GUIDELINE FOR DIAGNOSING OCCUPATIONAL NOISE-INDUCED HEARING LOSS PART 2

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1 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

2 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

3 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

4 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

5 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

6 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. vi

7 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 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

8 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

9 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. ix

10 Contents Title Page... i Executive Summary...iii Acknowledgements... ix List of Tables...xii List of Figures...xiii 1. Introduction Objectives Methodology Criteria for selecting studies for this review Search strategies and information sources Methods of the review Results Age Background Studies identified Evidence and implications Smoking Background Studies identified Evidence and implications Genetic factors Background Studies identified Evidence and implications Organic solvents Background Studies identified Evidence and implications Carbon monoxide (CO) Background Studies identified Evidence and implications Discussion Methodological quality Implications of findings x

11 5.3 Limitations Conclusions References Appendix: Literature search strategy xi

12 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 Table 3: Summary of the cohort studies on the association of smoking and hearing loss Table 4: Summary of the case control studies on the association of smoking and hearing loss Table 5: Summary of the cross-sectional studies on the association of smoking and hearing loss Table 6: Summary of the studies on the association of genetic factors in relation to antioxidant systems or oxidative stress and hearing loss Table 7: Summary of studies on the association of genetic factors in relation to the potassium recycling pathway and hearing loss Table 8: Summary of studies on the association of genetic factors in relation to heat-shock proteins and hearing loss 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 Table 11: Summary of the studies on the association of styrene and hearing loss Table 12: Summary of the studies on the association of a mixture of solvents and hearing loss Table 13: Summary of the studies on the association of carbon disulphide and hearing loss. 52 xii

13 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 xiii

14 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 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 In Washington state, in the USA, the number of compensation claims for hearing loss increased 12 times from 1984 to 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 workers 5. 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 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 loss 1,2,6. 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

15 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

16 A search strategy for different bibliographic databases was developed (Appendix 1). The literature was searched up to July 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 al 7 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 relationship 8. 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

17 4. Results 4.1 Age 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 life 9,10. Epidemiological studies have supported a clear trend of an annual decline in hearing ability 11,12. Hearing deterioration may become more rapid for both men and women after the fourth decade 13. 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-related 14. 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 range 10. 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 ageing 15,16. 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 stops 15,16. 4

18 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 of years old, data from the Danish Work Environment Cohort shows that older age s 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 model 17. In the study reported on by Starck et al 18, 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 studied 18. In the genetic study reported by Rabinowitz et al 19, 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 al 20 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 paper 16 based on the same cohorts reveals the 5

19 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 ( ) 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 study 12 ; 56% of them were occupationally exposed to noise. A five-year follow-up examination was conducted from 1998 to 2000, with 2,800 participants 21. A 10-year follow-up examination was carried out from 2003 to 2005, with 2, 395 participants 22. At the baseline ( ) 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 ( ), incidence of hearing loss (new cases of hearing loss in the period) significantly increased with age. The increase was observed in both males and females 21. At the 10-year follow-up ( ), analysis of auditory thresholds showed that 22 : continuing decline in hearing ability (increase in hearing threshold) occurred with advancing age at all frequencies for younger age s (50-60 years old, as defined at the baseline), the increase in thresholds was greatest at higher frequencies (3-8 khz) for older age s (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 thresholds 22. 6

20 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 of Ageing (BLSA) 23. Changes in hearing thresholds occurred in all age s 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 study 22. The authors conclude that the rate of change for the older males is faster in the speech-range frequencies khz than in the higher frequencies, since their hearing has already diminished at the high frequencies 23. The study reported by Davis et al 24 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

21 Table 1: Summary of the studies on ageing and noise-induced hearing loss design population Comparison Confounders controlled Results Notes Burr et al, Cohort study Based on Danish Work Environment Cohort, 7,221 workers aged years without hearing injury. Sub analysis was conducted in 4,766 workers of Nordic origin. Age s yrs yrs yrs Age : yrs Occupational noise, height and smoking stratified by gender Males: yrs: OR=1.62 ( ) yrs: OR=2.78 ( ) yrs: OR=3.60 ( ) Females: yrs: OR=2.19 ( ) yrs: OR=2.74 ( ) yrs: OR=3.36 ( ) Self-reported data Five-year incidece of hearing loss Age was associated with hearing loss in three noise exposure strata. Starck et al, Crosssectional study 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. Rabinowitz et al, Crosssectional study 77 volunteer workers who were exposed to noise above 85 db(a), male and female, aged yrs; 58 workers included in the final analysis Not in linear regression Linear regression: Audiometric high frequency average Age: coefficients=0.55, R 2 =0.27, P= Audiometric low frequency average Age: coefficients=0.17, R 2 =0.11, P=0.01 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, R 2 for age was higher than the value for years of reported noise exposure. Pedersen et al, Cohort study Two cohorts of elderly persons in Gothenburg, Sweden. Those in F01 cohort were born in (376 subjects at age 70); those in F06 cohort were born in (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. Noise exposure and other risk factors were not taken into account. Unscreened study subjects Loss of followup 8

