PON1Q192R polymorphism:
No statistical association
PON2 (SC+CC) genotypes:
OR=5.01 (1.11-22.54)
SOD2 IVS3-23T/G, IVS3-60T/G
polymorphisms:
OR=5.09 (1.27-20.47)
Hearing loss was
defined as HTL
>25 dB at any
frequency of
0.125, 0.25, 0.5,
1, 2, 3, 4, 6 and
8 kHz.
Small sample
size
Age: OR=1.22 (1.09-1.36)
Smoking: OR=49.49 (5.09-480.66)
Genetic factors in relation to the potassium recycling pathway
The sensory cells of the inner ear are bathed in endolymph in the scala media. The endolymph
has a high concentration of K+, which is the charge carrier for sensory transduction. K+ is
secreted into the endolymph by the stria vascularis, and recycled back to the stria vascularis
by the network of gap junctions in supporting cells and fibrocytes of the spiral ligament. This
33
circulation is necessary for the process of hearing. Mutations in the gap junction genes are
considered to cause dysfunction of this circulation and may lead to hearing loss63-65.
Van Laer et al65 report on a case control study that investigated the genetic variation between
the 10% most susceptible and 10% most resistant extremes of 1,200 Swedish noise-exposed
workers. Thirty-five SNPs selected from 10 candidate genes were studied. Significant
differences between susceptible and resistant individuals for the allele, genotype and
haplotype frequencies were found in three SNPs of the KCNE1 gene, and for the allele
frequencies for one SNP of KCNQ1 and one SNP of KCNQ4. However, no differences were
found for the other seven genes of CJB1, GJB2, GJB3, GJB4, GJB6, KCJ10 and SLC12A2.
Odds ratios are not reported in this case control study.
Pawelczyk et al64 studied the genetic variations in 10 genes putatively involved in the
potassium recycling pathway between the most sensitive noise-exposed workers in Poland.
Among 99 SNPs genotyped, SNP7 in KCNE1, SNP10 in KCNQ4, and SNP1 in GJB2 were
found to be associated with hearing loss susceptibility. The association for genes of KCNE1
and KCNQ4 (see Table 6) was also previously reported in the Swedish study65.
The characteristics of the above studies are summarised in Table 7.
Table 7: Summary of studies on the association of genetic factors in relation to the
potassium recycling pathway and noise-induced hearing loss
Study
design
Study
population
Study
group
Comparison
group
Confounders
controlled
Results
Notes
Van Laer et
al, 200665
1,261 noiseexposed
workers at two
paper pulp
mills and one
steel factory in
Sweden; males
only
The most
susceptible
(n=104)
The most
resistant (n=114)
Age and noise
exposure levels
Among 35 SNPs from 10 candidate
genes analysed, three SNPs
(rs2070358, rs180527 or p.S38G and
rs180528 or p.D85N) of KCNE1
genes were found to be statistically
different between the two groups of
subjects in allele, genotype and
haplotype frequencies.
Swedish
workers: hearing
threshold levels
(HTL) of the left
ear at 3 kHz as a
measure of noise
susceptibility
Case control
study
Majority
(79%) of the
subjects in the
study were
exposed to
noise for 20-30
years.
One SNP (rs163171) of KCNQ1, and
one SNP (H455Q) of KCNQ4 were
found to be statistically different
between the group in the allele
frequency.
34
Extreme
sampling (most
susceptible and
most resistant
subjects)
Study
design
Study
population
Study
group
Comparison
group
Confounders
controlled
Results
Notes
Pawelczyk et
al, 200964
Study group
drawn from a
database of
more than
3,860 noiseexposed
workers at a
Polish lacquer
and paint
factory, a
dockyard, a
glass bottle
factory, a
power station
and a coal
mine; males
only
Most
sensitive
subjects
based on the
mean
hearing
thresholds
for the left
ear at 4 and 6
kHz; 119
cases
Most resistant
subjects based
on the mean
hearing
thresholds for
the left ear at 4
and 6 kHz; 119
controls
Age and noise
exposure level
“The most prominent results” were
obtained for one SNP (rs2070358) in
the gene of KCNE1, and one SNP
(Q455H, rs34287852) in the gene of
KCNQ4.
Extreme
sampling (most
susceptible and
most resistant
subjects)
Case control
study
Rs2070358: OR=1.549 (1.0142.367), which was similar to the
effect in a Swedish sample set65
Rs34287852: OR=2.030 (1.0314.000). The result of this SNP was
also significant in a Swedish sample
set65 but with opposite direction of
the association (Figure 3 in the
paper).
Rs3751385 (SNP1) in GJB2:
OR=2.064 (1.153-3.694; p=0.012)
Genetic factors in relation to heat shock proteins
Heat shock proteins (hsps) are a class of functionally related proteins that are introduced by
physical and physiological stresses, including heat and noise63,66,67. In animal studies, hsps
can condition the ear to withstand effects of loud noise and protect the ear from hearing loss67.
They are named according to their molecular weight (kilodaltons e.g. hsp70).
Yang et al67 genotyped three polymorphisms in the hsp70-1 (rs1043618), hsp70-2 (rs1061581)
and hsp70-hom (rs2227956) genes and analysed the associations of these polymorphisms with
risk of developing NIHL in 194 automobile workers in China. The study results showed that
there was no statistically significant difference in the genotype and allele distributions of
hsp70-1, hsp70-2 and hsp70-hom between the hearing loss group and the normal group, with
and without adjustment for age, sex, smoking, history of explosive noise exposure, and
cumulative noise exposure. However, in haplotype analysis, Hap5 and Hap6 were found to be
significantly more frequent in those with hearing loss than in the normal group. This study
suggests that some haplotypes of the hsp70 genes may be associated with a higher
susceptibility to hearing loss67.
In the case control study reported by Konings et al66, three polymorphisms (rs1043618,
rs1061581 and rs2227956) in hsp70 genes were genotyped in 206 Swedish and 238 Polish
DNA samples of noise-exposed workers. The study found rs2227956 in hsp70-hom to be
significantly associated with hearing loss in both sample sets. Moreover, rs1043618 and
rs1061581 were significant in the Swedish sample set but not in the Polish sample set. The
35
authors of this study also suggest that hsp70 genes may be hearing loss susceptibility genes,
but further functional studies are required to confirm this finding66.
The characteristics of the above studies are summarised in Table 8.
Table 8: Summary of studies on the association of genetic factors in relation to heatshock proteins and noise-induced hearing loss
Study
design
Study
population
Study
group
Comparison
group
Confounders
controlled
Results
Notes
Yang et al,
200667
194 Chinese
automobile
workers; males
and females
Hearing loss;
HTL>25 dB
(n=93)
Non-hearing loss
(n=101)
Age, sex,
smoking,
historical noise
exposure (yes or
no), and
cumulative noise
exposure
There was no statistically significant
difference in the distribution of both
genotypes and alleles of hsp70-1,
hsp70-2 and hsp70-hom gene.
Mean HTL in
low frequency
(0.5, 1 and 2
kHz), and high
frequency (4, 6
and 8 kHz)
Case control
study
Haplotype analysis (compared with
Hap1 AAA):
Hap5 (ABA i.e. +190A/+1267B and
+2437A) was significantly higher in
the hearing loss group (p=0.022;
OR=2.66, 1.13 to 6.27).
Hap6 (ABB i.e. +190A/+1267B and
+2437B) was significantly higher in
the hearing loss group (p=0.005; the
haplotype was not found in the
control).
Konings et
al, 2009b66
Case control
study
1,261 noiseexposed
workers at two
paper pulp
mills and one
steel factory in
Sweden
The most
susceptible
(103
Swedish
workers and
119 Polish
workers)
The most
resistant (112
Swedish workers
and 119 Polish
workers)
Age and noise
exposure levels
Three SNPs (single nucleotide
polymorphisms) located in three
genes of the HSP70 family,
rs1043618 in gene HSP70-1;
rs1061581 in HSP70-2; and
rs2227956 in gene HSP-hom
Rs1043618: OR=0.99 (0.65-1.51), in
the Polish sample set; OR=0.61
(0.39-0.97) in the Swedish sample set
Approx. 1,100
male workers
were finally
included in the
study, and
3,860 male
Polish workers
from different
industries.
