Document Nqx2r5GggqvQ2nZwqYXKqwaV

310 M. Goodman et al. Downloaded from http://annhyg.oxfordjournals.org by on July 28, 2010 brakes typically contained chrysotile asbestos embedded in a solid binder.) The process of brake replacement involves two potential opportunities for release of asbestos fibers: (i) small amounts of chrysotile asbestos (usually less than 1%) that may be present in the brake wear debris and (ii) asbestos that can be released during grinding and beveling of new asbestos brake linings or pads. Some authors (Lorimer et al., 1976), regulatory agencies (EPA, 1986c) and trade organizations (World Trade Organization, 2000) have opined in the past that motor vehicle mechanics are likely to be at increased risk of developing asbestos-related disease, most notably mesothelioma. These opinions have been based primarily on the fact that asbestos expo sures can occur during brake work and cases of mesothelioma have been reported among workers who had done brake repair (EPA, 1986a,b,c). When the EPA conducted its evaluation (EPA, 1986b,c) the epidemiological information on mesothelioma among vehicle mechanics was limited to only three studies (McDonald and McDonald, 1980; Teta et al., 1983; Spirtas et al., 1985). However, in more recent years a number of addi tional epidemiological studies have examined the risk of mesothelioma and/or lung cancer among motor vehicle mechanics or specifically among brake workers. These studies are preferable to case reports and case series in assessing associations between exposure and disease. We conducted a systematic review of the epidemi ological literature examining the relative risks of mesothelioma and lung cancer among workers engaged in motor vehicle repair and, when possible, among workers occupationally exposed to brake dust. A previous review of the literature examined six case-control studies of mesothelioma among garage mechanics (Wong, 2001). However, we felt that these analyses could be enhanced by including additional published and unpublished studies and by including a re-analysis of one of the original data sets. In addi tion, we expanded the scope of our review beyond mesothelioma to include studies of lung cancer. This issue is of growing scientific, public health and societal importance (Schneider and Smith, 2000; Truby, 2002). Large numbers of people have been exposed to brake dust over the last several decades (Lorimer et al., 1976; Nicholson et al., 1984; Huncharek, 1990) and an increased risk of asbestosrelated cancers among these workers could translate into a substantial burden of disease. METHODS Study selection A number of electronic literature databases were searched using a variety of search strategies and multiple combinations of keywords such as `asbestos', `brakes', `mesothelioma', `lung cancer', `cancer', `garage mechanics', `automobile mechanics', `motor mechanics', `mechanics', etc. Copies of the articles were obtained, including those from foreign language journals, which were trans lated into English. Reference lists of identified arti cles were examined to locate additional studies. Internet and literature searches were also conducted to identify relevant studies that were not published in the peer-reviewed literature. Of partic ular interest were government documents and book chapters. When information was missing from published reports, attempts were made to contact the authors to obtain the missing information. In order to be included in the review, studies were required to meet all of the following criteria: outcomes of interest included mesothelioma and/or lung cancer; relative risk estimates and associated variance measures were either reported by the authors or could be calculated based on the data obtained from the authors or reported in the papers; the exposed population was involved in motor vehicle repair, excluding general mechanics. After this initial study selection, the meta-analysis included two steps: (i) a review and quality scoring of each study and (ii) a quantitative analysis of the pooled measures of association from studies that met the inclusion criteria. Review of the literature All potentially relevant studies underwent a formal evaluation and were assigned a quality score according to their methodological strengths and weaknesses. The general approach involved awarding each study a point (+1) for each methodo logical strength and penalizing with a negative score (-1) for each evident shortcoming. The quality scoring was conducted according to the following criteria. Overall study design: proportionate mortality/ incidence ratio (PMR/PIR) studies or death cer tificate-based standardized mortality odds ratio (SMOR) studies = -1; else (cohort or case-con trol studies) = 0. Asbestos exposure: non-specific = 0 (e.g. `car mechanic'); specific = 1 [e.g. `brake repairmen' or industrial hygiene (IH) based]. Age adjustment: no = -1; yes = 0. Confounding by other occupational exposure: likely = -1 (e.g. studies where motor vehicle mechanics with other multiple occupations were compared with persons with no history of any atrisk occupations); possible but not clearly evi dent = 0; unlikely/addressed = 1 (e.g. studies that Mesothelioma and lung cancer among motor vehicle mechanics 311 Downloaded from http://annhyg.oxfordjournals.org by on July 28, 2010 accounted for other known at-risk occupations in the analysis). Exposure-response analysis: no = 0; yes = 1. Analysis by latency: no = 0; yes = 1. For case-control studies: response rate <80% or not reported = -1; >90% = 1; else = 0. For cohort studies: follow-up: <10 years = -1; >20 years = 1; else = 0. Reporting bias: likely = -1 (e.g. interview-based case-control studies with clear differences in terms of sources of information between cases and controls); possible but not clearly evident = 0; unlikely/addressed = 1 (e.g. in case-control studies using recorded occupational histories). Selection bias: likely = -1 (e.g. due to reliance on referral of cases to a clinic or using inappropriate controls); possible but not clearly evident = 0 (e.g. in hospital-based case-control studies); unlikely/addressed = 1 (e.g. in cohort studies or population-based case-control studies). In addition to the above criteria, mesothelioma studies were evaluated based on whether or not the diagnoses were confirmed by a pathology review (i.e. + 1 if yes, 0 if no). Lung cancer studies were also eval uated based on their ability to adjust results for smoking habit. Studies that did not control for smoking received a negative score (-1), studies that adequately controlled for both smoking status (current, former or never) and intensity (duration and/or number of cigarettes per day) received a posi tive score (+1) and studies that had only partial control for smoking (e.g. using only ever-never cate gories, only pack-years or using blue collar/internal reference groups) were neither penalized nor rewarded. The scoring was used as a formal approach to clas sify all studies into three tiers. Tier III included studies that had an overall negative score (i.e. less than 0) and were considered unreliable. These studies were only mentioned for completeness and were not included in the meta-analysis. Those studies that had scores of zero or above were divided into two approx imately equal groups. Studies with the higher (above median) total score were included in Tier I and considered most informative. Tier II included the remaining studies that received a total score of >0 but were considered less useful due to methodological shortcomings. Statistical analysis We calculated a meta relative risk (meta-RR) for Tiers I and II separately, followed by stratified anal yses of both tiers combined, based on study design or exposure characterization and, for lung cancer studies, based on adequate adjustment for smoking. The necessary input from each study included (i) an RR estimate and (ii) the associated measure of variance, which usually can be derived from the 95% confidence interval (95% CI). When case-control studies did not report the results in terms of RRs but did provide information necessary to reconstruct the two-by-two tables, the odds ratios (ORs) and 95% CIs were calculated using Epi Info software (CDC, 2001). Some cohort studies did not report 95% CIs, but did provide information on the numbers of observed and expected cases. In those instances, 95% CIs were calculated based on the Poisson distribution, as recommended by Breslow and Day (1987). In one study (Morabia et al., 1992), the information needed to calculate 95% CIs was not provided. However, we were able to calculate the standard deviation based on the information that there were 39 exposed controls (1.2% of all controls) and the statis tical power to detect an OR of 1.5 was 0.41, as reported by the authors. There are two general approaches for combining the data in a meta-analysis: a fixed effects model or a random effects model. The fixed effects method assumes no heterogeneity among studies and attributes all observed variations among results to sampling error alone (Sutton et al., 1998). The random effects model assumes that the study-specific effect sizes arise from a random distribution of effect sizes with a certain mean and variance. All analyses involved a test for heterogeneity. However, the interpretation of the test for heteroge neity is problematic because of the wide variation in study designs, study populations and reference groups. Therefore, we used both the fixed and random effects models for each analysis. Where the variability among studies was negligible (high level of homogeneity), the random effects model reduced to a fixed effects model (Sutton et al., 1998). The details of calculations for both models are provided in the Appendix. RESULTS Mesothelioma Overview of the literature. Relative risk estimates could not be calculated for three cohort studies of motor vehicle mechanics (two from Sweden and one from Denmark) that provided information on mesothelioma (Jarvholm and Brisman, 1988; Hansen, 1989; Gustavsson et al., 1990). For this reason, these studies could not be included in the meta-analysis. These three cohort studies combined reported three observed cases of mesothelioma and one case of `pleural cancer'. All three mesothelioma cases had other potential occupational asbestos expo sures. For the remaining case of pleural cancer, infor mation regarding other exposures was not provided. 