22 design population Comparison Confounders controlled Results Notes Cruickshanks et al, 1998, ,21 Cohort study (Beaver Dam study) Populationbased study, with 3,753 participants at baseline ( ), average age 65.8 years (48-92 years) Age s yrs yrs yrs yrs Three notch categories Prevalence at baseline (based on 3,556 participants, males and females, %) yrs yrs yrs yrs 90.0 Five-year incidence (based on 1,576 participants, male and female, %) yrs 11.6 ( ) yrs 23.1 ( ) yrs 49.0 ( ) yrs 95.5 ( ) Incident case: pure-tone average of thresholds at 0.5, 1, 2 and 4 khz, >25 db, and without hearing loss at baseline. Five-year incidence of hearing loss Brant and Fozard, Cohort study (Baltimore study) Volunteers in the Baltimore Longitudinal of Ageing; 813 males aged years who had hearing tests at least twice between 1968 and 1987 Age s 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 db per year). 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. Exposure to noise was not assessed. Most participants were white-collar workers. The rates of change for the speech frequencies and 3 khz were greater than for 8 khz. Davis et al, Cohort study 405 adults aged years in UK with year follow-up Age s 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 There was no change in average hearing levels for occupational, 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 al 25, Morata et al 26,27 and Sliwinska-Kowalska et al 28,29, age was found to be significantly associated with hearing loss after adjustment for noise and solvent exposure. Gender 28 and ear infection 25,27 are also controlled in the analyses in some of these studies. 9

23 In the multiple linear regression analyses reported by Sass-Kortsak et al 30 and Sliwinska- Kowalska et al 31, 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

24 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 s 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 stopped 33. 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 study 34 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

25 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 study 35. 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 Spoor 37. 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 al 16 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 susceptibility 16. 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 report 16 ), 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 khz 16. At 2 khz, the threshold change in noise-exposed participants was 17.5 db (from

26 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. design Table 2: Summary of the studies on the co-effect of ageing and noise on hearing loss population Comparison Confounders controlled Results Notes Lee et al, Cohort study 188 older adults recruited through advertisements and subject referral. Average age 68 years (60-81 years) at baseline; hearing threshold followed up within years Age s: yrs yrs >=70 yrs 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. Females >=70 yrs had significantly faster rate of change at khz and slower rate of change at 10 and 11 khz than females in younger age s. Males >= 70 had a faster rate of change at 6 khz than males in the younger age s. No difference in change of threshold for those with or without historical noise exposure (see Figure 2) History of noise exposure was collected by questionnaire. The slope of a linear regression was used to calculate the rate of change in pure-tone thresholds. Extended high frequencies (9-18 khz) included design population Comparison Confounders controlled Results Notes Gates et al, 33,38,39 Cohort study 1,662 older adults from Framingham study; aged years, with average age 73 years Age s: yrs yrs yrs yrs At the baseline ( ), a generalised worsening of thresholds with increasing age is apparent at all frequencies but particularly in the high frequencies. At six-year follow-up ( to ): 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). Exposure to noise was not directly assessed. 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, Case series About 240 war veterans who received audiogram testing (retesting), out of approx. 360 None, apart from the criteria used for exclusion 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 13

27 patients who had normal hearing for their age at 1 khz, and hearing loss at 4 khz at initial testing 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. Rosenhall et al, Cohort study Two cohorts of elderly persons in Gothenburg, Sweden. Those in F01 cohort were born in ; those in F06 cohort were born in 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 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 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. 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. Noise exposure was assessed by years of exposure only. Other risk factors were not taken into account. No statistical analysis was reported in testing the differences between the noise-exposed and non-exposed. 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 noise 40. 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 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 years of exposure. 14

28 At 4 khz, the total hearing loss increase during the first years of noise exposure was extremely steep. The increase was, on average, 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 years 40. 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 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 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 db, the assumption of additive effects of ageing and noise exposure appears to be no longer valid 40. In the review by Rosler 40, the analysis is based on the mean or median of hearing impairment of occupational s 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 studies 16,32 that found 15

29 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 s is significant, then the space left for further hearing loss (e.g. effect of ageing) in the older age s would be limited. For the hearing frequencies significantly impaired by noise (3-8 khz), the impact of ageing in the older age s 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 s. 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. Corso 15 and Rosler 40 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 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 al 33, 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

30 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 Macrae 36 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 s with higher ages and hearing loss levels of more than db in several studies 40. This finding indicates that the additive model also has limitations in some situations. Sometimes it could lead to an overadjustment as those reported by Rosler 40. 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 db 41. In principle, the additive effect model with modification can be considered the best approach available. Some studies support such an approach 35,42. 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

31 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

32 4.2 Smoking 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 effects 17, Smoking is more common in some occupational s who are also more likely to be exposed to noise, for example industrial plant operators, building workers and machine operators 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 workers 47 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, ) 47. Another cohort study (the Baltimore Longitudinal of Ageing 48 ) 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

33 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 design population Comparison Confounders controlled Results Notes Nakanishi et al, Cohort study, follow-up from 1994 to 1999 Male Japanese office workers aged 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) Ex-smokers: RR=1.70 ( ) Current smokers: 1-20 cigarettes/day RR=1.82 ( ) cigarettes/day RR=2.00 ( ) >=30 cigarettes/day RR= 2.20 ( ) RR of high frequency hearing loss (4 khz): Cumulative lifetime exposure: pack-year: RR=1.74 ( ) Hearing impairment: loss of 30 db at 1 khz and 40 db at 4 khz 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 pack-year: RR=2.27 ( ) pack-year: RR=1.69 ( ) >=40.0 pack-year: RR=2.45 ( ) 20