Rs1061581: OR=1.21 (0.82-1.80), in
the Polish sample set; OR=1.63
(1.04-2.55) in the Swedish sample set
Rs2227956: OR=1.75 (1.00-3.04), in
the Polish sample set; OR=2.09
(1.19-3.67) in the Swedish sample set
Swedish
workers: hearing
threshold level
(HTL) of the left
ear at 3 kHz as a
measure of noise
susceptibility;
Polish workers:
mean HTLs of
the left ear at
4kHz and 6kHz
were used.
Extreme
sampling (most
susceptible and
most resistant
subjects)
Other studies
Konings et al68 analysed 644 SNPs in 53 candidate genes in the Swedish sample and Polish
sample. One SNP in the GRHL2 gene and seven SNPs with significant association,
interaction or close toward significant association were selected. These eight SNPs were
further analysed with additional Polish samples. One SNP in PCDH15 (rs7095441) was
36
significantly associated in both sample sets. Two SNPs in MYH14 (rs667907 and rs588035)
were significantly associated in the Polish sample set and significantly interacted with the
noise exposure level in the Swedish sample set.
The PCD15 gene is a member of the cadherin superfamily encoding integral membrane
proteins that mediate calcium-dependent cell-cell adhesion. The gene is considered to play an
essential role in the maintenance of normal retinal and cochlear function68. The MYH14 gene
encodes a member of the myosin superfamily. Myosins are actin-dependent motor proteins
with diverse functions including regulation of cytokinesis, cell motility and cell polarity68.
This study suggests that PCDH15 and MYH14 may be noise exposure susceptibility genes,
but further studies in independent sample sets are needed to test whether they are true positive
associations.
Using the Swedish sample of 1,200 workers exposed to noise, Carlsson et al45 also report the
distribution of mutation of Cx26 (GJB 2 gene) and Cx30 (GJB 6 gene) and null genotypes of
GSTM1 and GSTT1 between the most susceptible and most resistant subjects. No statistically
significant differences were found for these genetic variations between the subjects.
Characteristics of these two studies are summarised in Table 9.
Table 9: Summary of the studies on the association of other genetic factors and noiseinduced hearing loss
Study
design
Study
population
Study
group
Comparison
group
Confounders
controlled
Results
Notes
Konings et
al, 2009a68
1,261 noiseexposed
workers at two
paper pulp
mills and one
steel factory in
Sweden
The most
susceptible
(103
Swedish
workers and
119 Polish
workers),
with
additional
134 Polish
samples
The most
resistant (112
Swedish workers
and 119 Polish
workers)
Age and noise
exposure levels
Three SNPs (single nucleotide
polymorphisms) were significantly
associated with NIHL both in the
total Polish and Swedish sample sets:
Swedish
workers: hearing
threshold level
(HTL) of the left
ear at 3 kHz as a
measure of noise
susceptibility;
Polish workers:
mean HTLs of
the left ear at
4kHz and 6kHz
were used.
Case control
study
Approx. 1,100
male workers
were finally
included the
study, and
3,860 male
Polish workers
from different
industries.
Rs7095441 located in PCDH15 gene;
rs667907 and rs588035 in MYH14
gene
Rs7095441:
OR=1.66 (1.063-2.610), interaction P
value=0.026 in the Polish sample set
OR=2.076 (1.344-3.206), interaction
P value=0.001 in the Swedish sample
set
Rs667907:
OR=1.828 (1.162-2.875), interaction
37
Extreme
sampling (most
susceptible and
most resistant
subjects)
P value=0.009 in the Polish sample
set
OR not statistically significant,
interaction P value=0.049 in the
Swedish sample set.
Rs588035:
OR=0.570 (0.353-0.918), interaction
P value=0.021 in the Polish sample
set
OR=0.399 (0.180-0.886, high noise
exposure category), interaction P
value=0.012 in the Swedish sample
set
A significantly different interaction P
value indicated that a significant
difference in genotype distribution
was observed between sensitive and
resistant persons for different noise
exposure levels. In other words, a
differential effect of the genotype on
the noise sensitivity according to the
noise exposure level may exist.
Study
design
Study
population
Study
group
Comparison
group
Confounders
controlled
Results
Notes
Carlsson et
al, 200745
1,261 noiseexposed
workers at two
paper pulp
mills and one
steel factory in
Sweden
10% most
susceptible
(n=103;
hearing
threshold
level
considered)
10% most
resistant (n=112;
hearing
threshold level
considered)
Separately tested
in univariate
analysis
For mutations in C x 26 and C x 30,
no significant difference between the
resistant and susceptible groups was
observed.
Hearing
threshold of left
ear at 3 kHz was
used as a
measure of noise
susceptibility.
Case control
study
The fraction of heterozygous
mutation carriers of C x 26 and C x
30 was not significantly different
between both groups.
Approx. 1,100
male workers
were finally
included the
study.
The incidence of the null-genotype of
the GSTM1 gene was 51.4% and
47.7% in the noise-susceptible and
noise-resistant groups respectively.
The corresponding percentages for
the GSTT1 gene were 12.2 and 7.5
respectively. The frequency of the
deleted alleles was not significantly
different between the two groups.
38
4.3.3 Evidence and implications
Genetic studies on noise-induced hearing loss appear to be at an early stage. Numbers of the
studies on individual genes or SNPs are still limited. Six of the 10 studies found are based on
two sample sets in Sweden and Poland.
It is noted that some genetic mutations are associated with susceptibility to noise-induced
hearing loss. However, some of these findings are based on analysis of relatively large
numbers of genetic markers (e.g. SNPs). It is possible that some of the findings are false
positive associations rather than true associations. Further studies are needed to test these
associations in different sample sets so that true associations can be established.
Based on odds ratios reported in these studies, and the sampling methodology used (e.g. the
most susceptible versus most resistant), available studies appear to suggest that genetic
markers currently investigated are not strong risk factors for noise-induced hearing loss.
The contribution of genetic factors to noise-induced hearing loss is also dependent on the
frequency of related genetic markers in the local population, which appears to be unclear at
this stage.
Potential combination effects of different related genes remain unexplored. The studies
included in this review only investigate the effect of individual genes. The implication of the
results from these available genetic studies on the diagnosis and management of noiseinduced hearing loss appears to be limited. Clinical applications of these studies have not
been developed.
39
4.4 Organic solvents
4.4.1 Background
Organic solvents are a large group of chemical compounds that are widely used in industry to
dissolve or make oils, fats, resins, rubber and plastics. Workers in related occupations are
exposed to organic solvents by inhalation, ingestion and dermal absorption. Neurotoxic
effects of organic solvents such as narcosis, central nervous system depression, and death
have been recognised for many years69,70. Potential ototoxic effects of some organic solvents
have also been investigated in recent years71-73.
4.4.2 Studies identified
Toluene
Toluene is frequently used in the manufacture of paints, thinners, adhesives, rubber and tyres.
It is also used in rotogravure printing and leather tanning.
Schaper et al25,74 report on a cohort study on 333 rotogravure printing workers with a fiveyear follow-up in Germany. Workers exposed to a relatively high level of toluene in the
printing area (average 25.7± 20.1 ppm) were compared with those exposed to a low level of
toluene in the end-processing area (average 3.2± 3.1 ppm). Mean noise exposure was similar
in these two groups (81.1± 3.5 dB(A) versus 81.6± 4.2 dB(A)). No toluene exposure-related
variables (duration, level, hippuric acid and o-cresol: the biologic markers for toluene in urine)
were found to be significant in the logistic regression model. Ototoxic effects of toluene were
not found at the exposure level investigated.
Morata et al27 report on a cross-sectional study of 124 workers exposed to noise and a mixture
of organic solvents (mainly toluene, ethyl acetate, and ethanol). The workers were exposed to
toluene levels ranging from 0.14 mg/m3 (0.037 ppm) to 919 mg/m3 (244 ppm) and noise
levels ranging from 71 to 93 dB(A). By a stepwise logistic regression approach, age and
hippuric acid were the only variables that met the significance level criterion in the final
multiple logistic regression model. The odds ratio estimates for hearing loss were 1.07 times
greater for each increment of one year of age (95% confidence interval (95% CI) 1.03-1.11)
40
and 1.76 times greater for each gram of hippuric acid per gram of creatinine (95% CI 1.002.98). Eight percent of the workers had a level of urinary hippuric acid that exceeded 2.5g/g
creatinine. This level of hippuric acid is usually considered to correspond to 100 ppm of
toluene in air.
