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Occupational exposure to asbestos and lung cancer in men: evidence from a population-based case-control study in eight Canadian provinces

Occupational exposure to asbestos and lung cancer in men: evidence from a population-based... Background: Asbestos is classified as a human carcinogen, and studies have consistently demonstrated that workplace exposure to it increases the risk of developing lung cancer. Few studies have evaluated risks in population-based settings where there is a greater variety in the types of occupations, and exposures. Methods: This was a population based case–control study with 1,681 incident cases of lung cancer, and 2,053 controls recruited from 8 Canadian provinces between 1994 and 1997. Self-reported questionnaires were used to elicit a lifetime occupational history, including general tasks, and information for other risk factors. Occupational hygienists, who were blinded to case–control status, assigned asbestos exposures to each job on the basis of (i) concentration (low, medium, high), (ii) frequency (<5%, 5-30%, and >30% of the time in a normal work week), and (iii) reliability (possible, probable, definite). Logistic regression was used to estimate odds ratios (ORs) and their corresponding 95% confidence intervals (CI). Results: Those occupationally exposed to (i) low, and (ii) medium or high concentrations of asbestos had ORs for lung cancer of 1.17 (95% CI=0.92 – 1.50) and 2.16 (95% CI=1.21-3.88), respectively, relative to those who were unexposed. Medium or high exposure to asbestos roughly doubled the risk for lung cancer across all three smoking pack-year categories. The joint relationship between smoking and asbestos was consistent with a multiplicative risk model. Conclusions: Our findings provide further evidence that exposure to asbestos has contributed to an increased risk of lung cancer in Canadian workplaces, and suggests that nearly 3% of lung cancers among Canadian men are caused by occupational exposure to asbestos. Keywords: Lung cancer, Asbestos, Cigarette smoking, Case–control, Occupational epidemiology Background describe six naturally fibrous minerals, and one of these, Lung cancer continues to be the leading cause of cancer chrysotile, accounts for 95% of the asbestos ever used among Canadian men, and in 2012, it was estimated that worldwide, and until recently was the only type produced 13,300 men would be diagnosed with lung cancer and in Canada [2]. All forms of asbestos have long been 10,800 would die of it [1]. While cigarette smoking is recognized as human carcinogens by the United States recognized as the leading cause of lung cancer, many oc- Environmental Protection Agency [3], the International cupational exposures, including asbestos, have also been Agency for Research on Cancer [4], and the National shown to increase risk. Asbestos is a term used to Toxicology Program [5]. This conclusion is based largely on unequivocal evidence assembled from epidemiological studies that have found excesses of lung cancer and meso- * Correspondence: [email protected] thelioma in highly exposed textile workers, miners, and Population Studies Division, Health Canada, Ottawa, Ontario, Canada cement factory workers [4,6]. Division of Occupational and Environmental Health, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada Full list of author information is available at the end of the article © 2012 Villeneuve et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Villeneuve et al. BMC Cancer 2012, 12:595 Page 2 of 10 http://www.biomedcentral.com/1471-2407/12/595 Today, more than 90% of the asbestos produced have suggested that the combined effects of smoking and worldwide is used to manufacture asbestos sheets and asbestos are more than additive but less than multiplica- pipes [7]. The World Health Organization has estimated tive. This conclusion is consistent with very recent work that approximately 125 million individuals continue to by Frost et al. that revealed interactions that were greater be exposed to asbestos in the workplace [8]. Occupa- than additive, although the multiplicative association tional exposure to asbestos in Canada has decreased dra- could not be rejected [18]. Apart from the studies by matically over the past two decades due to provincial Gustavsson et al. and Pintos et al., we know of no other re- occupational health and safety controls that have been search that has evaluated the joint relationship between implemented. While those involved in the mining of as- asbestos and smoking on lung cancer risk in the general bestos are at higher risk of developing asbestos-related population where exposure levels are much lower than in disease, the precautions offered to these workers to limit asbestos workers, yet with fewer precautions and protec- exposure are greater than those unwittingly exposed tions offered to reduce exposure. In the Gustavsson et al. through other trades. Overall, the mining of asbestos in study, the association between asbestos and smoking on Canada has decreased dramatically, and in 2011, for the lung cancer risk was found to be between additivity and first time in over 130 years, production was halted [9], multiplicativity [11]. In the Montreal study, the association Today, in Canada, the most common sources of asbestos