34 design population Comparison Confounders controlled Results Notes Brant et al, Cohort study, maximum follow-up 22.8 years in men and 13.0 in women 1,247 men and 588 women, representing a predominantly white uppermiddle class 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 Moderate: one pack or less/day High: more than one pack/day No cigarette smoking RR adjusted for age by four age strata Relative risk (RR, male only): Moderate vs none (p=0.35): RR=1.38 ( ) Higher vs none (p=0.61): RR=1.23 ( ) Hearing loss was determined if average puretone threshold at 0.5, 1, 2 and 3 khz >= 30 db in either ear. 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 of 2,348 noise-exposed white male workers at an aerospace company 44. 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 al 9 report a case control study nested in a population-based cohort comprising 197 cases of hearing loss and 394 matched controls aged 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

35 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 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 al 45 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 al 49 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

36 design Table 4: Summary of the case control studies on the association of smoking and noiseinduced hearing loss population Comparison Confounders controlled Results Notes Barone et al, Case control study 2,348 noiseexposed workers in an aerospace company in the USA, aged workers in the top third of the hearing loss distribution (at 3, 4 and 6 khz) cases of hearing loss (defined by NIOSH criteria 1972) Noise exposure (TWA) 88.7 db(a) workers in the lowest third of the hearing loss distribution (at 3, 4 and 6 khz) workers with the least hearing loss (non-impaired as defined by NIOSH criteria 1972) Noise exposure (TWA) 89.1 db(a) 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) 2. Present smokers, beta= (P=0.03) (changing to an OR of about 1.59); past smokers, not statistically significant The trend in risk for packyears smoked was significant (P=0.007). Nondahl et al, Nested case control study; however, serum cotinine testing was taken at the 5-year follow-up not at the baseline. Communitybased cohort aged years in the baseline 197 new cases in a five-year follow-up period, aged years 394 matched controlled subjects selected from the cohort aged years Education level was the only variable in the logistic regression model. Stratified by gender and age There was no association between levels of serum cotinine and hearing loss in the logistic regression model. 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 Carlsson et al, Case control study 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) 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 contained more smokers than the resistant (p=0.05; Fisher s exact test). Effect of present smoking on NIHL susceptibility is independent of noise exposure level; the Mantel- Haenzel common odds ratio =2.25 ( ; p=0.045). Hearing threshold of left ear at 3 khz was used as a measure of noise susceptibility. 23

37 design Itoh et al, Case control study population 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 years. 496 subjects with bilateral hearing loss (hearing threshold >40 db at 4 khz) Comparison 2,807 control subjects (hearing threshold <=40 db at 4 khz for both ears) were recruited from the participants. Confounders controlled Age, sex, laboratory testing, BMI, lung function. Exposure to noise is not mentioned in the report. Results Ex-smokers: OR=1.22 ( ) Current smokers: OR=2.10 ( ) <20 cigarettes/day OR=2.23 ( ) >=20 cigarettes/day OR=2.01 ( ) Brinkmann index: 0: OR= : OR=1.27 ( ): : OR=1.37 ( ); >=800: OR=1.76 ( ) Notes Trend analysis of different doses of smoking exposure was reported. Cross-sectional studies Mizoue et al 50 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 additive 50. The study reported on by Burr et al 17 is based on the data from the Danish Work Environment Cohort. 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

38 Cocchiarella et al 51 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 insignificant 51. Two reports by Palmer et al 52,53 are based on a postal survey carried out in 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 significance 52. 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 neversmokers 53. Starck et al 18 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 Rampal 54 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 s (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

39 Cunningham et al 55 studied the differences in extra-high-frequency (EHF) auditory sensitivity at 18 khz between young smokers and non-smokers (aged 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 al 56, smoking was found to be a strong risk factor for hearing loss (OR=49.49, ) 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 design population Comparison Confounders controlled Results Notes Mizoue et al, Crosssectional study 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 Non-occupational noise exposure and medical history e.g. head injury and acoustic diseases were not taken into account owing to lack of information. No association was found for hearing loss at 1 khz. Hearing loss at 4kHz: Non-smokers with noise exposure PRR=1.77 ( ) Smokers without noise exposure PRR=1.57 ( ) Smokers with noise exposure PRR=2.56 ( ) Ex-smokers excluded; hearing loss defined as >25 db at 1 khz, or >40 db at 4 khz Dose-response relationship between cigarettes/day and hearing loss Burr et al, Crosssectional study Based on the Danish Work Environment Cohort ; 7,221 workers aged years without head injury. Sub 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 ( ) Current: <15g/day: OR=1.60 ( ) Current: >=15g/day: OR=1.81 ( ) Females: Former: OR =1.05 ( ) Current: <15g/day: OR=0.90 ( ) Current >=15g/day: OR=1.52 ( ) Self-reported data including hearing loss Five-year incidence of hearing loss 26