Chang et al75 report on a cross-sectional study of 174 workers at an adhesive materials
manufacturing plant in Taiwan. Environmental exposures to toluene and noise were assessed
in the workplace. Average toluene concentrations were 33.0 ppm in the toluene recovery
division, 107 ppm in the adhesive materials manufacturing division and 164.6 ppm in the
adhesive division. This study found that the prevalence of hearing loss of > or =25 dB in the
toluene plus noise group (86.2%) was much higher than in the comparison groups of noise
exposure only (44.8%) and the administrative clerks (5.0%) (p<0.001). This study also found
that the odds ratio in the workers exposed to both toluene and noise was 10.9 higher than the
noise exposure only group when 0.5 kHz was included in the study, but the ratio decreased to
5.8 when hearing impairment at 0.5 kHz was excluded in the logistic regression model. This
difference suggests that toluene may have an impact on hearing loss at the lower frequency.
The characteristics of the above studies are summarised in Table 10.
Table 10: Summary of the studies on the association of toluene and noise-induced
hearing loss
Study
design
Study
population
Study
group
Comparison
group
Confounders
controlled
Results
Notes
Schaper et
al, 200825
333
rotogravure
printing
workers in
Germany,
followed up
over five years
(1996-2001)
High toluene
exposure
(average
25.7 ppm)
Low exposure
(average 3.2
ppm)
Age and noise
exposure levels
ANOVA analysis:
64.9% (216/333)
completed at the
follow-up the
examination 4
Schaper et
al, 200374
Cohort study
Mean noise
exposure
81.1 dB(A)
Distribution of the cases was not
significant between toluene exposure
level and duration.
Mean noise
exposure 81.6
dB(A)
Logistic modelling:
No exposure-related variables
(including toluene exposure duration,
levels, Hippuric acid and o-Cresol )
were significant in the model, except
for age (year, OR=1.14, 1.05-1.24).
Case definition:
“HTL at least 25
dB in any of the
tested
frequencies, if
the audiogram
revealed a notch
in one of the
frequencies
between 1 and 6
kHz, or the
thresholds were
the poorest in
this frequency
range”
Hippuric acid:
0.84g/g
creatinine (total
average?)
41
Study
design
Study
population
Study
group
Morata et al,
199727
124 male
workers
exposed to
noise and a
mixture of
organic
solvents
(toluene,
ethanol and
ethyl acetate)
in a
rotogravure
printing
factory
Toluene
exposure
status
Crosssectional
study
Comparison
group
Air toluene
level ranged
from 0.037
to 243.8
ppm; 8% of
workers’
urinary
hippuric acid
levels were
higher than
2.5 g/g
creatinine.
Confounders
controlled
Results
Notes
Age, tenure, noise
exposure and
repeated ear
infections were
significant in a
stepwise logistic
regression
approach.
Multiple logistic regression:
Audiometry
tested at 0.5, 1,
2, 3, 4, 6 and 8
kHz; HTL less
than 25 dB
defined as
normal hearing.
If the audiogram
revealed a notch
in one of the
frequencies
between 3 and 6
kHz, or the
thresholds were
the poorest in
this frequency
range, it was
classified as high
frequency
hearing loss.
Age (year):
Beta=0.07, p=0.0003; OR=1.07
(1.03-1.11)
Biological exposure index (hippuric
acid g/g creatinine):
Beta=0.57, p=0.0338; OR=1.76
(1.00-2.98)
No significant interactions were
found between solvents and noise.
Noise
exposure
level 71-93
dB(A)
Small sample
size
Chang et al,
200675
Crosssectional
study
Male workers
in a plant with
an adhesive
materials
manufacturing
section in
Taiwan;
average age
40-41 years
Workers
exposed to
toluene and
noise (n=58)
Average
toluene
levels: see
text
Noise level:
78.6-87.1
dB(A)
1. Workers
exposed to noise
only (n=58);
noise level:
83.5-90.1 dB(A)
Age, smoking,
drinking and
hearing protection
use
2.
Administrative
workers not
exposed to
toluene and
significant noise
(n=60?); noise
level: 67.9-72.6
dB(A)
Logistic regression model 1 (0.5 kHz
included):
Air sample of
toluene only
Administrative: OR=1.0
Noise only: OR=12.8 (3.4-47.6)
Toluene and noise: OR=140 (32.1608)
Small sample
size; overlaps on
the ORs between
noise only and
toluene +noise
Logistic regression model 1 (0.5 kHz
excluded):
Administrative: OR=1.0
Noise only: OR=5.0 (1.7-15.1)
Toluene and noise: OR=29.1 (9.391.4)
Hearing loss:
HTL>=25 dB
(with or without
0.5 kHz)
Less than 15%
of noise-exposed
workers used
hearing
protectors.
Note: The New Zealand workplace exposure standard: toluene – 50 ppm or 188 mg/m3 (time-weighted
average)76
These studies indicate that exposure to toluene is a risk factor for hearing impairment. The
risk effect may only be observed when the exposure level reaches a certain level as reported
in the studies27,75. The risk effect may not be seen when the toluene exposure level is lower
than 50 ppm25. Exposure to toluene may be associated with hearing impairment at a lower
frequency (0.5 kHz); however, more studies are needed to confirm this finding.
42
Styrene
Styrene is a component of fibreglass and commonly used in the manufacture of polyester
laminates, polymers and copolymers in the yacht and ship building industry. It is primarily a
synthetic chemical that is used in some related industries.
Morioka et al77 report on a study of the upper limit of hearing in 93 male workers exposed to
organic solvents in seven factories that produced plastic buttons or baths in Japan. The upper
limit of hearing frequency was reduced in workers who were exposed to the solvents for five
years or more. This reduction was dose-dependent and was related to styrene concentrations
in breathing-zone air and urinary mandelic acid (a biological marker for styrene exposure)
concentrations in urine. The upper limit of hearing frequency in the group with mandelic acid
>=0.3g/l was significantly reduced compared with those with mandelic acid <0.3g/l (30% vs
63%; p=0.002). No potential confounders were controlled in this study.
Sass-Kortsak et al30 report on a cross-sectional study of 299 workers in the fibre-reinforced
plastics manufacturing industry. These workers were exposed to styrene (arithmetic mean
17.25 ppm) and noise (average 87.2 dB(A)). Hearing testing and the personal time-weighted
average exposures to styrene and noise were measured on the same day. Age and noise
exposure were found to be significant in the multiple linear regression analysis. However, no
significant association between styrene exposure and hearing impairment was found at all
frequencies measured.
Morata et al26 report on a cross-sectional study of 313 workers from fibreglass and metal
products manufacturing plants and a mail distribution terminal. Noise exposure levels for
these workers ranged from 69 to 116 dB(A); 154 workers were exposed to styrene at a level
that ranged from 0.05 to 22.54 ppm, 65 workers were exposed to styrene at a mean level of
3.76 ppm, and 89 workers were exposed to both styrene (at a mean level of 2.82 ppm) and
noise. This study found that workers exposed to noise and styrene had significantly worse
pure-tone thresholds at 2, 3, 4 and 6 kHz when compared with noise-exposed or non-exposed
workers. Age, noise exposure, and urinary mandelic acid were significant variables in the
multiple logistic regression analysis. The odds ratios for hearing loss were 2.44 for each
43
millimole of mandelic acid per gram of creatinine in urine (95% CI, 1.01-5.89). This study
suggests that exposure to styrene even below recommended values had a toxic effect on the
auditory system.
Sliwinska-Kowalska et al28 report on a study of 290 yacht yard and plastic factory workers
who were exposed to a mixture of organic solvents (mainly styrene) and 223 workers who
were not exposed to styrene. Styrene exposure levels ranged from 0.85 to 72.31 ppm with a
mean of 14.5 ppm. Noise exposure levels ranged from 70.3 to 97.4 dB(A). This study found
an almost four times increase in the odds of developing hearing loss related to styrene
exposure. For those exposed to both styrene and noise, the odds ratios were two or three times
higher than for those exposed to noise or styrene only. A positive linear relationship was
found between the average working life exposure to styrene and the hearing threshold at the
frequencies of 6 and 8 kHz.
Johnson et al78 also report on a cross-sectional study based on the same groups of workers as
studied by Morata et al26. No risk-effect-related statistical measurements (e.g. odds ratios) are
reported in the paper. It is also unclear whether or how confounders (e.g. age) were controlled.
The authors state that workers exposed to noise and styrene had significantly poorer pure-tone
thresholds in the high-frequency range (3-8 kHz) than the control, the noise-exposed workers
and those listed in a Swedish age-specific database.