312 M. Goodman et al. There were 11 studies that reported (or permitted calculations of) the relative risk estimates for mesothe lioma. These studies underwent formal evaluation and scoring. The results of scoring for each study are presented in Table 1. Four studies were included in Tier III (Coggon et al., 1995; Hodgson et al., 1997; Milham and Ossiander, 2001; NIOSH, personal communication, 2002). Of the seven remaining studies, four studies with scores between 3 and 5 were included in Tier I (Table 2A) and three studies with scores between 0 and 2 were included in Tier II (Table 2B). All relevant studies were published in English. Two studies were conducted exclusively in the USA, one study was conducted in Canada, one combined US and Canadian data and three took place in Europe (one in Germany, one in Denmark and one in Spain). The years of publication ranged from 1980 to 2004. A more detailed discussion of each Tier I and Tier II study follows. Tier I. McDonald and McDonald (1980). The study here compared histologically confirmed mesothelioma cases to matched controls who had pulmonary metastases from non-pulmonary malignancies. Occupa tional histories obtained through interviews with relatives were ranked according to their potential for asbestos exposure. Of the 156 cases and 156 controls without a recognized increase in mesothelioma risk, the occupation `garage' was reported for 11 cases and 12 controls, from which we calculated an OR of 0.91 (95% CI 0.35-2.34). This study had a large sample size, a high response rate and used pathologists to establish the diagnosis of mesothelioma. The use of non-pulmonary cancers as controls has both advantages and disadvantages. Hospital-based cancer cases may not be representa tive of the general population (i.e. possible selection bias). However, the choice of controls with other cancers may have reduced recall bias. The use of the highest asbestos exposure to characterize each partic ipant's occupational history helped decrease poten tial confounding by other asbestos exposures. However, the occupational category defined as `garage' is insufficiently specific. Teta et al. (1983). After a pathology review, cases from the Connecticut Tumor Registry and from a large Veterans Administration hospital were compared with controls selected from the death certificate files of the Connecticut State Department of Health Services. Occupational histories for cases and controls were obtained from death certificates and from city directories. The OR for subjects employed in `automobile repair and related service' was 0.65 (95% CI 0.08-5.53). Unlike other case-control studies, Teta et al. (1983) relied on objective historical employment information rather than subjective reports from inter views. The choice of population controls, the high response rate and the histological confirmation of the mesothelioma diagnoses have to be considered as methodological strengths. The main shortcomings are non-specific exposure characterization and the inability to eliminate other exposures due to its small size. Downloaded from http://annhyg.oxfordjournals.org by on July 28, 2010 Table 1. Quality scores of studies evaluating the association between mesothelioma risk and employment as a motor vehicle mechanic Quality criteria Study 1 2 3 4 5 6 7 8 9 10 11 Overall study design: PMR/PIR/SMOR = -1; else = 0 0 0 0 0 0 0 0 -1 -1 -1 -1 Asbestos exposure: non-specific (e.g. `car mechanic') = 0; specific (e.g. brake repairman, or IH-based) = 1 0 1 1 00 0 1 0 0 0 0 Age adjustment: no = -1; yes = 0 0 0 0 -1 0 0 -1 0 0 0 0 Confounding by other occupational exposure: likely = -1; possible = 0; unlikely/addressed = 1 1 11 00 0 00000 Exposure-response analysis: no = 0; yes = 1 0 1 0 00 0 0 0 0 0 0 Analysis by latency: no = 0; yes = 1 0 0 1 00 0 0 0 0 0 0 For case-control studies: response rate: <80% or not reported = -1; >90% = 1; else = 0 1 --1 0 11 1 1 0000 For cohort studies: follow-up <10 yr = -1; >20 yr = 1; else = 0 0 00 00 0 00000 Reporting bias: likely = -1; possible = 0; unlikely/addressed = 1 0 0 1 -1 1 0 00000 Selection bias: likely = -1; possible = 0; unlikely/addressed = 1 0 10 11 0 00000 Diagnosis of mesothelioma by pathology review: no = 0; yes = 1 1 11 11 0 1 0000 Total score 3 4 5 1 4 1 2 -1 -1 -1 -1 1, McDonald and McDonald (1980); 2, Hessel et al. (2004); 3, Teschke et al. (1997); 4, Agudo et al. (2000); 5, Teta et al. (1983); 6, Hansen (personal comunication, 2003); 7, Woitowirz and Rodelsperger (1994); 8, Coggon et al. (1995); 9, Hodgson et al. (1997); 10, Milham and Ossiander (2001); 11, NIOSH (personal comunication, 2002). Mesothelioma and lung cancer among m otor vehicle mechanics Table 2. Summary of mesothelioma studies and corresponding RR estimates included in the meta-analysis First author (A) Tier I studies McDonald Teta Hessel Teschke (B) Tier II studies Hansen Woitowitz Year 1980 1983 2004 1997 2003 1994 Design Exposure definition Source of cases Case-control Case-control Case-control Case-control Garage workers Hospital records Automobile repair and related services CT Tumor Registry Brake lining installation or repair NY Cancer Registry, LA County Cancer Surveillance Program, VA Hospitals Other asbestos exposures controlled Vehicle mechanics British Columbia's Cancer Registry Brake lining installation or repair Vehicle mechanics (ever employed in at risk occupations excluded) Case-control Case-control Repair of motor vehicles and motorcycles Motor vehicle repair workers Danish Cancer Registry Not specified Agudo 2000 Definitely engaged in brake service Case-control Mechanics, motor vehicles Hospital records Comparison group RR estimate (95% CI) Non-pulmonary cancers 0.91 (0.35-2.34) Connecticut decedents 0.65 (0.08-5.53) Deaths from causes other than cancer, 1.04 (0.46-2.22) respiratory disease, suicide or violence 0.82 (0.36-1.80) Randomly selected from voters lists 0.8 (0.2-2.3) 0.3 (0.0-1.4) 0.4 (0.0-3.2) All other occupations combined 0.8 (0.4-1.5) Lung resection patients and population 0.87 (0.43-1.70) controls 0.89 (0.31-2.47) Patients with non-asbestos-related conditions 0.62 (0.11-2.36) CI, confidence interval; CT, Connecticut; LA, Los Angeles; NIOSH, National Institute for Occupational Safety and Health; NY, New York; RR, estimate of relative risk; VA, Veterans Administration. 