was found to be sub-multiplicative [10]. To add to this exposure arise from the repair, renovation, and demoli- knowledge, we examined the joint relationship between tion of older (pre-1980) buildings. smoking and asbestos in this population-based case–con- Relatively few studies have examined associations be- trol study. tween workplace exposure to asbestos and lung cancer With this background, the primary objective of our using a population-based design. Population-based designs study is to build upon past research by reporting on the provide important features that include an ability to esti- association between occupational exposure to asbestos mate risks over a wider range of exposure levels than and lung cancer among Canadian men. The secondary ob- those typically reported in industry-specific studies. They jective of the study is to evaluate the combined effects oc- provide the opportunity to characterize the frequency and cupational exposure to of asbestos and cigarette smoking nature of exposures in the general population. Moreover, on the risk of lung cancer. because such studies cover diverse occupational groups, there is a reduced impact of confounders that may be spe- Methods cific to particular occupations. Recently, a population- Study population based case–control study in Montreal found that workers A case–control study design was used to address the re- with substantive exposure to asbestos had a greater risk of search objectives, and the data come from the lung cancer lung cancer, however, this finding did not achieve statis- case–control component of the National Enhanced Can- tical significance (odds ratio (OR) =1.78, 95% CI=0.94, cer Surveillance System (NECSS). The overall objective of 3.36) [10]. Cumulative exposure was positively associated the NECSS was to improve our understanding of both en- with lung cancer risk in a case–control study in Stock- vironmental and occupational determinants of cancer holm, Sweden [11], while a multi-center European case– [19]. The NECSS was a collaborative project between control study found no association between occupational the Public Health Agency of Canada and cancer regis- exposure to asbestos and lung cancer in six Central and tries in eight Canadian provinces (British Columbia, Eastern European countries, but a nearly twofold Alberta,Saskatchewan, Manitoba, Ontario, Nova Scotia, (OR=1.85, 95% CI=1.07-3.21) increased risk was observed Newfoundland, and Prince Edward Island). There were among UK workers [12]. no subjects (cases or controls) from the province of While both cigarette smoking and asbestos are recog- Quebec. Detailed information was collected from cases nized lung carcinogens, there remain uncertainties about and controls for a number of potential risk factors includ- how they operate together to increase the risk of lung can- ing: sociodemography, anthropometry, diet, smoking, expo- cer. Attempts to understand the joint effects of smoking sure to second hand smoke, and participation in physical and asbestos on the risk of lung cancer extend back to activities. Individuals were also asked to provide lifetime Selikoff et al.’s seminal work in the late 1960s [13]. A sub- residential and occupational histories. Questionnaires were sequent review of this literature suggested that the inter- administered between 1994 and 1997. active effects are multiplicative [14], which implies that The NECSS endeavoured to collect information for asbestos exposure increases the risk of lung cancer by the each incident cancer within three months of diagnosis. same factor in smokers and non-smokers alike. An addi- Among men, there were a total of 3,718 histologically tive relationship, on the other hand, would assume that confirmed lung cancer cases (ICD-9 rubric 162) identi- the effects of asbestos exposure and smoking are inde- fied between 1994 and 1997. Letters were sent to the pendent. Other reviews [15,16] and a meta-analysis [17] physicians of 3,033 (81.6%) of these cases to solicit their Villeneuve et al. BMC Cancer 2012, 12:595 Page 3 of 10 http://www.biomedcentral.com/1471-2407/12/595 participation. Physician consent was obtained and ques- sufficient information for exposure assessment. No tionnaires were mailed to 2,548 (69%) of the cases; phy- exposures were assigned for jobs that were self-reported sician consent was refused for 229 (6%) of all eligible to be retirement (n=185), disability (n=10), and un- cases and 653 (18%) were deceased at the time of the re- employment (n=8). quest and therefore excluded. Completed questionnaires Occupations and industry titles were assigned by one were returned by 1,736 of the 2,548 cases who were of two hygienists, who were blinded to case–control sta- mailed a questionnaire yielding an overall response rate tus, using the Canadian Classification and Dictionary of of 68.1%. Occupation codes (originally published in 1971 with The NECSS assembled a series of controls from the revisions up until 1986), and Standard Industrial Codes general population. For 5 provinces, controls were iden- [21]. The hygienist coded each job on the basis of expo- tified through provincial health insurance plans (Prince sure to known or suspected lung cancer carcinogens. Edward Island, Nova Scotia, Manitoba, Saskatchewan These exposures included: asbestos, diesel and gasoline