40 design Cocchiarella et al, Crosssectional study population 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) Comparison Confounders controlled Results Never-smokers Age Result was reported as ageadjusted regression coefficient between AVE468 and smoking status: (95% CI: to 0.20) Unadjusted regression coefficient between AVE and smoking status: -7.7 (95% CI: to -4.7) Notes 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. Palmer et al, Crosssectional study 22,194 adults of working age randomly selected from the registries of 34 British general practices, aged years Ever-smokers Never-smokers PR was mutually adjusted and adjusted also for age (in three bands). Prevalence ratio (PR) of severe hearing difficulty (severe difficulty in hearing or cannot hear at all, and/or use of hearing aid) Males PR =1.3 ( ) By questionnaire 58% response rate Analysis of smoking was limited to those aged years. Females PR =0.9 ( ) Palmer et al, Crosssectional study 21,201 adults randomly selected from the registries of 34 British general practices, aged years 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: Never-smokers: PR=4.6 ( ) Hearing difficulty was assessed by question in questionnaire 58% response rate. Former smokers PR=5.9 ( ) Current smokers PR=5.8 ( ) Starck et al, 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. 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. 27

41 design Noorhassim and Rampal, Crosssectional study population 263 rural village males aged 16 years and older in Malaysia Smokers aged years (Group II) Non smokers aged 41 years and older (Group III) Smokers aged 41 years and older (Group IV) Comparison Non-smokers aged years (Group I) Confounders controlled Apart from age (stratified), other risk factors or confounders were not analysed. Results Prevalence rate ratio: II/I=1.7 III/I=4.3 IV/I=7.5 IV/III=1.7 (calculated from data reported) Prevalence rate (both ears) by pack-years: Notes Hearing impairment: average threshold level at 0.5, 1, 2 and 3 khz was 25 db and above. 0 pack-years: 11.0% 1-10 pack-years: 13.6% pack-years: 25.6% 21 and above: 50% Cunningham et al, Crosssectional study 25 adult smokers and 18 smokers aged 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. At 18 khz, 88% of the nonsmokers and 66% of the smokers responded to stimulus. Young age s studied; exposure dose was not reported. Small sample size Other study Dengerink et al 57 report on an experimental study of temporary threshold shift (TTS) in 18 students (aged 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, for example years of smoking history. There is also a lack of information on hearing threshold levels at the baseline for both the study s 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

42 area 58. 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 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

43 4.3 Genetic factors 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 loss 59. 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 noise 60. Currently, some genetic studies on human noise-induced hearing loss have been reported and are included in this review 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 al 19 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

44 However, the protective effect could not be confirmed by a case control study reported by Carlsson et al 61. 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 s. 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 al 62 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 al 56 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

45 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 design population Comparison Confounders controlled Results Notes Rabinowitz et al, Crosssectional study 77 volunteer workers exposed to noise above 85 db(a); males and females, aged years GSTM1 and GSTT1 status Age, gender, race and years of noise exposure High frequency audiometric average (standard test, negative coefficient indicates protective effect): 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. 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. 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, Case control study 1,261 noiseexposed workers at two paper pulp mills and one steel factory in Sweden; males only Majority (79%) of the subjects in the study were exposed to noise for years. The most susceptible (n=103) The most resistant (n=112) Stratified analysis by age and noise exposure level Null genotype: GSTM1: Susceptible : 51.4% ( %) Resistant : 47.7% ( %) p=0.68 GSTT1: Susceptible : 12.2% ( %) Resistant : 7.5% ( %) p=0.37 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) In addition, there were no significant differences between the s in 14 SNPs in the genes CAT, SOD, GPX1, GSR and GSTP1. 32

46 design Konings et al, Case control study population 1,261 noiseexposed workers at two paper pulp mills and one steel factory in Sweden Approx. 1,100 male workers were finally included in the study, and approx. 4,500 male Polish workers from different industries. The most susceptible (104 Swedish workers and 347 Polish workers) Comparison The most resistant (114 Swedish workers and 338 Polish workers) Confounders controlled Age and noise exposure level Results SNP 5 (rs494024), CAT gene: 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). 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. Notes 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. 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, 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 ( ) SOD2 IVS3-23T/G, IVS3-60T/G polymorphisms: OR=5.09 ( ) 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 ( ) Smoking: OR=49.49 ( ) 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

47 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 loss Van Laer et al 65 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 al 64 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 study 65. 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 design population Comparison Confounders controlled Results Notes Van Laer et al, Case control study 1,261 noiseexposed workers at two paper pulp mills and one steel factory in Sweden; males only Majority (79%) of the subjects in the study were exposed to noise for years. 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 (rs , rs or p.s38g and rs or p.d85n) of KCNE1 genes were found to be statistically different between the two s of subjects in allele, genotype and haplotype frequencies. One SNP (rs163171) of KCNQ1, and one SNP (H455Q) of KCNQ4 were found to be statistically different between the in the allele frequency. Swedish workers: hearing threshold levels (HTL) of the left ear at 3 khz as a measure of noise susceptibility Extreme sampling (most susceptible and most resistant subjects) 34