313 010Z `QZ A|nr uo Aq 6jo'S|BUjnorpjojxo'6AquuB//:d}}q luojj pspBO|UMOQ 314 M . Goodman et al. Table 3. Summary of mesothelioma studies and corresponding RR estimates not included in the meta-analysis First author Malkera Jarvholm Schiffman Hansen Gustavsson Coggon Year 1985 1988 1988 1989 1990 1995 Design Cohort Cohort Case-control Cohort Cohort Proportionate mortality RR estimate 2.4 (P < 0.01) NA (1 case) 0 (no cases, 2 controls) NA (1 case) NA (2 cases) 0.46 95% CI NA NA NA NA NA NA Hodgson Milham NIOSH 1997 2001 2002 Proportionate mortality Proportionate mortality Proportionate mortality 0.4 approximated from figure 0.75 0.81 0.3-0.7 approximated from figure 0.30-1.55 0.45-1.34 Reason for eclusion Exposure defined as `mechanics' Unable to calculate relative risk Exposure defined as `mechanics' Unable to calculate relative risk Unable to calculate relative risk Total score <0; data overlapping with Hodgson et al. (1997) PMR design; total score <0 PMR design; total score <0 PMR design; total score <0 CI, confidence interval; NIOSH, National Institute for Occupational Safety and Health; NA, not available; PMR, proportionate mortality ratio; RR, estimate of relative risk. aOf the 16 mechanics with mesothelioma in this study, only one was likely to be an auto mechanic (Blot, personal communication, 2003). 010Z `QZ A|nr uo Aq 6jo'S|BUjnorpjojxo'6AquuB//:d}}q luojj pspBO|UMOQ Mesothelioma and lung cancer among motor vehicle mechanics 315 Downloaded from http://annhyg.oxfordjournals.org by on July 28, 2010 National Cancer Institute study (Spirtas et al., 1994, 1985; Hessel et al., 2004, in press). The 1994 report of a case-control study by the National Cancer Institute (NCI) identified mesothelioma cases in the Los Angeles County Cancer Surveillance Program, the New York State Cancer Registry (excluding New York City) and 39 Veterans Administration hospitals. A pathology review was conducted in most cases. Controls included patients who died of causes other than cancer, respiratory disease, suicide or violence. The authors did not calculate ORs by occupational category because of multiple confounding exposures, preferring to discuss attributable risk of asbestos exposure in general. Among subjects engaged in `brake lining installation or repair', 33% also had shipbuilding or shipyard work and 55% had performed insulation work. In an earlier analysis of the same data, but with cases and controls matched for age, the authors did calculate the ORs for different occupational groups (Spirtas et al., 1985). Brake lining installation or repair had an OR of 1.0 (95% CI 0.6-1.6). A re-analysis of these data (Hessel et al., 2004, in press) for the occupational category `brake instal lation or repair' yielded an OR of 1.04 (95% CI 0.46 2.22). After adjusting for any of eight occupations with potential asbestos exposure, the OR was 0.82 (95% CI 0.36-1.80). When cases and controls with a history of employment in any of the eight occupa tions were removed from the analysis, the OR for occupational brake installation and repair was 0.62 (95% CI 0.01-4.71). These NCI data have several important features: (i) exposure was defined as brake installation and repair, (ii) confounding by other occupational exposures could be addressed, (iii) information on duration of employment allowed an exposure-response analysis and (iv) and the majority of the mesotheliomas underwent pathology review. A limitation of this data set is the relatively low (<80%) response rate. Teschke et al. (1997). Teschke and colleagues compared pathology-confirmed mesothelioma cases from the British Columbia Cancer Agency data to matched controls selected among provincial voters. Occupational and exposure histories were obtained, whenever possible, directly from cases and controls. The OR for `vehicle mechanics' considered as an a priori suspect occupational group was 0.8 (95% CI 0.2-2.3). The OR for the category `brake lining installation or repair' was 0.3 (95% CI 0.0-1.4). After removing cases and controls with at-risk occu pational asbestos exposures, the OR for `vehicle mechanics' was 0.4 (95% CI 0.0-3.2). The results did not change after 20 years of latency. The authors also reported that, after removal of at-risk exposures, `brake installation and repair did not appear to be associated with mesothelioma'. Although fairly small in size, this study is strong methodologically because it considered other asbestos exposures, specified exposure as `brake lining installation or repair', relied on histologically confirmed diagnoses of mesothelioma and frequency matched next-of-kin interviews among cases and controls. Unlike other studies, the analyses in Teschke et al. (1997) considered latency. Tier II studies. Olsen and Jensen (1987) and Hansen (personal communication, 2003). In 1987, Olsen and Jensen published a proportionate inci dence ratio (PIR) surveillance study that linked cases from the Danish Cancer Registry with occu pational histories (Olsen and Jensen, 1987). There were no cases of mesothelioma (pleural or perito neal) for the occupational category `repair of motor vehicles and motorcycles' and for the industry category `garage'. We contacted the authors of this study and learned that the data had been updated in a case-control study (Hansen, personal communication, 2003). For the category `repair of motor vehicles and motorcycles' the OR was 0.8 (95% CI 0.4-1.5), based on 10 cases. The weaknesses of this study are lack of histological confirmation of mesothelioma diagnosis and inability to obtain a complete work history. Its strengths include analysis by latency and a relatively