and British Columbia). These insurance plans cover engine exhaust emissions, and crystalline silica. This as- more than 95% of residents in the province. Elsewhere, sessment was guided by the scientific and technical lit- either random digit dialing (Newfoundland and Alberta), erature, consultation with experts, and a review of or property assessment data (Ontario) were used as the existing databases of exposure assessment. The assign- sampling frame to recruit controls. Frequency matching ment of workplace exposures took into account the to the overall case grouping (19 types of cancers) was manner that asbestos was used over the years. For used to select controls with similar age and sex distribu- example, before 1976, drywall installers used dry-wall tion, such that there would be at least one control for joint cement that contained asbestos, while after 1980 every case within each sex and 5-year age group for any asbestos was banned in this cement. specific cancer site within each province. In total, ques- The assignment of occupational exposures was done tionnaires were mailed to 4,270 men identified as pos- according to three dimensions: concentration, frequency sible controls in the 8 provinces. Approximately 7% of and reliability. The frequency of exposure was assigned these (n=287) were returned because the address was in- based on the proportion of work time during a normal correct, and no updated address could be found through work week that the subject was exposed; this assignment publicly available sources. In all, 2,547 male controls took into account whether the work was part-time or returned completed questionnaires, representing 64% of seasonal in nature. ‘Low’ frequency corresponded to less those contacted and 60% of those ascertained. than 5% of the work time, ‘Medium’ between 5% and For the purposes of our analyses, we restricted the 30%, and ‘High’ represented more than 30%. Concentra- study population to only include men given that we tion was assessed on a relative scale. For each substance, expected few women to have been exposed to asbestos benchmarks were established and exposures were coded in the workplace. We used the same analysis file previ- with respect to these benchmarks. Non exposure was ously used to evaluate associations between diesel engine interpreted as exposure up to background levels found exhaust emissions and lung cancer which excluded indi- in the general environment. The relative benchmarks for viduals under the age of 40, and those who had not concentration levels used by our team of hygienists were worked for at least one year [20]. In the NECSS, among ‘Low’ for welders and boiler operators, ‘Medium’ for all participating incident lung cancer cases only 0.7% boiler and pipe insulators and marine firemen and ‘High’ (n=13) were diagnosed before the age of 40; the cor- for miners and insulation workers (blowers and responding number of controls excluded to meet the age sprayers). It is very difficult to provide a reliable estimate requirement was 438. A total of 42 cases and 56 controls of the absolute number of fibres per unit of volume cor- were excluded because their reported length of employ- responding to the different exposure levels. However, as ment was less than one year. After applying these exclu- a crude indicator, we can suggest that our ‘Medium’ sion criteria we were left with a total of 1,681 cases and level corresponded roughly to the 1976 American Con- 2,053 controls. ference of Governmental Industrial Hygienists threshold limit values (TLV) given that these values were in force Occupational assignment of exposures in Canada in 1983 at a time when our study subjects Cases and controls were asked to provide information were working. Specifically, the TLV for chrysotile asbes- for each job held in Canada for at least 12 months from tos fibers over 5 microns was 5 fibres per/cc in these the time they were 18 years old until the time of inter- Quebec guidelines. Finally the third dimension of expos- view. Information sought for each job included: job title, ure, reliability, refers to the hygienists’ degree of confi- main tasks, type of industry, location, and the start and dence that the exposure was actually present in the job end dates of employment. A total of 15,646 jobs were under evaluation; ‘Low’ refers to a possible exposure, identified, of these 15,234 (97.4%) jobs contained ‘Medium’ to a probable exposure and ‘High’ to a certain Villeneuve et al. BMC Cancer 2012, 12:595 Page 4 of 10 http://www.biomedcentral.com/1471-2407/12/595 exposure. Estimates of the inter-rater reliability of the eight cross-classification categories, while the ninth ca- exposure assignment method, which were based on the tegory (no asbestos exposure, < 10 cigarette pack-years) work of chemists from the group that conducted the ex- was used as the referent. The joint effects of smoking posure assessment our study, lend credibility to the va- and asbestos on lung cancer risk were evaluated using lidity of the approach we used. Specifically, Goldberg two previously derived indices: the Synergy (S) [24] and et al. reported that the percent agreement among raters Multiplicativity (V) [25]. We followed a similar ap- was between 95% to 98% with a Cohen’s kappa from 0.5 proach that Frost et al. used to evaluate the relationship to 