48 design Pawelczyk et al, Case control study population 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 Comparison Most resistant subjects based on the mean hearing thresholds for the left ear at 4 and 6 khz; 119 controls Confounders controlled Age and noise exposure level Results The most prominent results were obtained for one SNP (rs ) in the gene of KCNE1, and one SNP (Q455H, rs ) in the gene of KCNQ4. Rs : OR=1.549 ( ), which was similar to the effect in a Swedish sample set 65 Rs : OR=2.030 ( ). The result of this SNP was also significant in a Swedish sample set 65 but with opposite direction of the association (Figure 3 in the paper). Rs (SNP1) in GJB2: OR=2.064 ( ; p=0.012) Notes Extreme sampling (most susceptible and most resistant subjects) 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 noise 63,66,67. In animal studies, hsps can condition the ear to withstand effects of loud noise and protect the ear from hearing loss 67. They are named according to their molecular weight (kilodaltons e.g. hsp70). Yang et al 67 genotyped three polymorphisms in the hsp70-1 (rs ), hsp70-2 (rs ) and hsp70-hom (rs ) 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 and the normal, 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. This study suggests that some haplotypes of the hsp70 genes may be associated with a higher susceptibility to hearing loss 67. In the case control study reported by Konings et al 66, three polymorphisms (rs , rs and rs ) in hsp70 genes were genotyped in 206 Swedish and 238 Polish DNA samples of noise-exposed workers. The study found rs in hsp70-hom to be significantly associated with hearing loss in both sample sets. Moreover, rs and rs were significant in the Swedish sample set but not in the Polish sample set. The 35

49 authors of this study also suggest that hsp70 genes may be hearing loss susceptibility genes, but further functional studies are required to confirm this finding 66. 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 design population Comparison Confounders controlled Results Notes Yang et al, Case control study 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. Haplotype analysis (compared with Hap1 AAA): Mean HTL in low frequency (0.5, 1 and 2 khz), and high frequency (4, 6 and 8 khz) Hap5 (ABA i.e. +190A/+1267B and +2437A) was significantly higher in the hearing loss (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 (p=0.005; the haplotype was not found in the control). Konings et al, 2009b 66 Case control study 1,261 noiseexposed workers at two paper pulp mills and one steel factory in Sweden Approx. 1,100 male workers were finally included in the study, and 3,860 male Polish workers from different industries. 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, rs in gene HSP70-1; rs in HSP70-2; and rs in gene HSP-hom Rs : OR=0.99 ( ), in the Polish sample set; OR=0.61 ( ) in the Swedish sample set Rs : OR=1.21 ( ), in the Polish sample set; OR=1.63 ( ) in the Swedish sample set Rs : OR=1.75 ( ), in the Polish sample set; OR=2.09 ( ) 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 al 68 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 (rs ) was 36

50 significantly associated in both sample sets. Two SNPs in MYH14 (rs 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 function 68. 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 polarity 68. 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 al 45 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 design population Comparison Confounders controlled Results Notes Konings et al, 2009a 68 Case control study 1,261 noiseexposed workers at two paper pulp mills and one steel factory in Sweden Approx. 1,100 male workers were finally included the study, and 3,860 male Polish workers from different industries. 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: Rs located in PCDH15 gene; rs and rs in MYH14 gene Rs : OR=1.66 ( ), interaction P value=0.026 in the Polish sample set OR=2.076 ( ), interaction P value=0.001 in the Swedish sample set Rs667907: 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) OR=1.828 ( ), interaction 37

51 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 ( ), interaction P value=0.021 in the Polish sample set OR=0.399 ( , 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. design Carlsson et al, Case control study population 1,261 noiseexposed workers at two paper pulp mills and one steel factory in Sweden Approx. 1,100 male workers were finally included the study. 10% most susceptible (n=103; hearing threshold level considered) Comparison 10% most resistant (n=112; hearing threshold level considered) Confounders controlled Separately tested in univariate analysis Results For mutations in C x 26 and C x 30, no significant difference between the resistant and susceptible s was observed. The fraction of heterozygous mutation carriers of C x 26 and C x 30 was not significantly different between both s. The incidence of the null-genotype of the GSTM1 gene was 51.4% and 47.7% in the noise-susceptible and noise-resistant s respectively. Notes Hearing threshold of left ear at 3 khz was used as a measure of noise susceptibility. 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 s. 38

52 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

53 4.4 Organic solvents Background Organic solvents are a large 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 years 69,70. Potential ototoxic effects of some organic solvents have also been investigated in recent years 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 al 25,74 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 s (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 al 27 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/m 3 (0.037 ppm) to 919 mg/m 3 (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) ) 40

54 and 1.76 times greater for each gram of hippuric acid per gram of creatinine (95% CI ). 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 al 75 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 ppm in the adhesive division. This study found that the prevalence of hearing loss of > or =25 db in the toluene plus noise (86.2%) was much higher than in the comparison s 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 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 design Schaper et al, Schaper et al, Cohort study population 333 rotogravure printing workers in Germany, followed up over five years ( ) High toluene exposure (average 25.7 ppm) Mean noise exposure 81.1 db(a) Comparison Low exposure (average 3.2 ppm) Mean noise exposure 81.6 db(a) Confounders controlled Age and noise exposure levels Results ANOVA analysis: Distribution of the cases was not significant between toluene exposure level and duration. 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, ). Notes 64.9% (216/333) completed at the follow-up the examination 4 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

