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