0.7 [22]. between asbestos and smoking and lung cancer in wor- kers in Great Britain [18]. We used our derived odds Statistical analysis ratios (ORs) to calculate the index S [24] as follows: We constructed several metrics to characterize occupa- OR  OR AS 0 tional exposure to asbestos. These metrics included: ever S ¼ OR þ OR  2OR A S 0 exposed, highest attained concentration (high, medium, low), as well as a duration of exposure. Given the small Where OR is the odds ratio of lung cancer exposed number of individuals that had high concentrations of to ‘medium or high’ levels of asbestos among those with exposure, we combined medium and high into one little to no smoking history (<15 pack-years), OR is the group. Those with a low reliability score (“possibly odds ratio of lung cancer among smokers (≥ 40 pack- exposed”) were assumed to have had no exposure. years) with no exposure to asbestos, OR is the odds AS Logistic regression was used to estimate the odds ratio of lung cancer among smokers (≥ 40 pack-years) ratios (OR) and their corresponding 95% confidence exposed to asbestos, where each odds ratio is estimated intervals (CI) for the various exposure metrics. Adjust- relative to the referent group of men who had accrued ments were made for the potential confounders: age, less than 10 cigarette pack-years and were not exposed cigarette smoking, socioeconomic status, exposure to to asbestos (OR ).The Multiplicativity index was calcu- second hand smoke, and occupational exposure to silica, lated as: and diesel exhausts. Occupational exposure to silica, and diesel engine exhausts were assigned to the cases and OR OR 0 AS V ¼ controls using the same methodology that was used for OR OR A S asbestos. Silica and diesel exposures were modelled as cumulative time-weighted measures. While gasoline en- A value that exceeds one for the S index suggests an gine emission exposure measures were also derived for interactive effect between smoking and asbestos expos- the cases and controls, they did not confound the risk ure on lung cancer that could imply a multiplicative ef- estimates for asbestos, and therefore, were not included fect. In contrast, a value of S near one suggests that the in the models as adjustment factors. Multivariable mo- two risk factors would operate in an additive fashion on dels were adjusted for cigarette smoking through the use the risk of lung cancer. For the V index, a value of one of a pack-years variable which incorporated aspects of indicates a multiplicative interaction, whereas as values both smoking duration and intensity. Cigarette pack- greater and less than one indicate an interaction that is years were defined as the number of years of smoking an more or less than multiplicative, respectively. average of 20 cigarettes per day. For exposure to second- hand smoke, a composite measure was used that took Ethics approval into account lifetime exposures received both at home, The participating provincial cancer registries obtained and in the workplace [23]. It was derived as a function approval of the NECSS study protocol through their re- of the number of years of exposure that incorporated spective ethics review boards. All participants provided both the number of regular smokers that lived in each informed consent. residence, and the number of smokers who smoked regularly in the subjects’ immediate work environment Results The joint effect of smoking and occupational exposure Of the 15,234 occupations ever held by the study subjects, to asbestos was first examined by estimating the odds a total of 801 were coded as having either ‘probable’ or ratios for cross-classification categories of cigarette ‘definite’ exposure to asbestos. The most commonly pack-years (<10, 10 - <40, ≥40) and the highest attained reported exposed occupations were mechanics and repair- occupational exposure to asbestos (none, low, medium/ men, stationary engine and utility workers, pipefitters, and high). The small numbers of lung cancers among never construction workers (Table 1). Water transport operating smokers (n=34; 2% of all cases) precluded a separate occupations represented the only group deemed to have a evaluation of asbestos risks in this group. The odds high frequency of exposure to asbestos. Specific jobs ratios and 95% confidence intervals were estimated for included in this group that worked on ships included: deck Villeneuve et al. BMC Cancer 2012, 12:595 Page 5 of 10 http://www.biomedcentral.com/1471-2407/12/595 Table 1 Most frequent occupations among the 801 jobs held by subjects that were classified as having probable or definite exposure to asbestos SOC Number of jobs % Most common exposure coding Confidence Frequency Concentration Mechanics and Repairmen (except electrical) 8580 – 8589 214 26.7 Probable Low Low Stationary Engine and Utilities Equipment 9530 - 9539 124 15.0 Probable Medium Low Pipefitting 8791 89 11.1 Probable Low Low Construction 8733 79 9.9 Probable Low Low Metal shaping occupations 8330 – 8339 48 6.0 Probable Medium Low Fabricating, assembling electrical and electronics 8530 – 8539 34 4.2 Probable Medium Low Water Transport Operating Occupations 9151 – 9159 42 5.2 Probable High Low Firefighters 6111 31 3.9 Definite Medium Low Plasterers 8784 23 2.9 Probable Medium Low Total 801 84.5 A – defined by highest percentage. officers, engineering