large sample size. Woitowitz and Rodelsperger (1994). This German case-control study compared occupational histories of 324 pathology confirmed mesothelioma with two groups of controls: 315 hospital controls selected among patients who underwent lung resection and 182 population controls. Sixteen cases, 16 hospital controls and 12 population controls were listed as `motor vehicle repair workers'. Calculations based on these data produced an OR of 0.97 (95% CI 0.45 2.12) using hospital controls and 0.74 (95% CI 0.32 1.75) using population controls. For people definitely engaged in brake service, the OR was 0.75 (95% CI 0.25-2.23) using hospital controls and 1.32 (95% CI 0.30-6.51) using population controls. When the two types of controls were combined, the OR was 0.87 (95% CI 0.43-1.70) for motor vehicle mechanics and 0.89 (95% CI 0.31-2.47) for persons definitely engaged in brake servicing. (These calculations use updated numbers provided by the authors, Prof. H.-J. Woitowitz and Dr K. Rodelsperger, of Justus-Liebig University, Germany.) The strengths of this study are its ability to examine the association with brake repair, its high response rate and the pathology review of cases. The most important shortcomings include the lack of adjust ment for age and an inadequate description of subject selection. Downloaded from http://annhyg.oxfordjournals.org by on July 28, 2010 316 M. Goodman et al. Agudo et al. (2000). This hospital-based casecontrol study compared pathology-confirmed cases of mesothelioma to population/hospital controls selected using a two-step procedure (Agudo and Gonzalez, 1999). The authors reported that there were three cases and 14 controls in the category `mechanics, motor vehicle'. The non-exposed cate gory included 51 cases and 148 controls that had never worked in any of the at-risk occupations. Based on this information, the crude OR for `mechanics, motor vehicle' was 0.62 (95% CI 0.11-2.36). The comparison of motor vehicle mechanics who may have had other potential asbestos exposure to persons without any exposure is problematical. However, the result indicates that substantial confounding by other exposures in this study population is unlikely. Because 44% of cases and less than 1% of controls had next of kin interviews, information bias needs to be considered. The study's high response rate, novel methods of control selection and confirmation of diagnosis by pathology review are among its strengths. Meta-analysis. The results of the meta-analysis for mesothelioma are presented in Table 4. All tests for heterogeneity produced non-significant results regardless of stratification and in all analyses the random effects model reduced to a fixed effects model. The meta-RR estimates for Tier I and Tier II studies were 0.92 (95% CI 0.55-1.56) and 0.81 (95% CI 0.52-1.28), respectively. Analysis limited to studies evaluating the associ ation between mesothelioma and brake repair, as opposed to motor vehicle repair, resulted in a metaRR of 0.86 (95% CI 0.48-1.56). Inclusion of only those studies that considered other asbestos exposures resulted in a meta-RR of 0.80 (95% CI 0.46-1.40). Lung cancer Overview of the literature. Twenty-nine studies were identified initially. Of these, seven were elimi nated because they did not meet the three initial inclusion criteria or they presented data that over lapped with other studies. The remaining 22 studies were evaluated and scored (Table 5). Thirteen studies were further excluded from the meta-analysis because they had an overall negative score. Nine studies remained, of which four (scores of 3 or 4) were included in Tier I (Table 6A) and five (scores 0-2) were included in Tier II (Table 6B). Tier I included two cohort studies (Gustavsson et al., 1990; Hrubec et al., 1992) and two case-control studies (Lerchen et al., 1987; Benhamou et al., 1988). Tier II included two cohort studies (Jarvholm and Brisman, 1988; Hansen, 1989) and three case-control studies (Williams et al., 1977; Vineis et al., 1988; Morabia etal., 1992). Only six studies adequately controlled for smoking; of these, three were included in Tier I. Despite adequate control for smoking, three studies (Williams et al., 1977; Vineis et al., 1988; Morabia etal., 1992) were included in Tier II due to other limitations. The earliest of the studies included in the meta-analysis was published in 1977 (Williams et al., 1977) and the most recent were published in 1992 (Hrubec et al., 1992; Morabia et al., 1992). Notably, none of the Tier I or II studies was published in the last 10 yr. Three of the four cohort studies included in the meta-analysis were published in Europe: two in Sweden (Jarvholm and Brisman, 1988; Gustavsson et al., 1990) and one in Denmark (Hansen, 1989). The fourth cohort study was published in the USA (Hrubec et al., 1992, 1995) and presented in two reports, one evaluating cancer risk by occupation and one evaluating cancer risk by industry. All but one (Benhamou et al., 1988) of the case-control studies were conducted in the USA. Tier I. Lerchen et al. (1987). This case-control study compared lung cancer patients from the New Mexico tumor registry to matched controls selected either through random digit dialing or from the Health Care Financing Administration records. The information for roughly half of all cases and 2% of controls was available from the next of kin inter views. Smoking variables used for adjustment included smoking status (current, former or never), number of cigarettes/day and smoking duration. The non-exposed group included subjects never employed in the industry