Moller et al79 report the otoneurological findings of 18 Swedish workers who were exposed to
styrene with air concentrations in a range of 25-100mg/m3 (5.9-23.5 ppm) for 6-15 years
(mean 10.8 years). The authors state that “the pure-tone audiometry and speech discrimination
scores did not indicate hearing losses due to causes other than age and/or exposure to noise”.
However, the paper contains no detailed information about audiometry testing.
The characteristics of the above studies are summarised in Table 11.
44
Table 11: Summary of the studies on the association of styrene and noise-induced
hearing loss
Study
design
Study
population
Study
group
Comparison
group
Confounders
controlled
Results
Notes
Morioka et
al, 199977
115 male
workers in
seven Japanese
factories that
produced
plastic buttons
or baths (22
workers
excluded)
Subgroup of
54 workers
exposed to
solvent for
more than
five years,
and mandelic
acid >0.3 g/l
(group A)
Subgroup of 54
workers exposed
to the solvent for
more than five
years, and
mandelic acid
=<0.3 g/l (group
B)
None
Among the 54 workers, the
percentage of upper limit of hearing
below the 75th percentile curve
increased as the styrene
concentrations in breathing zone air
increased (r=0.226, p<0.05).
Upper limit of
hearing testing,
stimuli from 0.5
to 50 kHz,
output sound
pressure level 75
dB within 0.5-25
kHz. It was the
frequency that
the subjects first
perceived as a
tone.
299 male
workers in
glass fibrereinforced
plastic
manufacturing
industry,
Canada
Directly
exposed:
TWA
styrene 58.6
(geometric)
or 108.7
(arithmetic)
mg/m3; noise
88.1 dB(A)
(Leq)
Not exposed:
TWA styrene
1.7 (geometric)
or 10.7
(arithmetic)mg/
m3; noise 80.0
dB(A) (Leq)
Only those
younger than 50
years analysed:
smoking
(cigarette-years),
recreational
exposure to
chemicals, noise
and occupational
exposure to other
solvents
Multiple regression model
Age, noise
exposure (which
were significant in
logistic regression
model) and other
variables
One-way ANOVAs:
Sample size
The difference in the prevalence of
bilateral high frequency hearing loss
among styrene-exposed (47%),
styrene and noise-exposed (48%),
and noise-exposed (42%) was not
statistically significant from that of
the control group (33%).
Historical noise
exposure in the
control
Logistic regression analysis:
Case definition:
>25 dB at any
tested frequency
Crosssectional
study
Sass-Kortsak
et al, 199530
Crosssectional
study
Significantly more workers in group
A had the upper hearing limit below
75th percentile curve compared with
group B (p<0.01).
Indirectly
exposed:
TWA
styrene 12.8
(geometric)
or 36.0
(arithmetic)
mg/m3; noise
89.2 dB(A)
(Leq)
Morata et al,
200226
Crosssectional
study – the
same study
subjects as
Johnson et
al’s study78
313 workers
from fibreglass
manufacturing,
metal
products, and a
mail
distribution
terminal in
Sweden
65 workers
exposed to
styrene and
noise (>85
dB) in
fibreglass
factories, and
89 workers
exposed to
styrene and
noise (<85
dB)
78 workers
exposed to noise
in metal
products
manufacture
81 workers
without
exposure to
styrene and
noise from the
mail distribution
terminal
Age was significantly associated with
“hearing loss” in all frequencies
measured in both ears (p<0.01).
Styrene exposure was not significant
in all frequencies measured (p>0.05).
Cigarette-years was significant at 6
kHz in the right ear (regression
coefficient=0.01, p<0.01).
Mandelic acid in urine (1 mmol or
152 mg per gram of creatinine in
urine):
Styrene
exposures
never
exceeded the
Swedish
limits, which
are among
the world’s
lowest (90
mg/m3; or 20
ppm).
Beta=0.89; p=0.0478 (OR=2.44,
1.01-5.89)
Current noise (dB above 85 dB):
Beta=0.17; p=0.0325 (OR=1.18,
1.01-1.34)
Age (year):
Beta=0.18; p=0.0001 (OR=1.19,
1.11-1.28)
45
Decibel hearing
level was
measured in both
ears over
frequencies of 3,
4, 6, 8 kHz.
Unclear
definition of
“hearing loss”;
decibels of
hearing
threshold level
may be directly
used in the
modelling.
Lower level
exposure in
styrene
Study
design
Study
population
Study
group
Comparison
group
Confounders
controlled
Results
Notes
SliwinskaKowalska et
al, 200328
Workers in
four yacht
building yards,
plastics
factory, whitecollar metal
factory
workers in
Poland
290 workers
exposed to
styrene,
including 40
exposed to
both styrene
and toluene,
and 70
exposed to
both noise
and styrene
223 workers
unexposed to
solvents,
including some
exposed to noise
(>85 dB(A))
Age, gender, noise
exposure currently
and historically
Multiple logistic regression analysis:
Audiometry
testing carried
out in office
where noise was
<30 dB.
Crosssectional
study
Age:
Beta =0.10, p<0.001; OR=1.1 (1.081.14)
Current noise exposure (unit?):
Beta=0.067, p<0.01; OR=1.1 (1.041.10)
Styrene exposure (unit?):
Styrene
levels: 3.6308 mg/m3
(mean 61.8
mg/m3)
Beta=1.35, p<0.01; OR=3.9 (2.406.22)
Subgroup analysis:
Non-exposure: OR=1;
Noise only: OR=3.3 (1.7-6.4)
Styrene only: OR=5.2 (2.9-8.9)
Styrene and noise: OR=10.9 (4.924.2)
Styrene and toluene: OR=13.1 (4.537.7)
Styrene and toluene and noise:
OR=21.5 (5.1-90.1)
Johnson et
al, 200678
Crosssectional
study
313 workers
from fibreglass
manufacturing,
metal
products, and a
mail
distribution
terminal in
Sweden
65 workers
exposed to
styrene and
noise (>85
dB) in
fibreglass
factories, and
89 workers
exposed to
styrene and
noise (<85
dB)
78 workers
exposed to noise
in metal
products
manufacture
Unclear
Audiometry:
Significantly higher thresholds at 2,
3, 4 and 6 kHz were observed in the
styrene-exposed workers in both
ears, compared with the other groups
including the control.
81 workers
without
exposure to
styrene and
noise from the
mail distribution
terminal
1-8kHz tested,
HTL>25db
defined as
abnormal.
Sample size in
subgroups (see
95% CIs)
Effect on HTL
was seen in all
frequencies,
especially in 6
and 8 kHz.
Interactions
between
exposures?
Case: HSL>25
dB
Confounding
effects?
Errors in table 1.
Compared with median and the 90th
percentiles of non-occupationally
noise-exposed Swedish population:
Significantly greater proportions than
expected in both the styrene-exposed
groups for the worst ear at 4 kHz
(p<0.001) and 8K (p<0.01)
Note: New Zealand workplace exposure standard: styrene – 50 ppm or 213 mg/m3 (time-weighted
average); 100 ppm or 426 mg/m3 (short-term exposure limit)76
Most included studies indicate that exposure to styrene is associated with a risk of developing
hearing impairment. One study28 also suggests that the damaging effects could occur at a low
styrene exposure level (20 ppm) in workplaces with a low level of noise exposure. Styrene
exposure may be associated with hearing impairments at high frequencies (6-8 kHz).
It is worth mentioning that all these included studies were designed as cross-sectional studies.
The study design has significant limitations in the determination of causal relationship,
including pre-existing hearing loss, which cannot be ruled out.
46
Mixtures of solvents
Morioka et al80 studied the upper limit of hearing in 48 male workers exposed to organic
solvents and/or noise in a factory producing plastic buttons in Japan. These workers were
exposed to a mixture of styrene, methanol and methyl acetate at a level “within the
occupational exposure limits”80. The study found that the percentage of workers at the upper
limit of hearing below the 75th percentile curve was higher in the workers exposed to the
solvent mixture and noise than in those exposed to noise only and in office workers. No
difference in hearing threshold levels by conventional audiometry testing was found between
the groups. Apart from using standard upper limit age curves, potential confounders were not
controlled in this study.
Sliwinska-Kowalska et al29,31,81 report on three studies investigating the association between
hearing impairment and exposure to a mixture of solvents and noise.