officers, deck crew, engine and boiler variable, the adjusted odds ratio of lung cancer for an in- room crew workers. crease in 10 years of exposure was 1.03 (95%% CI=0.94- A total of 233 cases and 224 controls, respectively, were 1.13). This risk increased to 1.13 (95% CI=0.84-1.52) when exposed to asbestos at some point during their lifetime oc- analyses were restricted to those who were only exposed cupational history (Table 2). Those who were ever exposed to medium or high concentrations; this result however to asbestos had a 28% increased risk of lung cancer rela- was not statistically significant (p=0.44). The frequency of tive to those who were not (OR=1.28, 95% CI: 1.02, 1.61). the jobs that were deemed to have ‘medium’ or ‘high’ con- The risks according to highest concentration of occupa- centrations of asbestos is presented in Figure 1. The most tional exposure ever attained were more pronounced. common of these jobs were pipefitters and boilermakers, Only two cases and one control reported working in a job and insulators. with an assigned ‘high’ concentration of exposure. As a re- None of the first-order interaction terms between sult, we combined ‘medium’ and ‘high’ concentrations into cigarette smoking pack-years and the three measures of one category. Those who had ever been exposed to asbestos exposure were statistically significant. The cor- medium or high levels had a more than twofold increase responding p-values for the smoking interaction terms in risk (OR=2.16, 95% CI=1.21-3.88). with ‘ever’, ‘highest attained’ and ‘duration’ asbestos ex- We found that duration of occupational exposure to as- posure were 0.33, 0.77, and 0.88, respectively. bestos was not related to the risk of lung cancer (Table 2). Stratified analyses of highest attained asbestos expo- When we modeled duration of exposure as a continuous sure across cigarette pack years categories are presented Table 2 Adjusted odds ratios of lung cancer in relation to occupational exposure to asbestos A B Occupational exposure Cases Controls Odds ratio and 95% CI Odds ratio and 95% CI Unexposed* 1448 1829 1.0 - 1.0 - Ever exposed 233 224 1.31 1.07 – 1.59 1.28 1.02 – 1.61 Highest attained exposure Unexposed 1448 1829 1.0 - 1.0 Low 194 200 1.22 0.99 – 1.51 1.17 0.92 – 1.50 Medium / High 39 24 2.02 1.20 – 3.97 2.16 1.21 – 3.88 Total 1681 2053 Duration of exposure (years) < 10 88 68 1.68 1.21 – 2.33 1.60 1.10 – 2.33 10 - < 20 46 50 1.08 0.74 – 1.69 0.89 0.56 – 1.42 ≥ 20 87 103 1.05 0.78 – 1.42 1.18 0.84 – 1.66 A – Adjusted for age, province, B – Adjusted for age, province, cigarette pack years, occupational exposure to diesel and silica, exposure to second hand smoke. Villeneuve et al. BMC Cancer 2012, 12:595 Page 6 of 10 http://www.biomedcentral.com/1471-2407/12/595 Pipefitter Boilermaker Insulation Welder/sheet metal Other Construction Industrial mechanic Marine craft repair Miner Masonry Excavator Textile worker 0 5 10 15 20 25 30 35 40 45 Number of jobs Figure 1 Most common occupations among mean with medium or high concentration levels of asbestos, NECSS lung cancer case- control study. in Table 3. There was an approximate two-fold increase factors for lung cancer. The approximate 28% increased in risk among those with ‘medium’ or ‘high’ occupational risk observed among men ever exposed to asbestos is simi- exposure to asbestos relative to those with no such ex- lar to the finding of Pintos et al. [10]. In their Montreal posure in each of the three pack-year categories. This is based case–control study, those who were exposed to consistent with a multiplicative relationship between the asbestos had an odds ratio of 1.21, (95% CI=0.98-1.49) rela- two factors. Those who had at least 40 pack-years of tive to those with no exposures. The population attribut- smoking and were exposed to medium or high asbestos able risk (PAR) percent is often used to provide an levels had the highest risk of lung cancer; relative to estimate of the percentage of cases that be avoided if the those with no asbestos exposure, and less than 10 putative exposure was eliminated [26] . We calculated the cigarette pack-years, their risk nearly 38-fold higher PAR in our study using the odds ratio of 1.28 among ever (OR=38.59, 95% CI=10.78-138.08) (Table 4). The calcu- exposed, and an estimated prevalence of exposure of 11.3% lated values of the S and V indices were 2.10 and 0.99 (based on our control series). This yielded a PAR of 3.1% respectively, supporting the notion that the interaction which suggests that a relatively small percentage of Canad- between asbestos and smoking is multiplicative. ian male lung cancer cases are due to occupational expos- ure to asbestos. Based on an estimated 13,300 incident Discussion lung cancers among men in Canada in 2012 [1] this would This population-based study of men employed across a di- account for approximately 412 incident cases. verse range of jobs found that workplace exposure to as- Our study provided support for a dose–response rela- bestos was associated with an increased risk of lung tionship between asbestos exposure and lung cancer as cancer. This association persisted after adjusting for higher risks were observed among those who were ever cigarette smoking, second hand smoke, and other occupa- exposed to ‘medium’ or ‘high’ concentrations of asbestos. tional