or occupation of interest. For auto mechanics the adjusted OR was 0.9 (95% CI 0.5-1.9). Table 4. Meta-analysis results for mesothelioma Analyses Tier I studies Tier II studies Studies that eliminated other exposures3 Studies that defined exposure as `brake work'b K Meta-RR 95% CI Q-test 4 0.92 0.55-1.56 0.97 3 0.81 0.52-1.28 0.92 4 0.80 0.46-1.40 0.94 3 0.86 0.48-1.56 0.46 K, number of studies; 2-test, P-value of the test for heterogeneity; RR, an estimate of relative risk; CI, confidence interval. aAgudo et al. (2000), McDonald and McDonald (1980), Teschke et al. (1997) and Hessel et al. (2004, in press). bWoitowitz and Rodelsperger (1994), Teschke et al. (1997) and Hessel et al. (2004, in press). Mesothelioma and lung cancer among m otor vehicle mechanics Table 5. Quality scores of studies evaluating the association between lung cancer risk and employment as a motor vehicle mechanic Quality criteria Overall study design: PMR/PIR/SMOR = -1; else = 0 Asbestos exposure: non-specific (e.g. `car mechanic') = 0; specific (e.g. brake repairman, or iH-based) = 1 Age adjustment: no = -1; yes = 0 Confounding by other occupational exposure: likely = -1; possible = 0; unlikely/addressed = 1 Exposure-response analysis: no = 0; yes =1 Analysis by latency: no = 0; yes = 1 For case-control studies: response rate: <80% or not reported = -1; >90% = 1; else = 0 For cohort studies: follow-up <10 yr = -1; >20 yr = 1; else = 0 Adjustment for smoking: none = -1, partial/inadequate = 0; adequate/ detailed = 1 Reporting bias: likely = -1; possible = 0; unlikely/addressed = 1 Selection bias: likely = -1; possible = 0; unlikely/addressed = 1 Total score Study 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 00 00 0 0 0 0 0 0 0 -1 0 0 0 0 -1 0 -1 -1 -1 -1 01 00 0 0 0 1 00000000000000 00 00 00 0 0 0 000000000000000 0 0 0 0 0 -1 0 0 -1 0 0 0 0 0 0 0 0 0 0 0 01 00 00 00 0 0 0 000 1 00000000000 00 0 0 0 000000000000 1 00 0 0 0 0 1 -1 -1 -1 -1 0 0 0 0 0 0 -1 1 0 0 0 -1 1 00 1 0 0 -1 0 -1 0 1 1 1 0 0 0 0 0 0 -1 -1 -1 -1 0 0 0 0 0 1 1 1 0 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 00 11 -1 4 00 0 1 0 11 1 1 0 01 3 3 2 000000000000000 0 0 0 -1 0 0 1 1 1 0 0 0 0 0 0 0 0 0 -2 -2 -1 -1 -1 -1 -3 -2 -1 -1 -2 -2 1, Rushton et al. (1983); 2, Gustavsson et al. (1990); 3, Jarvholm and Brisman (1988); 4, Hansen (1989); 5, Hrubec et al. (1992); 6, Lerchen et al. (1987); 7, Benhamou et al. (1988); 8, Vineis et al. (1988); 9, Williams et al. (1977); 10, Morabia et al. (1992); 11, Swanson et al. (1993); 12, Achwartz (1987); 13, Finkelstein (1995); 14, Enterline and McKiever (1963); 15, Menck and Henderson (1976); 16, Leigh (1996); 17, Petersen and Milham (1980); 18, Milne et al. (1983); 19, Dubrow and Wegman (1984); 20, Olsen and Jensen (1987); 21, Milham and Ossiander (2001); 22, NIOSH (personal communication, 2002). 317 010Z `QZ A|nr uo Aq 6jo'S|BUjnorpjojxo'6AquuB//:d}}q luojj pspBO|UMOQ Mesothelioma and lung cancer among m otor vehicle mechanics Table 7. Summary of lung cancer studies and corresponding RR estimates not included in the meta-analysis First author Enterline Menck Decoufle Petersen Rushton Milne Dubrow Blair Olsen Schoenberg Schwartz Carstensen Zahm Burns Swanson Year 1963 1976 1977 1980 1983 1983 1984 1985 1987 1987 1987 1988 1989 1991 1993 Design RR estimate Cohort 1.28 Cohort 1.46 Cohort 1.12 Proportionate mortality 1.23 Cohort 1.01 (workers in bus garages) 0.92 (bus mechanics)d Case-control 1.2 Case-control 1.38 Cohort 1.03 Proportionate incidence 1.17 Case-control 1.4 Proportionate mortality 1.12 Cohort 1.07 Case-control 1.3 Case-control 1.72 (mechanics, motor vehicles) 1.56 (automobile repair) Case-control Presented OR by number of years employed 95% CI NR NR NR NR NR NR NR NR NR 0.8-1.63 0.84-2.3 0.82-1.53 0.92-1.22 1.0-1.7 1.15-2.59 0.85-2.87 Presented OR by number of years employed Finkelstein De Stefani Leigh 1995 1996 1996 Case-control Case-control Cohort 0.88 0.6 1.31 0.39-1.85 0.3-1.2 1.08-1.54 Pezzotto Milham NIOSH 1999 2001 2002 Case-control Proportionate mortality Proportionate mortality 1.3 1.15 1.15 0.7-2.4 NR NR Reason for eclusion No control for smoking, follow up 1 yr; total score <0 No control for smoking, follow up 5 yr; total score <0 Exposure defined as `mechanics and repairmen' No control for smoking, follow up 3 yr; total score <0 No control for smoking, follow up <10 yr; total score <0 No control for smoking, does not report response rate; total score <0 No control for smoking; total score <0 Updated in Hrubec et al. (1992) PIR design, no control for smoking; total score <0 Included in a larger study by Vineis et al. (1988) PMR design, no control for smoking; total score <0 Exposure defined as `mechanics and repairmen' Exposure defined as `mechanics, repairers' Updated in Swanson et al. (1993); selection bias due to use of colon or rectum cancer cases as controls, confounding by other occupations, total score <0 Selection bias due to use of colon or rectum cancer cases as controls, confounding by other occupations, poor response rate; inadequate control for smoking; total score <0 No control for smoking; total score <0 Exposure defined as `mechanic' No control for smoking, follow up 3 yr, relative risk related to large occupational group (auto, bus, truck, stationary engine mechanics); total score <0 Exposure defined as `mechanics' PMR design, no control for smoking; total score <0 PMR design, no control for smoking; total score <0 CI, confidence interval; NR, not reported; PIR, proportionate incidence ratio; PMR, proportionate mortality ratio; RR, estimate of relative risk. aAdequately controlled for smoking. bValues used in meta-analysis. c95% CI recalculated, authors only reported 90% CI. dAs reported in Wong (1993, 2001). 