55 design Morata et al, Crosssectional study population 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 Air toluene level ranged from to ppm; 8% of workers urinary hippuric acid levels were higher than 2.5 g/g creatinine. Noise exposure level db(a) Comparison Confounders controlled Age, tenure, noise exposure and repeated ear infections were significant in a stepwise logistic regression approach. Results Multiple logistic regression: Age (year): Beta=0.07, p=0.0003; OR=1.07 ( ) Biological exposure index (hippuric acid g/g creatinine): Beta=0.57, p=0.0338; OR=1.76 ( ) No significant interactions were found between solvents and noise. Notes 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. Small sample size Chang et al, Crosssectional study Male workers in a plant with an adhesive materials manufacturing section in Taiwan; average age years Workers exposed to toluene and noise (n=58) Average toluene levels: see text Noise level: db(a) 1. Workers exposed to noise only (n=58); noise level: db(a) 2. Administrative workers not exposed to toluene and significant noise (n=60?); noise level: db(a) Age, smoking, drinking and hearing protection use Logistic regression model 1 (0.5 khz included): Administrative: OR=1.0 Noise only: OR=12.8 ( ) Toluene and noise: OR=140 ( ) Logistic regression model 1 (0.5 khz excluded): Administrative: OR=1.0 Noise only: OR=5.0 ( ) Toluene and noise: OR=29.1 ( ) Air sample of toluene only Small sample size; overlaps on the ORs between noise only and toluene +noise 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/m 3 (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 studies 27,75. The risk effect may not be seen when the toluene exposure level is lower than 50 ppm 25. 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

56 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 al 77 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 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 al 30 report on a cross-sectional study of 299 workers in the fibre-reinforced plastics manufacturing industry. These workers were exposed to styrene (arithmetic mean 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 al 26 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 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

57 millimole of mandelic acid per gram of creatinine in urine (95% CI, ). This study suggests that exposure to styrene even below recommended values had a toxic effect on the auditory system. Sliwinska-Kowalska et al 28 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 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 al 78 also report on a cross-sectional study based on the same s of workers as studied by Morata et al 26. 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 al 79 report the otoneurological findings of 18 Swedish workers who were exposed to styrene with air concentrations in a range of mg/m 3 ( 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

58 Table 11: Summary of the studies on the association of styrene and noise-induced hearing loss design population Comparison Confounders controlled Results Notes Morioka et al, Crosssectional study 115 male workers in seven Japanese factories that produced plastic buttons or baths (22 workers excluded) Sub of 54 workers exposed to solvent for more than five years, and mandelic acid >0.3 g/l ( A) Sub of 54 workers exposed to the solvent for more than five years, and mandelic acid =<0.3 g/l ( 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). Significantly more workers in A had the upper hearing limit below 75th percentile curve compared with B (p<0.01). Upper limit of hearing testing, stimuli from 0.5 to 50 khz, output sound pressure level 75 db within khz. It was the frequency that the subjects first perceived as a tone. Sass-Kortsak et al, Crosssectional study 299 male workers in glass fibrereinforced plastic manufacturing industry, Canada Directly exposed: TWA styrene 58.6 (geometric) or (arithmetic) mg/m 3 ; noise 88.1 db(a) (Leq) Indirectly exposed: TWA styrene 12.8 (geometric) or 36.0 (arithmetic) mg/m 3 ; noise 89.2 db(a) (Leq) Not exposed: TWA styrene 1.7 (geometric) or 10.7 (arithmetic)mg/ m 3 ; 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 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). 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. Morata et al, Crosssectional study the same study subjects as Johnson et al s study 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) Styrene exposures never exceeded the Swedish limits, which are among the world s lowest (90 mg/m 3 ; or 20 ppm). 78 workers exposed to noise in metal products manufacture 81 workers without exposure to styrene and noise from the mail distribution terminal Age, noise exposure (which were significant in logistic regression model) and other variables One-way ANOVAs: 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 (33%). Logistic regression analysis: Mandelic acid in urine (1 mmol or 152 mg per gram of creatinine in urine): Beta=0.89; p= (OR=2.44, ) Current noise (db above 85 db): Beta=0.17; p= (OR=1.18, ) Age (year): Sample size Historical noise exposure in the control Lower level exposure in styrene Case definition: >25 db at any tested frequency Beta=0.18; p= (OR=1.19, ) 45