exposures previously implicated as possible risk Pipefitters accounted for nearly half of these cases and Table 3 Adjusted odds ratios* and 95% C.I. according highest occupational exposure to asbestos across cigarette pack- year smoking categories Cigarette smoking (pack-years) Highest occupational exposure to asbestos < 10 10 - <40 ≥ 40 N OR* 95% C.I. N OR* 95% C.I. N OR* 95% C.I. None 84 1.0 - 630 1.0 - 678 1.0 - Low 13 1.54 0.79 – 3.00 90 1.28 0.91 – 1.80 85 0.88 0.58 – 1.35 Medium or high 2 2.01 0.39 – 10.43 20 2.30 1.09 – 4.84 16 2.50 0.73 – 9.28 N = number of lung cancer cases. * adjusted for age, province, occupational exposure to diesel and silica, and second hand cigarette smoke. Villeneuve et al. BMC Cancer 2012, 12:595 Page 7 of 10 http://www.biomedcentral.com/1471-2407/12/595 Table 4 Synergy and multiplicative indices between asbestos exposure and cigarette smoking Cigarette smoking (pack-years) Asbestos exposure Label Cases Controls Odds ratio* 95% CI < 10 None R 84 745 1.0 - Low — 13 69 1.47 (0.77 – 2.81) Medium/High R 2 7 2.20 0.42 – 11.41) 10 - < 40 None — 630 778 5.28 (3.90 – 7.14) Low — 90 90 6.67 (4.41 – 10.10) Medium/High — 20 13 10.39 (4.83 – 22.36) ≥ 40 None R 678 266 17.68 (12.90 – 24.22) Low — 85 40 15.62 (9.72 – 25.09) Medium/High R 16 3 38.59 (10.78 – 138.08) AS Synergy Index 2.10 Multiplicativity Index 0.99 * adjusted for age, province, occupational exposure to diesel and silica, and second hand cigarette smoke. controls (41 of 87). While the limited number of sub- when compared to durations spent at lower levels sug- jects did not allow us to characterize risks for specific gests that time exposed above a threshold level may be a types of jobs, our results are consistent with a previously relevant marker of risk. However, this finding should be published study of Ontario pipe trade workers [27]. They interpreted cautiously as it based on a very small num- reported a 53% increased risk of lung cancer mortality ber of subjects who were exposed to either medium or among pipefitters who had been registered trade mem- high intensities. bers for at least 30 years, relative to the Ontario general It is well recognized that there is a lengthy latency population. However, their study was somewhat limited period between the time of first exposure to an environ- due to a lack of data on smoking. Our findings support mental carcinogen and the development of a solid tumour the hypothesis that asbestos and cigarette smoking affect such as lung cancer. For example, the latency period asso- the risk of lung cancer in a multiplicative fashion. ciated with cigarette smoking and lung cancer has been In many occupational studies, duration of exposure is estimated to be several decades following the initiation of regarded as valid surrogate measure of cumulative ex- smoking [32]. By extension, the increased risks of lung posure due to the inherent difficulties in retrospective cancer due to exposure to asbestos observed in this study studies to precisely characterize exposure intensity. In are a reflection of workplace exposures many years if not their Montreal case–control study, Pintos et al. found a decades earlier. Indeed, among those classified has having higher risk of lung cancer among those exposed to as- ‘medium’ or ‘high’ concentrations to asbestos in the work- bestos for at least 20 years when compared to those place, the start date of employment was after 1980 in only exposed for shorter durations [10]. Duration of exposure 6% of these jobs. was also positively associated with lung cancer risk Participants in our study were asked to provide infor- in other industry-specific cohorts [28]. In contrast, mation for only those jobs that were held for at least we found that only intensity but not duration of expos- one year. The exclusion of these short-term jobs raises ure was associated with statistically significant increased the possibility that some exposure misclassification has risks of lung cancer. This observation is consistent been introduced. Previous analysis of 27.5 million work- with recently published findings on a cohort of work- ers found increased risks of lung cancer among those exposed to high levels of asbestos (20 to 40 fibers per ers employed in an asbestos reprocessing plant in the Calvados region of France [29]. In this study, Clin and cubic centimeter of air) for only a few months [33]. colleagues observed that the average exposure to asbes- Under a classical error model where the possible expo- sure misclassification error arising from excluding these tos expressed in terms of fibers per ml was associated with pleuro-peritoneal mesothelioma, lung cancer, and short term jobs is non-differential to case–control status, colorectal cancer (p<0.05), however, no statistically sig- our risk estimates would be understated. An important strength of this study was the availability nificant associations were evident with duration of ex- posure for any of these three cancer sites. Other studies of other risk factor data obtained through both the ques- of asbestos workers have also found associations with in- tionnaire, as well as expert-based coding of occupational histories. Unlike many other occupational case–control tensity but not duration of exposure [12,30,31]. Our finding of a stronger positive association between dur- studies, we