319 010Z `QZ A|nr uo Aq 6jo'S|BUjnorpjojxo'6AquuB//:d}}q luojj pspBO|UMOQ 320 M. Goodman et al. Downloaded from http://annhyg.oxfordjournals.org by on July 28, 2010 The standardized incidence ratio for lung cancer compared with the general population rates was 1.61 (95% CI 0.94-2.57). However, in this analysis two cases of mesothelioma and one case of alveolar cell cancer were counted as `lung cancers'. A nested case-control analysis using logistic regression reported the following RRs: index 0-20 = 1.0 (reference); 20-40 = 1.67 (95% CI 0.50-5.60); 40-60 = 1.26 (95% CI 0.32-5.00); >60 = 1.20 (95% CI 0.26-5.64). The limitations of this study are the potential inclusion of workers not involved in motor vehicle repair and the lack of smoking information. However, the use of internal comparisons in the nested case-control analysis potentially attenuated the confounding effect of smoking. A particularly important feature that sets this study apart from other studies is its ability to conduct IH-based doseresponse analyses. Hrubec et al. (1992, 1995). Hrubec and co-workers conducted a cohort study of 248 046 US veterans followed from 1954 through 1980. In addition to occupational history, the cohort members responded to questionnaires providing information on smoking habits. The response rate was 84%. The underlying cause of death was identified for 95% of the decedents. Cause-specific mortality by occupation was adjusted for smoking using information on smoking status and amount of smoking. For cancers of the respiratory system, the smoking-adjusted RR was 1.1 (90% CI 0.89-1.36) in the occupational group `automobile mechanics and repairmen' and 0.9 (90% CI 0.69-1.17) in the industry type `automobile repair services and garages'. This study's strengths included its large sample size, ability to control for smoking (unusual for a cohort study) and a long follow-up period. However, its weakness was the use of the category `respiratory cancer', which is less specific than `lung cancer'. Tier II. Williams et al. (1977). Using the data from the Third National Cancer Survey, Williams et al. conducted inter-cancer case-control analyses for various occupations and industries while controlling for age, sex, race, education, smoking, alcohol use and geographic location. Only 57% of the cases approached for interviews participated. The nonexposed category consisted of persons in any other known job. For the industry category `car repair serv ices' the lung cancer analysis showed an OR of 0.85 (confidence interval not reported). Although this study adequately controlled for tobacco, alcohol and socio-economic status in all analyses, its main weak ness was the poor response rate and the use of all other cancers as controls. Jarvholm and Brisman (1988). These authors used 1960 Swedish census records to identify men employed as `mechanics' in the `car repair' industry. This information was linked to the Swedish Death Register (1961-1973) and the Swedish Cancer Registry (1961-1979). There were 39 deaths from lung cancer versus 23 expected, yielding an SMR of 1.70. Ninety-three lung cancers occurred among car mechanics from 1961 to 1979, while 73.0 were expected, resulting in a standardized incidence ratio (SIR) of 1.27 (95% CI 1.03-1.56). These results are limited by the lack of adjustment for smoking and by the absence of asbestos-specific exposure infor mation. Vineis et al. (1988). Occupational data from five case-control studies from five US states were combined to determine the risk of lung cancer associ ated with different occupations. Cases were identi fied from cancer registries, hospitals or death certificates. Controls for one of the individual studies were population based and matched on vital status; the remaining studies used hospital controls or deceased controls from death certificates. The nonexposed group consisted of people without any history of exposure to established and suspected lung carcinogens. Odds ratios were calculated for everemployment in the selected occupations and were adjusted for age, birth cohort and cigarette use. Ninety-eight cases and 90 controls were ever employed as `automobile brake workers' (OR = 1.2, 95% CI 0.9-1.7). Among the limitations of this study is the lack of a uniform job classification scheme. The comparison of automobile brake workers who may have had other potential asbestos exposure to persons without any exposure potentially biased the results. The combined response rate was <80%. The study's advantages include a relatively large sample size, adequate control for smoking and information specific to brake repair workers. Hansen (1989). A cohort of 21 800 male `auto mechanics' and 52 000 male skilled workers identi fied from the 1970 Danish Census was followed for 10 yr. Deaths were identified through the Danish National Bureau of Statistics. The reference cohort of skilled workers included carpenters, electricians, instrument makers, dairymen, upholsterers and glaziers. There were 41 lung cancer deaths among the motor vehicle mechanics, compared to 40.7 deaths expected based on the reference rates (SMR = 1.01, 95% CI 0.72-1.37). Limitations of the study included short follow-up, inclusion of workers with potential exposure to asbestos (e.g. carpenters and electricians) in the comparison group and lack of control for smoking. However, the latter limitation may have been partially offset by the use of a comparison group of manual workers. Mesothelioma and lung