The first study81 investigated exposure to solvents, noise and hearing impairments of 517
workers in four paint and lacquer factories in Poland. In these factories, workers were
exposed to a solvent mixture of mixed xylene (otho, meta and para isomers) as one of the
predominant ingredients (the fractions varied from 13.6 to 55.6%) and other solvents
including ethyl acetate, white spirit, toluene, butyl acetate and ethyl benzene. The air
concentration of xylene ranged from 0 to 290mg/m3 (0 to 66.8 ppm). Cumulative solvent
exposure was estimated by an exposure index in which both solvent concentrations and time
periods were taken into account. Compared with white-collar workers (the reference group),
the relative risks (RR) of hearing loss in the solvent-only exposure group and both solvent and
noise-exposed group were significantly increased, but no significant difference was found
between the two exposed groups. Hearing thresholds were significantly poorer in a wide
range of frequencies (1-8 kHz) for both groups exposed to solvents, when compared with the
reference group. The mean hearing thresholds at frequencies of 2-4 kHz were poorer for
workers exposed to solvents and noise than for the solvent-only group; this finding suggests
an additional effect for noise. In general, no significant dose-response relationship was found
in the group exposed to solvents only.
The data of this study are analysed in a manner for cohort study. However, there is a lack of
information on follow-up.
47
The second study31 compares the hearing impairments of 701 dockyard workers (517 noise
and organic solvent mixture exposed and 184 noise only exposed) with 205 control subjects
not exposed to either noise or solvents. Concentration of xylene and toluene in the solvents
mixture ranged from 0.1 to 1,815.3 mg/m3 (0.02-418.1 ppm) and 0-225 mg/m3 (0-59.7 ppm)
respectively. Cumulative exposure was estimated by an exposure index to take the high
exposure levels in the past into account. The odds ratio (OR) of hearing loss was significantly
increased by approximately three times in the noise-only group and by almost five times in
the noise and solvent group. At 8 kHz, the hearing threshold in the noise and solvent group
was significantly worse than the threshold in the noise-only group. ORs for hearing loss were
1.12 for each increment per year of age, 1.07 for each increment per decibel of lifetime noise
exposure (dB(A)), and 1.004 for each increment of the index of lifetime exposure to solvents.
The results suggest an additive effect of co-exposure to noise and organic solvents.
The third study29 compares the hearing impairments of 1,117 workers exposed to both
mixtures of solvents (xylene, styrene, n-Hexane and toluene) and noise in yacht, ship, plastic,
shoe, paint and lacquer industries with 66 workers exposed to noise only and 157 workers
without exposure to noise and solvents. The average working life concentration was estimated
as 0.05-103.6 ppm for xylene, 0.85-72.5 ppm for styrene, 1.5-61.9 ppm for n-Hexane and 1.167.4 ppm for toluene. All solvent exposures were found to be associated with hearing
impairment, with the lowest odds ratios (OR=2.4) in the solvent-mixture-exposed group
(xylene as the main component), and the highest in the n-hexane and toluene exposed group.
Significantly increased ORs were found in the groups with combined exposure to solvents
and noise, compared with isolated exposure to each of these hazards. A positive linear
relationship was found between exposure to solvents and hearing thresholds at high
frequencies (4, 6 and 8 kHz). The authors also indicate that additional deterioration of
hearing at 8 kHz could be caused by co-exposure to solvents and noise29.
Rabinowitz et al82 also report on a retrospective cohort study that assessed the association
between hearing loss and exposure to a mixture of solvents in US aluminium workers. The
study followed a cohort of 1,319 young workers (aged 35 or less at the beginning of the study)
for five years. Exposure to the solvent mixture (toluene, methyl ethyl ketone and xylene) was
assessed according to historical industrial hygiene records of ambient concentration of the
48
solvents. Hearing impairment was assessed according to historical audiometric records at 3, 4
and 6 kHz. After controlling for age and other non-occupational noise exposure (hunting and
shooting, noisy hobbies), solvent exposure was found to be associated with high frequency
hearing loss82.
The characteristics of the above studies are summarised in Table 12.
Table 12: Summary of the studies on the association of a mixture of solvents and noiseinduced hearing loss
Study
design
Study
population
Study
group
Comparison
group
Confounders
controlled
Results
Notes
Morioka et
al, 200080
54 male
workers aged
20-68 years in
a Japanese
plastic buttons
factory.
Combined
group(n=23):
exposed to
styrene (2.928.9 ppm),
methanol
(4.7-34.3
ppm) and
methyl
acetate (9.169.7 ppm);
noise 69-76
dB(A)
Control group:
office workers
(n=12), noise
exposure 58-62
dB(A)
None
Percentage of cases where the upper
limit of hearing falls below 75th
percentile of standard age curve:
Small sample
size,
Crosssectional
study
Combined group: 50%
Noise exposed and control groups:
25% (p<0.05).
No significant correlation was found
between individual percentiles of the
upper limit of hearing and organic
solvent concentrations in the working
environments or the breathing zone.
Noiseexposed
group(n=19):
82-86 dB(A)
SliwinskaKowalska et
al, 200181
Crosssectional
study
517 workers in
four Polish
paint and
lacquer
enterprises.
Solventexposed
workers,
including
those
exposed to
noise =<85
dB(A)
(n=207)
Conventional audiometry testing:
Upper limit of
hearing testing,
stimuli from 0.5
to 50 kHz,
output sound
pressure level 75
dB within 0.5 to
25 kHz. It was
the frequency
that the subjects
first perceived as
a tone.
No difference of HTL between the
groups.
Primarily whitecollar workers
without
hazardous noise
or organic
solvent exposure
(n=214)
Noise exposure
level
Solvent exposure:
RR=2.8 (1.8-4.3)
Age and gender
were adjusted in
logistic
regression
model.
Solvent and noise exposure:
RR=2.8 (1.6-4.9)
Logistic regression model
Solvent and
noise (>85
dB(A))
exposed
workers
(n=96)
ORs were significant in frequencies of
2, 3, 4, and 6 kHz in both solvent only
and solvent + noise exposure groups.
However, there appears to be some
overlaps of 95% CIs between the
groups (reported in Figure 1)
Linear regression model
Mean HTL was higher in the solvent
and noise group at 3 and 4 kHz than
solvent only group.
Linear correlation was found between
some exposure indices (toluene) and
HTL at single frequencies only.
49
Solvent mixture
of xylene, ethyl
acetate, white
spirit, toluene,
butyl acetate
ethyl benzene
Audiometry
testing at 1, 2, 3,
4, 6 and 8kHz,
HTL<25 dB was
defined as
normal.
Incident and
relative risks ???
Study
design
Study
population
Study
group
Comparison
group
Confounders
controlled
Results
Notes
SliwinskaKowalska et
al, 200431
Dockyard
workers
exposed to
solvents and/or
noise.
Workers
exposed to
both noise
(mean
exposure
94.2 dB(A))
and solvents
(mean
xylene 245.2
mg/m3;
toluene 28.9
mg/m3); 517
workers
White-collar
workers not
exposed to noise
and solvents;
205 workers
Age, tinnitus and
current exposure
to noise were
significant in the
logistic
regression
model.
By study group:
Audiometric
testing at 1, 2, 3,
4, 6 and 8kHz,
HTL<25 dB was
defined as
normal.
Crosssectional
study
Crosssectional
study
Workers in
yacht, ship,
plastic, shoe,
and paint and
lacquer
industries;
exposed to a
mixture of
organic
solvents.
Solvent
mixture
exposed
(xylene as a
main
component;
noise 64-100
dB(A); 731
workers)
Noise and solvent exposed group:
OR=4.88 (3.09-7.68)
All subjects:
Age (years)
OR=1.12 (1.10-1.14)
Workers
exposed to
noise only
(mean 90.1
dB(A)); 184
workers
SliwinskaKowalska et
al, 200529
Noise exposed group:
OR=3.34 (2.06-5.43)
Significant
linear
relationship
between age and
hearing loss at
all frequencies
tested.
Lifetime noise exposure (dB(A))
OR=1.07 (1.04-1.09)
Lifetime exposure to solvents (index
numeric values)
OR=1.004 (1.00-1.01)
157 workers
exposed to
neither solvent
nor to noise and
66 workers
exposed to noise
only (77.9-97.4
dB(A))
Age, gender and
current exposure
to noise (solvent
mixture exposure
group, and nhexane and
toluene group),
or post noise
exposure (styrene
group)
Styrene
exposed
(noise 71.393.0 dB(A);
290 workers)
Solvent mixture exposure:
OR=2.4 (1.6-3.7); HL was seen at 4, 6.