had extensive data on cigarette smoking, ation of exposure at medium or high levels of asbestos most notably, exposure to second hand smoke. This Villeneuve et al. BMC Cancer 2012, 12:595 Page 8 of 10 http://www.biomedcentral.com/1471-2407/12/595 measure allowed our risk estimates to take into account it has been argued that these differences are not all that lifetime exposure to second-hand smoke incurred at important given that chrysotile is the most commonly both home and workplace settings. In addition, the in- used type of asbestos [40,41]. In our study, those who were dustrial hygienists also coded each job for possible ex- determined to have been exposed to asbestos were posure to other known or suspected lung carcinogens believed to have been exposed to chrysotile, however, it is including: crystalline silica, gasoline and engine emis- possible that some exposure to less prevalent yet more po- sions. We recently found that occupational exposure to tent types of fibers occurred and was unaccounted for. diesel but not gasoline engine emissions increased the Another limitation of our study was the relatively small risk of lung cancer; the risk of lung cancer was also number of study subjects who were ever exposed to increased among individuals exposed to crystalline silica medium or high levels of asbestos. In total, there were [34]. The addition of these two covariates (diesel and sil- only 39 cases and 24 controls exposed at these levels. ica) strengthened the association for asbestos by ap- These small numbers hindered our ability to characterize proximately 20%. the joint relationship between smoking and asbestos ex- Approximately 68% of eligible cases and 64% of eli- posure on the risk of lung cancer. It also limited our exam- gible controls completed a questionnaire. This raises the ination of the risks of lung cancer with exposure to potential to introduce some bias in our risk estimates, asbestos according to different histological subtypes. Se- and our results should be interpreted cautiously because veral studies have found associations that were most pro- of this possibility. However, for several reasons, we do nounced for adenocarcinoma subtypes [28,42-44], however, not believe this bias fundamentally changes our results. others did not [45-47]. The three most common histo- First, observed associations with known and suspected logical types of lung cancer in our study population were risk factors such as cigarette smoking, and exposure to squamous cell carcinoma (35%), adenocarcinoma (28%), second-hand smoke are similar in direction and magni- and small cell carcinoma (15.9%) [34]. When we restricted tude to risk estimates reported in other epidemiological analysis to adenocarcinoma, the odds ratio among those studies. Moreover, our published findings for other oc- exposed to medium or high levels of asbestos increased cupational exposures within the same study population from 2.16 to 3.14 (95% CI=1.50 – 6.58). However, the latter [34] are also consistent with the epidemiological litera- estimate was based on only 13 incident cases and therefore, ture. Lastly, the distribution of lung cancers by histology our study has very limited statistical power to make infe- in our study is remarkably similar to population-based rences by histological type. figures for North America [35] and provides some sup- port for the generalizeability of these results to incident Conclusions lung cancers in Canada. Unfortunately, the NECSS did In summary, the findings from this Canadian case–control not collect data from those diagnosed with mesotheli- study are consistent with the determination by inter- oma, and therefore, we were unable to investigate asso- national agencies that asbestos is a human lung carcino- ciations with this endpoint. gen. While chrysotile asbestos is the predominant type of We were unable to distinguish asbestos on the basis of asbestos in Canada, it is possible that some of the workers fiber type. Asbestos fibers can be described according to in our study were exposed to other types of asbestos fibers. two broad classes serpentines (phyllosilicates) and amphi- For this reason, and given the relatively small number of boles (inosilicates) that differ substantially with respect to individuals exposed to medium and high exposure where biopersistence and physical and chemical properties. Ser- the excess risks of lung cancer were found, we cannot con- pentines include chrysotile asbestos which is the predo- clusively attribute increased lung cancer risks to chrysotile. minant type of asbestos in Canada. The International Despite the limitation, our findings provide further sup- Agency for Research on Cancer has determined that there port that exposure to asbestos has contributed to an is sufficient evidence to conclude that all these forms of increased risk of lung cancer in Canadian workplaces. asbestos can cause cancer in humans [4,6]. There remains Abbreviations considerable uncertainty regarding differences in lung can- CI: Confidence interval; OR: Odds ratio; PAR: Population attributable risk; cer risk resulting from exposure to different types of asbes- NECSS: National enhanced cancer surveillance system; TLV: Threshold limit tos fibers. A review of cohort studies where quantitative value. measurements of asbestos exposure were available