59 design Sliwinska- Kowalska et al, Crosssectional study population 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 Styrene levels: mg/m 3 (mean 61.8 mg/m 3 ) Comparison 223 workers unexposed to solvents, including some exposed to noise (>85 db(a)) Confounders controlled Age, gender, noise exposure currently and historically Results Multiple logistic regression analysis: Age: Beta =0.10, p<0.001; OR=1.1 ( ) Current noise exposure (unit?): Beta=0.067, p<0.01; OR=1.1 ( ) Styrene exposure (unit?): Beta=1.35, p<0.01; OR=3.9 ( ) Sub analysis: Non-exposure: OR=1; Noise only: OR=3.3 ( ) Styrene only: OR=5.2 ( ) Styrene and noise: OR=10.9 ( ) Styrene and toluene: OR=13.1 ( ) Styrene and toluene and noise: OR=21.5 ( ) Notes Audiometry testing carried out in office where noise was <30 db. 1-8kHz tested, HTL>25db defined as abnormal. Sample size in subs (see 95% CIs) Effect on HTL was seen in all frequencies, especially in 6 and 8 khz. Interactions between exposures? Case: HSL>25 db Johnson et al, 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 81 workers without exposure to styrene and noise from the mail distribution terminal 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 s including the control. Compared with median and the 90th percentiles of non-occupationally noise-exposed Swedish population: Significantly greater proportions than expected in both the styrene-exposed s for the worst ear at 4 khz (p<0.001) and 8K (p<0.01) Confounding effects? Errors in table 1. Note: New Zealand workplace exposure standard: styrene 50 ppm or 213 mg/m 3 (time-weighted average); 100 ppm or 426 mg/m 3 (short-term exposure limit) 76 Most included studies indicate that exposure to styrene is associated with a risk of developing hearing impairment. One study 28 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

60 Mixtures of solvents Morioka et al 80 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 s. Apart from using standard upper limit age curves, potential confounders were not controlled in this study. Sliwinska-Kowalska et al 29,31,81 report on three studies investigating the association between hearing impairment and exposure to a mixture of solvents and noise. The first study 81 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/m 3 (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 ), the relative risks (RR) of hearing loss in the solvent-only exposure and both solvent and noise-exposed were significantly increased, but no significant difference was found between the two exposed s. Hearing thresholds were significantly poorer in a wide range of frequencies (1-8 khz) for both s exposed to solvents, when compared with the reference. The mean hearing thresholds at frequencies of 2-4 khz were poorer for workers exposed to solvents and noise than for the solvent-only ; this finding suggests an additional effect for noise. In general, no significant dose-response relationship was found in the 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

61 The second study 31 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/m 3 ( ppm) and mg/m 3 ( 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 and by almost five times in the noise and solvent. At 8 khz, the hearing threshold in the noise and solvent was significantly worse than the threshold in the noise-only. 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 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 study 29 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 ppm for xylene, ppm for styrene, ppm for n-hexane and 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 (xylene as the main component), and the highest in the n-hexane and toluene exposed. Significantly increased ORs were found in the s 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 noise 29. Rabinowitz et al 82 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

62 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 loss 82. 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 design Morioka et al, Crosssectional study population 54 male workers aged years in a Japanese plastic buttons factory. Combined (n=23): exposed to styrene ( ppm), methanol ( ppm) and methyl acetate ( ppm); noise db(a) Noiseexposed (n=19): db(a) Comparison Control : office workers (n=12), noise exposure db(a) Confounders controlled None Results Percentage of cases where the upper limit of hearing falls below 75th percentile of standard age curve: Combined : 50% Noise exposed and control s: 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. Conventional audiometry testing: No difference of HTL between the s. Notes Small sample size, 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. Sliwinska- Kowalska et al, Crosssectional study 517 workers in four Polish paint and lacquer enterprises. Solventexposed workers, including those exposed to noise =<85 db(a) (n=207) Solvent and noise (>85 db(a)) exposed workers (n=96) Primarily whitecollar workers without hazardous noise or organic solvent exposure (n=214) Noise exposure level Age and gender were adjusted in logistic regression model. Solvent exposure: RR=2.8 ( ) Solvent and noise exposure: RR=2.8 ( ) Logistic regression model ORs were significant in frequencies of 2, 3, 4, and 6 khz in both solvent only and solvent + noise exposure s. However, there appears to be some overlaps of 95% CIs between the s (reported in Figure 1) 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??? Linear regression model Mean HTL was higher in the solvent and noise at 3 and 4 khz than solvent only. Linear correlation was found between some exposure indices (toluene) and HTL at single frequencies only. 49

63 design Sliwinska- Kowalska et al, Crosssectional study population Dockyard workers exposed to solvents and/or noise. Workers exposed to both noise (mean exposure 94.2 db(a)) and solvents (mean xylene mg/m 3 ; toluene 28.9 mg/m 3 ); 517 workers Workers exposed to noise only (mean 90.1 db(a)); 184 workers Comparison White-collar workers not exposed to noise and solvents; 205 workers Confounders controlled Age, tinnitus and current exposure to noise were significant in the logistic regression model. Results By study : Noise exposed : OR=3.34 ( ) Noise and solvent exposed : OR=4.88 ( ) All subjects: Age (years) OR=1.12 ( ) Lifetime noise exposure (db(a)) OR=1.07 ( ) Lifetime exposure to solvents (index numeric values) OR=1.004 ( ) Notes Audiometric testing at 1, 2, 3, 4, 6 and 8kHz, HTL<25 db was defined as normal. Significant linear relationship between age and hearing loss at all frequencies tested. Sliwinska- Kowalska et al, 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 db(a); 731 workers) Styrene exposed (noise db(a); 290 workers) n-hexane and toluene exposed (noise db(a); 96 workers) 157 workers exposed to neither solvent nor to noise and 66 workers exposed to noise only ( db(a)) Age, gender and current exposure to noise (solvent mixture exposure, and n- hexane and toluene ), or post noise exposure (styrene ) Solvent mixture exposure: OR=2.4 ( ); HL was seen at 4, 6. 8 khz Styrene exposure : OR=3.9 ( ); HL was seen at 3-8 khz (right ear) and whole spectrum of frequencies (left ear) n-hexane and toluene OR=5.3 ( ); HL was seen at 4, 6. 8 khz Sub analysis (figure 1): Noise exposure only: OR=3.8 Noise + solvent mixture exposure: OR=6.7 Noise + styrene exposure : OR=10.9 <=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. Noise + n-hexane and toluene OR=20.2 Noise +styrene + toluene OR=