8 kHz
Styrene exposure :
OR=3.9 (2.4-6.2); HL was seen at 3-8
kHz (right ear) and whole spectrum of
frequencies (left ear)
n-Hexane and toluene
OR=5.3 (2.6-10.9); HL was seen at 4,
6. 8 kHz
Subgroup analysis (figure 1):
Noise exposure only: OR=3.8
n-Hexane
and toluene
exposed
(noise 73.488.8 dB(A);
96 workers)
Noise + solvent mixture exposure:
OR=6.7
Noise + styrene exposure :
OR=10.9
Noise + n-hexane and toluene
OR=20.2
Noise +styrene + toluene
OR=21.5
50
<=85 dB(A)
defined as not
exposed to
noise; >85
dB(A) as
exposed to noise
Audiometry
testing at 1, 2, 3,
4, 6 and 8kHz,
HTL<25 dB was
defined as
normal.
Study
design
Study
population
Study
group
Comparison
group
Confounders
controlled
Results
Notes
Rabinowitz
et al, 200882
1,359 workers
in five
locations of
Alcoa Inc, who
were 35 years
of age or
younger in
1989, with a
minimum of 46 years of
audiometric
follow-up, and
at least three
audiograms
performed
during the
period; eight
hour timeweighted
average 82
dB(A) or
greater.
116
individuals
with solvent
index greater
than the 90th
percentile
classified as
“solvent
exposed”
(top 10% of
solvent
exposures in
the study
population);
the mean
exposure
levels were
usually well
below the
threshold
limit values.
Others
Age, shooting or
hunting, noisy
hobbies, baseline
hearing status
Solvent exposed
Respective
cohort in
aluminium
industry
Retrospective
cohort study
Dichotomous outcome (>1dB/yr)
OR=1.97 (1.22 to 2.89)
Continuous outcome (dB/yr)
Β coefficients =0.58 (p<0.001)
Individual
exposure levels
assessed
according to
historical
ambient level of
the solvents
only, and
calculated as
“solvent index”.
Biological
monitoring was
not used.
Exposure to
aluminium
Hearing loss was
defined
dichotomously
as a rate of
change in excess
of 1 dB/year, or
the rate change
of average
hearing
thresholds at 3, 4
and 6 kHz in
dB/year (a
continuous
outcome).
Most were
exposed to a
mixture of the
solvents
toluene, xylene
and/or methyl
ethyl ketone
(MEK) at level
of 5 ppm or
more (eight
hour time
weightedaverage).
Note: New Zealand workplace exposure standard: xylene – 50 ppm or 217 mg/m3 (time-weighted
average); n-hexane: 20 ppm or 72 mg/m3 (time-weighted average)76
Based on these studies, exposure to mixtures of solvents appears to be a risk factor for hearing
impairment.
Carbon disulphide
Carbon disulphide is used in the manufacture of viscose rayon, explosives, paints,
preservatives, textiles, rubber cement and varnishes.
Morata83 reports on an analysis of 258 workers who were exposed to noise and carbon
disulphide in a rayon factory in Brazil. The analysis found that the percentage of hearing loss
may be associated with years exposed to noise and carbon disulphide. There was a
51
considerable lack of information on exposure assessment and detailed statistical analysis in
this study. Potential confounders appear to have not been controlled.
Chang et al84 report on a cross-sectional study of workers in a viscose rayon factory in Taiwan.
The 131 male workers exposed to both noise (80-91 dB(A)) and carbon disulphide (1.6-20.1
ppm) had a higher prevalence of hearing loss (67.9%) than the comparison groups exposed to
noise only (32.4%) and the administrative workers (23.6%). When exposure to carbon
disulphide was measured by cumulative exposure index (exposure level and employment
years), there was a significant dose-response relationship between carbon disulphide exposure
and hearing loss. This study also found that workers exposed to both carbon disulphide and
noise had higher hearing impairment than those exposed to noise only at speech frequencies
(0.5, 1 and 2 kHz).
The characteristics of these two studies are summarised in Table 13.
Table 13: Summary of the studies on the association of carbon disulphide and noiseinduced hearing loss
Study
design
Study
population
Study
group
Comparison
group
Confounders
controlled
Results
Notes
Morata,
198983
Workers in a
rayon factory
in Brazil
53
volunteers
and 205
randomly
selected
workers;
exposed to
noise (range
86-89
dB(A)) and
excessive
levels of
carbon
disulphide
(89.92
mg/m3 or 29
ppm)
None
None
Percentage of hearing loss (I-IV) by
year of exposure to noise and carbon
disulphide:
Pure-tone
audiometry
testing at 0.5, 1,
2, 3, 6 and 8 kHz
Workers
exposed to
CS2 (range
1.6-20.1
ppm) and
noise (80-91
dB(A)); 131
workers
Administrative
workers in the
plants with low
noise exposure
(75-82 dB(A));
110 workers
Crosssectional
study
Chang et al,
200384
Crosssectional
study
Male workers
in a plant
manufacturing
viscose rayon
in Taiwan, and
workers in
adhesive tape
and electronics
industries
0-2 yrs: 46.7%
3-5 yrs: 70.6%
6-10 yrs: 71.8%
11+ yrs: 69.3%
Using Preira
criteria (1978) in
Brazil to define
hearing loss;
level 0, I, II, III,
IV and nonnoise-induced
hearing loss
Lack of
information on
exposure
assessment
Age, noise
exposure level,
smoking, drinking
and the use of
personal
protection
equipment
By study group:
Administrative: OR=1.0 (control)
Noise only: OR=1.5 (0.8-2.8)
Noise and CS2: OR=6.8 (3.9-12.1)
By CEI of CS2:
<37 yr ppm: OR=0.8 (0.3-2.2)
37-214 yr ppm: OR=3.8 (1.5-9.4)
215-453 yr ppm: OR=14.2 (4.4-45.9)
454-483 yr ppm: OR=70.3 (8.7569.7)
Workers
exposed to
noise (83-90
dB(A)); 105
52
HTL testing at 1,
2, 3, 4, 6, 1 and
0.5 kHz,
>25 dB in worst
ear defined as
hearing loss
Without group
exposed to CS2
only
workers
>483 yr ppm: OR=74.5 (8.7-634.5)
Note: New Zealand workplace exposure standard: carbon disulphide – 10 ppm or 31 mg/m3 (timeweighted average)76
Exposure to carbon disulphide may increase the risk of hearing impairment. One included
study indicates that the chemical is associated with hearing loss at speech frequencies (0.5, 1
and 2 kHz). More studies, especially cohort studies, appear to be needed to confirm these
findings.
4.4.3 Evidence and implications
Based on the studies reviewed, exposure to solvents appears to be a risk factor for hearing
impairment. Styrene at relatively low exposure levels is associated with hearing impairment
in the workplace at a low level of noise exposure. Some studies found that there was a
potential synergistic effect of combined exposure to solvents (styrene and toluene) and noise.
The effect indicates that the combined noise and solvent exposure could potentially lead to a
greater risk of hearing loss than exposure to solvents and noise alone. According to available
studies, some solvents are associated with hearing impairments at low (0.5, 1 and 2 kHz, for
toluene and carbon disulphide) or high frequencies (6-8 kHz, for styrene) which are not
typically seen in noise-induced hearing loss at working age.
However, most of these study results are based on cross-sectional study design. More cohort
studies are obviously needed to further demonstrate and quantify the causal relationship
between solvent exposure and hearing loss. The relationship appears to be relevant to clinical
assessment.
It is recommended that information on solvent exposure be collected in hearing loss
assessment, especially for workers from related industries (e.g. yacht building). Input from
occupational health professionals may be needed in some cases. Currently, there is a lack of
clinical tools or guidelines to assess hearing impairment in association with solvent exposure
in the workplace. Surveillance data from hearing tests in the workers exposed to solvents can
be critical in the assessment.
53
It is worth mentioning that some of these solvents are also present in the cases of substance
abuse, for example inhalation of solvent-based propellants. Cases of hearing loss caused by
the substance abuse have been reported previously72,85. Related information and medical
history need to be asked and considered in hearing loss assessment.
Risk control to reduce solvent exposures may need to be considered in the programmes to
prevent noise-induced hearing loss in the workplace. Internationally, there is currently an
absence of clinical guidelines or criteria to determine solvent-related hearing loss at this stage.
54
4.5 Carbon monoxide (CO)
4.5.1 Background
Carbon monoxide is a leading cause of inhalation injuries in the workplace. It is generated by
incomplete combustion of any carbon-containing fuel or materials in machines or fire
accidents. People who work in such an environment are potentially exposed to carbon
monoxide86-88.