cancer among motor vehicle mechanics 323 Downloaded from http://annhyg.oxfordjournals.org by on July 28, 2010 confounding by other occupational exposures may further affect the results. It is important to point out that most asbestosexposed occupations showing a substantial increase in risk of asbestos-related lung cancer are expected to show an even higher elevated risk of mesothelioma. For this reason, it would be difficult to conclude that motor vehicle mechanics may be at risk for devel oping lung cancer from asbestos given the absence of any increase in risk of mesothelioma. Importantly, the only epidemiological study that used an IH-based exposure assessment (Gustavsson et al., 1990), among persons employed at as bus garage, found no dose-response relationship between the level of asbestos exposure and the risk of lung cancer. The role of meta-analyses in observational epide miology is the focus of ongoing discussion. By combining several studies, meta-analyses have an inherent ability to show relatively small statistically significant departures from null. However, these rela tively precise meta-RR estimates may not accurately reflect the magnitude of the association unless the analyses take into consideration potential sources of systematic error. It is perhaps more useful to view meta-analysis as a formal way of understanding and quantitatively describing the level of consistency and inconsistency among studies and to identify potential sources of error that may affect the result. One source of error that warrants consideration in a meta-analysis is publication bias, which tends to occur because studies with statistically significant positive findings are more likely to be published than studies with null results (Easterbrook et al., 1991). Publication bias can be evaluated through identifica tion of unpublished research or by calculating the fail-safe N, defined as the number of studies with a non-significant result that would bring a statistically significant meta-RR estimate to non-significant levels (Rosenthal, 1979). However, in this case the results are essentially null and thus publication bias would not be expected to affect our findings. The search for sources of error inevitably leads to evaluation of study quality. Several authors recom mend formalizing such evaluations by using quantita tive scoring of individual studies (Jenicek, 1989; Downs and Black, 1998). Others view the use of scoring schemes as somewhat arbitrary and advise against using them (Juni et al., 1999). We would agree that both points of view have merit. Using a quality score as a method of weighting study results or as a variable in a regression model may introduce a subjective element into an analysis (Greenland, 1998). On the other hand, it is important to consider and take into account methodological strengths and weaknesses that are likely to affect the results. For these reasons, we feel that the use of quality tiers is justified as long as the methodology of assigning studies to a particular tier is transparent to the readers. It would be difficult to ensure such transpar ency without some kind of formal scoring approach. The particular scoring method used in this study reflects the consensus of its authors, but we realize that other approaches may also exist. It is important to point out that if one were to compare the meta-analyses of all studies combined with those of individual tiers, the results would appear somewhat different. The meta-RRs for mesothelioma based on all three tiers is 0.67, with a 95% CI between 0.53 and 0.84, while the meta-RR for Tier I is 0.92 (95% CI 0.55-1.56). The corres ponding results for lung cancer are 1.16 (95% CI 1.13-1.19) and 1.07 (95% CI 0.88-1.31). These comparisons indicate that the statistically significant departures from null (down for mesothelioma and up for lung cancer) in a meta-analysis of all studies combined could be explained by methodological problems of individual studies. CONCLUSIONS The available epidemiological data show that employment as a motor vehicle mechanic does not increase the risk of developing mesothelioma. Although some studies showed a small increase in risk of lung cancer among motor vehicle mechanics, the epidemiological data on balance do not support a conclusion that lung cancer in this occupational group is related to asbestos exposure from vehicle repair. Acknowledgements--This research was funded primarily by Ford Motor Co., Daimler-Chrysler Corp. and General Motors Corp. Some of the authors have testified as expert witnesses in litigation regarding the potential health effects associated with brake repair. APPENDIX Meta-analysis calculations Using the fixed effects assumption, the general formula for the weighted average effect size of k studies is: k X wT T = i=1------ k X wi (1) i=1 where Ti is the effect size estimate of the ith study and wi is the weight associated with it. The weights that minimize the variance of T. are given by: w=-- vi (2) 324 M. Goodman et al. Downloaded from http://annhyg.oxfordjournals.org by on July 28, 2010 where vt is the variance in each study. The average effect size T. has a conditional variance v. given by: v. 1 (3) Equations for variance change for the random effects assumption. The total variance of an effect size esti mate is given by: *2 V = o + vi (4) where o2 is the random effects variance and vt is the conditional variance given above. The random effects variance o2 calculated is based on a weighted sample estimate Q of the unconditional variance of T;. 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