64 design Rabinowitz et al, Retrospective cohort study population 1,359 workers in five locations of Alcoa Inc, who were 35 years of age or younger in 1989, with a minimum of 4-6 years of audiometric follow-up, and at least three audiograms performed during the period; eight hour timeweighted average 82 db(a) or greater. 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). 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. Comparison Others Confounders controlled Age, shooting or hunting, noisy hobbies, baseline hearing status Results Solvent exposed Dichotomous outcome (>1dB/yr) OR=1.97 (1.22 to 2.89) Continuous outcome (db/yr) Β coefficients =0.58 (p<0.001) Notes Respective cohort in aluminium industry 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). Note: New Zealand workplace exposure standard: xylene 50 ppm or 217 mg/m 3 (time-weighted average); n-hexane: 20 ppm or 72 mg/m 3 (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. Morata 83 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

65 considerable lack of information on exposure assessment and detailed statistical analysis in this study. Potential confounders appear to have not been controlled. Chang et al 84 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 ( ppm) had a higher prevalence of hearing loss (67.9%) than the comparison s 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 design population Comparison Confounders controlled Results Notes Morata, Crosssectional study Workers in a rayon factory in Brazil 53 volunteers and 205 randomly selected workers; exposed to noise (range db(a)) and excessive levels of carbon disulphide (89.92 mg/m 3 or 29 ppm) None None Percentage of hearing loss (I-IV) by year of exposure to noise and carbon disulphide: 0-2 yrs: 46.7% 3-5 yrs: 70.6% 6-10 yrs: 71.8% 11+ yrs: 69.3% Pure-tone audiometry testing at 0.5, 1, 2, 3, 6 and 8 khz 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 Chang et al, Crosssectional study Male workers in a plant manufacturing viscose rayon in Taiwan, and workers in adhesive tape and electronics industries Workers exposed to CS 2 (range ppm) and noise (80-91 db(a)); 131 workers Workers exposed to noise (83-90 db(a)); 105 Administrative workers in the plants with low noise exposure (75-82 db(a)); 110 workers Age, noise exposure level, smoking, drinking and the use of personal protection equipment By study : Administrative: OR=1.0 (control) Noise only: OR=1.5 ( ) Noise and CS 2 : OR=6.8 ( ) By CEI of CS 2 : <37 yr ppm: OR=0.8 ( ) yr ppm: OR=3.8 ( ) yr ppm: OR=14.2 ( ) yr ppm: OR=70.3 ( ) HTL testing at 1, 2, 3, 4, 6, 1 and 0.5 khz, >25 db in worst ear defined as hearing loss Without exposed to CS 2 only 52

66 workers >483 yr ppm: OR=74.5 ( ) Note: New Zealand workplace exposure standard: carbon disulphide 10 ppm or 31 mg/m 3 (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 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

67 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 previously 72,85. 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

68 4.5 Carbon monoxide (CO) 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 monoxide Carbon monoxide may have an impact on the development of hearing loss possibly by oxidative stress and related neurotoxicity and potential ototoxicity 2,89. 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 study 87. Young et al 90 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 study 90. The concentration of CO level used in the study was relatively high and may not be found in the current working environment Studies identified Only an epidemiological study on occupational exposure to carbon monoxide and hearing loss was found 82. There are also some case reports in relation to non-occupational carbon monoxide poisoning and hearing loss. 55

69 Rabinowitz et al 82 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/m 3, 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 significant 82. 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) 91 and New Zealand workplace exposure standards 76. Morris 92 reports on a case of hearing loss following acute CO poisoning from a faulty anthracite-burning stove in 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 later 92. A case of temporary hearing loss in a six-year-old boy was reported in the UK 93. The puretone audiogram showed a bilateral sensorineural hearing loss with sparing at 4 khz (HTL between 20 and 40 db, frequencies of 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 al 94 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 al 95 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

70 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 journals 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

71 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 epidemiology 99, 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

72 relationship between solvent exposure and hearing loss, for example to directly measure the incidence in different levels of exposure dose. Only one cohort study 82 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 frequencies 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

73 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 effects 81. 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 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

74 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 priority

75 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 conditions 2,16,20,48, 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

76 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

77 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

78 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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87 Appendix: Literature search strategy 1 Occupational deafness/ 2 noise-induced hearing loss.ti,ab,kw. 3 industrial deafness.ti,ab,kw. 4 hearing loss, noise-induced/ 5 (industrial adj4 hearing loss).mp. 6 (occupational adj4 hearing loss).mp. 7 or/2-7 8 exp risk factors/ 9 ototoxic$.ab,ti,kw or and remove duplicates from 12 74

88 75