Carbon monoxide may have an impact on the development of hearing loss possibly by
oxidative stress and related neurotoxicity and potential ototoxicity2,89. Animal studies show
that CO itself (1,200 ppm for eight hours) had no persisting effects on compound action
potential sensitivity; thresholds for the rats receiving CO alone were comparable to control
rats (without exposure to CO and noise). However, as CO concentration increased (from 300
to 1,500 ppm) for rats receiving combined exposure of CO and noise, there was an orderly
increase in the extent of auditory threshold impairment relative to the rats receiving noise by
itself. Statistically significant elevations in NIHL were observed with CO exposures of 500
ppm and higher in the animal study87.
Young et al90 also report that rats’ exposure to CO alone was quite similar to that of control
subjects (without exposure to noise and CO). There was no evidence of any decrease in
auditory performance following a 210 minute exposure to 1,200 ppm of carbon monoxide at
either 10 or 40 kHz. A significant interaction between noise exposure (120 minutes at a level
of 110 dB(A)) and the CO exposure was also found in this study90. The concentration of CO
level used in the study was relatively high and may not be found in the current working
environment90.
4.5.2 Studies identified
Only an epidemiological study on occupational exposure to carbon monoxide and hearing loss
was found82. There are also some case reports in relation to non-occupational carbon
monoxide poisoning and hearing loss.
55
Rabinowitz et al82 report on a retrospective cohort study of 1,319 aluminium industry workers
in the USA. Individual exposure to carbon monoxide in a five-year period was estimated
according to historical industrial hygiene measurements and job titles. One hundred and forty
workers whose time-weighted exposures were greater than 13.7 mm (mg/m3, about 12 ppm;
90th percentile of the exposure measurements) were defined as “carbon monoxide-exposed”.
This study found that the association between the carbon monoxide exposure and hearing loss
was not statistically significant82. The level of carbon monoxide exposure in this study
appears to be well below the Permissible Exposure Limit (PEL) in the USA (50 ppm, average
over an eight-hour work shift)91and New Zealand workplace exposure standards76.
Morris92 reports on a case of hearing loss following acute CO poisoning from a faulty
anthracite-burning stove in 1967. The patient’s (22-year-old male) carboxy-haemoglobin was
25% on admission to hospital. The symptom of hearing loss was found 12 hours after the
poisoning and the patient had a hearing difficulty for the psychiatric interview. Bilateral
hearing loss was confirmed by pure-tone audiometry testing at day 6. The patient’s hearing
gradually improved in the following four weeks but remained significantly impaired 11
months later92.
A case of temporary hearing loss in a six-year-old boy was reported in the UK93. The puretone audiogram showed a bilateral sensorineural hearing loss with sparing at 4 kHz (HTL
between 20 and 40 dB, frequencies of 0.25-8 kHz). The hearing impairment was considered
to be caused by exposure to carbon monoxide from the gas central heating boiler in his home.
The concentration of CO was reported as “extremely high”. The hearing impairment lasted for
about 21 months when the audiogram showed spontaneous improvement and remained within
the normal range in a test 10 months later.
Lee et al94 report a case of sensorineural hearing loss after an attempted suicide by burning
charcoal and inhaling the fumes. The hearing loss was “clinically documented” at day 4.
Partial improvement in hearing ability was found at day 14. No other detail about the hearing
loss is reported in this case.
Shahbaz Hassan et al95 also report two cases of hearing loss after CO poisoning. The first case
was an acute poisoning that occurred in a closed garage. Bilateral moderate to severe hearing
56
impairment was found 18 hours after hospital admission. The hearing impairment partially
recovered after two months with residual hearing loss between 1 and 8 kHz. The second case
was a chronic poisoning caused by a fault with a gas fire at a patient’s home. Pure-tone
audiometry showed bilateral moderate sensorineural hearing loss. The patient’s hearing
ability improved gradually after the source of exposure was removed and the patient received
treatment with high-flow oxygen for the poisoning.
Several cases of hearing loss after carbon monoxide poisoning have also been reported in
English abstracts in non-English journals96-98.
4.5.3 Evidence and implications
The findings from animal studies and human case reports differ. No hearing impairment was
found in animal studies even with a significantly high concentration exposure of carbon
monoxide (up to 1,500 ppm). However, human cases of hearing loss have been reported after
carbon monoxide poisoning. Exposure levels of carbon monoxide are not available in the
accidental poisoning reports. It is reasonable to assume that the poisoning levels were higher
than the exposure levels in most workplaces.
Based on the case reports, carbon monoxide poisoning-related hearing loss could be described
as bilateral sensorineural impairment and is at least partly reversible. The hearing impairment
may be frequency specific (1-8 kHz)92,95. It is unclear whether the hearing loss is related to
potential ototoxicity and/or neurotoxicity of carbon monoxide.
There is only a very limited number of epidemiological studies on occupational exposure to
carbon monoxide and hearing impairment in the working population. More studies appear to
be needed in the future. The risk of hearing loss in association with long-term occupational
exposure to carbon monoxide in the working environment, and the possible interaction
between exposure, noise and other risk factors, remains unclear.
It is recommended that a patient’s medical history of carbon monoxide poisoning be asked
and recorded during the diagnosis of noise-induced hearing loss. Audiometric testing results
after the poisoning need to be considered in the assessment if they are available.
57
5. Discussion
5.1 Methodological quality
Risk factors are the variables of personal behaviour (e.g. smoking), environmental exposure
(e.g. exposure to noise) or inherited characteristics (e.g. genetic markers) associated with an
increased risk of diseases or conditions.
In epidemiological studies, risk factors can also be confounding factors that have effects on
diseases or conditions and need to be separated or controlled to estimate the true effects of the
factor/s under investigation. In terms of the assessment of noise-induced hearing loss, related
risk factors need to be considered to interpret the hearing impairment presented. Some of the
risk factors can be work related (e.g. exposure to organic solvents), while others may not be.
Theoretically, a cohort study is an ideal study design to investigate the effect of any risk
factor. Based on the study design, the likelihood of a causal relationship, the differences in
incidence of new hearing loss cases, can be assessed. However, cohort studies require
relatively long study periods and significant resources. Case control studies and crosssectional studies, which have the advantage of needing fewer resources, can also be used to
investigate risk factors. Nevertheless, these two study designs have limitations in testing the
likelihood of a causal relationship and usually cannot be used to measure the differences in
incidence (except some specified types of case control studies). In general, cohort studies
provide relatively strong epidemiological evidence to determine the different aspects of the
effect of risk factors.
Of the 56 studies assessed in this review, 12 are cohort studies. Eight of these cohort studies
relate to age and hearing loss; the other four relate to smoking and solvents. Nine of the 10
studies for genetic factors and hearing loss are case control studies. Even though case control
design is considered a suitable approach in the early stages of genetic epidemiology99, there is
a need for well-designed cohort studies in the future to confirm some preliminary findings.
Thirteen of the 15 studies on solvents are cross-sectional. The cases of hearing loss in the
cross-sectional design are “prevalent cases” rather than “incident cases”, and include hearing
loss that occurred before and during the exposure to solvents. In addition, exposure assessed
in the cross-sectional studies may not represent the real exposure levels over time. Therefore,
there is room for more cohort studies to be carried out to demonstrate the quantitative
58
relationship between solvent exposure and hearing loss, for example to directly measure the
incidence in different levels of exposure dose.
Only one cohort study82 reporting on hearing loss and carbon monoxide exposure in the
workplace was found. There is a need for studies on hearing loss and carbon monoxide
exposure in occupational settings.
In addition to the types of study design, the quality of each individual study also depends on a
number of factors (see section 3.3, Methods of the review), particularly on the methods of
exposure assessment, confounding control and outcome measurement. These quality issues
are commented on in the summary tables relating to the studies appraised.
It is worth noting that cases of “hearing impairment” or “hearing loss” were defined
differently between studies. The outcome measurements were based on self-reported results,
pure-tone audiometry or other methods of audiometric testing. Self-reported questionnaires
may be unable to identify hearing damage at high frequencies31.
5.2 Implications of findings
Prevention of occupational hearing loss
Risk factors identified from epidemiological studies have been the basis for disease
prevention. Among the factors assessed in this review, exposure to organic solvents,
especially toluene, styrene and the mixture of solvents, appears to be a risk factor for hearing
loss, with potential interaction with noise exposure. It is a concern that increased risk of
hearing loss was found at an exposure level of styrene lower than the recommended exposure
limit.
In addition to noise control, it would be appropriate to consider these chemicals in hearing
loss prevention in the workplace. Smoking cessation can also be considered a part of the
prevention since the workplace has many advantages as a setting for public health
intervention. Smoking cessation is likely to have other health benefits for workers.
Nevertheless, there is a lack of studies to demonstrate the effectiveness of smoking cessation
in preventing occupational hearing loss at this stage.
59
When more data from high quality studies, especially from cohort studies, become available
for dose-response assessments, work exposure standards may need to consider the effect of
the solvents on hearing loss. Current standards are only based on the safety assessment on
neurotoxic and hepatotoxic effects81.
Occupational health surveillance
The available studies indicate that there could be some certain audiometric patterns of hearing
damage in relation to solvent exposure. However, the findings of these patterns need to be
confirmed by further studies. These findings alone appear to be inadequate to determine
whether these risk factors cause the hearing impairment. Other supporting evidence is needed
for clinical assessment.
Historical audiometric records from continuous occupational health surveillance appear to be
relevant in such a circumstance. The records may include baseline audiograms (before or at
the start of exposure to hazardous noise), monitoring audiograms (regular or annual testing),
confirmation audiograms (for those with a detected threshold shift) and exit audiograms (for
those leaving employment or a noise-exposed job)100.
A national surveillance system including national databases on noise exposure, audiometric
testing and exposure to other risk factors (e.g. smoking and solvents) may be desirable in New
Zealand. Such a system would be very useful for the prevention and clinical assessment of
occupational hearing loss.
Clinical assessment of noise-induced hearing loss
Compared with the use of the findings from epidemiological studies on risk factors for
prevention, it is relatively difficult to use the findings for clinical assessment on individual
patients. Effects of the risk factors are assessed at population or group level in
epidemiological studies. Related exposures and outcomes are often measured as a mean or
median. So there are limitations in generalising the findings for an individual. Moreover, the
exposure “dose” of the risk factors (apart from age) for an individual is usually unclear and
difficult to obtain quantitatively. Exposure to multiple risk factors also makes the assessment
much more difficult. As mentioned previously, there is also a lack of high quality cohort
studies for some risk factors reviewed.
60
Based on recent available research evidence on most of the risk factors reviewed, it is very
difficult to develop clinical tools to quantitatively determine how much of an individual
hearing loss is caused by smoking and how much is caused by solvents. Internationally, there
is currently an absence of such clinical tools at this stage. In short, it is difficult to use the
findings in a “quantitative approach” in the clinical assessment in most cases.
However, these limitations do not hinder the findings being used in a “qualitative approach”
in a clinical assessment. For example, if hearing impairment in a yacht building worker does
not match with the level of noise exposure, information in relation to other risk factors (e.g.
exposure to styrene, smoking and other non-occupational related exposure) can be considered
when interpreting the hearing impairment. It would be very useful if historical audiometric
records for the worker were available.
Practically, noise exposure needs to be considered as the highest risk factor for occupational
hearing loss at present. A position paper from the Committee for Occupational Medicine in
the research institutes of the German Social Accident Insurance states:

“If the current limit values for industrial chemicals are adhered to, the probability of
significant hearing loss is low.

There can be a higher risk in activities involving ototoxic industrial chemicals if the
limit values are exceeded (e.g. when processing styrene).

Noise is the highest risk factor for hearing damage. Going by the knowledge currently
available, effects of a similar proportion to those caused by other confounders (for
example, cigarette smoke or a genetically determined heightened sensitivity to noise)
cannot be ruled out if there is also a high exposure to ototoxic substances. Measures
to combat noise-induced hearing loss continue to have top priority101.”
61
5.3 Limitations
It should be noted that the risk factors for hearing loss are not limited to the factors reviewed
in this report. A number of other risk factors for hearing loss have been reported in the
literature. They include gender, socio-economic status, heavy metals, medications,
cardiovascular disorders and other medical conditions2,16,20,48,102-105. These factors are not
included in this review primarily because of time constraints; users should be aware of this
limitation and seek other related information when it is needed.
62
6. Conclusions
The findings of this review on some risk factors for hearing loss can be summarised as:
Age
All related studies included in this review show that age is strongly associated with hearing
loss.
Evidence that supports a synergistic effect of ageing and noise exposure appears to be very
weak. Compared with those without historical noise exposure, older adults previously
exposed to occupational noise do not have a higher rate of threshold changes or may even
have a lower rate of the changes. These findings support that noise exposure in working age is
very unlikely to be an attribute of hearing deterioration in older people who are no longer
exposed to noise. In other words, previous noise exposure is very unlikely to cause older
people to be more prone to age-related hearing loss, even though hearing loss caused by the
previous noise exposure will still exist.
In terms of clinical assessment, an additive effect model of ageing and noise exposure on
hearing loss is much more acceptable than the assumption of synergistic effect. Nevertheless,
the additive effect model is not always in agreement with some data from available studies.
An additive effect model with modification can be considered as the best approach available.
Smoking
Smoking can be considered a risk factor for hearing loss.
However, all included studies have significant weaknesses in methodology, especially in the
measurement of noise exposure and in controlling the exposure as a relevant confounder.
Even though most included studies indicate that smoking is associated with hearing loss, more
well-designed studies with appropriate control for relevant confounders are needed.
63
Genetic factors
Genetic studies on noise-induced hearing loss appear to be at an early stage. The number of
studies on individual genes or SNPs is still limited. Six of the 10 studies found are based on
two sample sets in Sweden and Poland.
It is noted that some genetic mutations are associated with susceptibility to noise-induced
hearing loss. However, some of these findings are based on analysis of relatively large
numbers of genetic markers (e.g. SNPs). It is possible that some of the findings are false
positive associations rather than true associations. Further studies are needed to test these
associations in different sample sets so that true associations can be established.
Based on odds ratios reported in these studies, and the sampling methodology used (e.g. the
most susceptible versus most resistant), available studies appear to suggest that genetic
markers currently investigated are not strong risk factors for noise-induced hearing loss.
The contribution of genetic factors to noise-induced hearing loss also depends on the
frequency of related genetic markers in the local population, which appears to be unclear at
this stage.
Potential combination effects of different related genes remain unexplored at this stage. The
studies included in this review only investigate the effect of individual genes.
Organic solvents
Based on the studies reviewed, exposure to solvents appears to be a risk factor for hearing
impairment. Styrene at relatively low exposure levels is associated with hearing impairment
in the workplace at a low level of noise exposure. Some studies found that there was a
potential synergistic effect of combined exposure to solvents (styrene and toluene) and noise.
The effect indicates that the combined noise and solvent exposure could potentially lead to a
greater risk of hearing loss than exposure to solvents and noise alone. According to available
studies, some solvents are associated with hearing impairments at low (0.5, 1 and 2 kHz, for
toluene and carbon disulphide) or high frequencies (6-8 kHz, for styrene) which are not
typically seen in noise-induced hearing loss at working age.
64
However, most of these study results are based on cross-sectional study design. More cohort
studies are obviously needed to further demonstrate and quantify the causal relationship
between solvent exposure and hearing loss. The relationship appears to be relevant to clinical
assessment.
Carbon monoxide
The findings from animal studies and human case reports are different. No hearing
impairment was found in animal studies even with a significantly high concentration exposure
of carbon monoxide (up to 1,500 ppm). However, human cases of hearing loss have been
reported after carbon monoxide poisoning. Exposure levels of carbon monoxide are not
available in the accidental poisoning reports. It is reasonable to assume that the poisoning
levels are higher than the exposure levels in most workplaces.
Based on the case reports, carbon monoxide poisoning-related hearing loss could be described
as bilateral sensorineural impairment and is at least partly reversible. It is unclear whether the
hearing loss is related to the potential ototoxicity and/or neurotoxicity of carbon monoxide.
There is only a very limited number of epidemiological studies on occupational exposure to
carbon monoxide and hearing impairment in the working population. More studies appear to
be needed in the future. The risk of hearing loss in association with long-term occupational
exposure to carbon monoxide in the working environment, and the possible interaction
between the exposure, noise and other risk factors, remains unclear.
65
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73
Appendix: Literature search strategy
1
2
3
4
5
6
7
8
9
10
11
12
Occupational deafness/
noise-induced hearing loss.ti,ab,kw.
industrial deafness.ti,ab,kw.
hearing loss, noise-induced/
(industrial adj4 hearing loss).mp.
(occupational adj4 hearing loss).mp.
or/2-7
exp risk factors/
ototoxic$.ab,ti,kw.
9 or 10
8 and 11
remove duplicates from 12
74
75