demon- Competing interests strated clearer and consistent associations between expo- The authors have no competing interests to declare. sure and lung cancer for crocidolite or amosite [36]. On the other hand, associations from cohorts exposed prima- Authors’ contributions PV contributed to the design of the study, conducted analysis of the data, rily to crysotile asbestos were less consistent [37,38]. It is and took the lead in preparing the manuscript. SH contributed to the design generally accepted that amphibole fibers are more harmful of the study, and assisted in the development of the manuscript. KJ is the than chrysotile fibers for mesothelioma [36,39]. However, principle investigator of the NECSS and oversaw the original collection of the Villeneuve et al. BMC Cancer 2012, 12:595 Page 9 of 10 http://www.biomedcentral.com/1471-2407/12/595 data, design of the questionnaire, and contributed to the writing of this asbestos and man-made vitreous fibres and risk of lung cancer: a manuscript. MEP oversaw the assignment of the occupational exposures for multicentre case–control study in Europe. Occup Environ Med 2007, this study, contributed to the design, and played a prominent role in the 64(8):502–508. writing of this manuscript. All authors read and approved the final 13. Selikoff IJ, Hammond EC, Churg J: Asbestos exposure, smoking, manuscript. and neoplasia. JAMA 1968, 204(2):106–112. 14. Vainio H, Boffetta P: Mechanisms of the combined effect of asbestos and smoking in the etiology of lung cancer. Authors’ information Scand J Work Environ Health 1994, 20(4):235–242. The Canadian Cancer Registries Epidemiology Research Group comprised a 15. Berry G, Liddell FD: The interaction of asbestos and smoking in lung principal investigator from each of the provincial cancer registries involved in cancer: a modified measure of effect. Ann Occup Hyg 2004, 48(5):459–462. the National Enhanced Cancer Surveillance System: Bertha Paulse, 16. Liddell FD: The interaction of asbestos and smoking in lung cancer. Newfoundland Cancer Foundation; Ron Dewar, Nova Scotia Cancer Registry; Ann Occup Hyg 2001, 45(5):341–356. Dagny Dryer, Prince Edward Island Cancer Registry; Nancy Kreiger, Cancer 17. Wraith D, Mengersen K: Assessing the combined effect of asbestos Care Ontario; Erich Kliewer, Cancer Care Manitoba; Diane Robson, exposure and smoking on lung cancer: a Bayesian approach. Saskatchewan Cancer Foundation; Shirley Fincham, Division of Epidemiology, Stat Med 2007, 26(5):1150–1169. Prevention and Screening, Alberta Cancer Board; and Nhu Le, British 18. Frost G, Darnton A, Harding AH: The effect of smoking on the risk of lung Columbia Cancer Agency. cancer mortality for asbestos workers in Great Britain (1971–2005). Ann Occup Hyg 2011, 55(3):239–247. Acknowledgements 19. Johnson KC, Mao Y, Argo J, Dubois S, Semenciw R, Lava J: The National We thank Benoit Latreille and Louise Nadon for their tireless efforts in Enhanced Cancer Surveillance System: a case–control approach to assigning the occupational exposures. We are also grateful to the helpful environment-related cancer surveillance in Canada. Envirometrics 1998, comments provided on earlier drafts of this manuscript by Paul Demers of 9:495–504. the Ontario Occupational Cancer Research Centre, and Michel Camus of 20. Villeneuve PJ, Parent ME, Sahni V, Johnson KC, Canadian Cancer Registries Health Canada. This study was funded by Health Canada. Epidemiology Research G: Occupational exposure to diesel and gasoline emissions and lung cancer in Canadian men. Environ Res 2011, 111 Author details (5):727–735. Population Studies Division, Health Canada, Ottawa, Ontario, Canada. 21. Department of Manpower and Immigration, Immigration Canada: Canadian Division of Occupational and Environmental Health, Dalla Lana School of classification and dictionary of occupations. Vol 1. Ottawa, Canada: Public Health, University of Toronto, Toronto, Canada. Occupational Cancer Immigration Canada; 1971. Research Centre, Toronto, Ontario, Canada. INRS-Institut Armand-Frappier, 22. Goldberg MS, Siemiatycki J, Gerin M: Inter-rater agreement in assessing University of Quebec, Laval, Quebec, Canada. Division of Epidemiology, occupational exposure in a case–control study. Br J Ind Med 1986, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada. 43(10):667–676. Prevention and Cancer Control, Cancer Care Ontario, Toronto, Ontario, 23. Johnson KC, Hu J, Mao Y: Passive and active smoking and breast cancer Canada. Health Promotion and Chronic Disease Prevention Branch, Public risk in Canada, 1994–97. Cancer Causes Control 2000, 11(3):211–221. Health Agency of Canada, Ottawa, Canada. 24. Rothman KJ: The estimation of synergy or antagonism. Am J Epidemiol 1976, 103(5):506–511. Received: 19 September 2012 Accepted: 10 December 2012 25. Lee PN: Relation between exposure to asbestos and smoking jointly and Published: 13 December 2012 the risk of lung cancer. Occup Environ Med 2001, 58(3):145–153. 26. Last JM: A Dictionary of Epidemiology. 4th edition. New York: Oxford References University Press; 2000. 1. Canadian Cancer Society’s Steering Committee: Canadian Cancer Statistics 27. Finkelstein MM, Verma DK: A cohort study of mortality among Ontario 2012. Toronto: Canadian Cancer Society; 2012. pipe trades workers. Occup Environ Med 2004, 61(9):736–742. 2. Vitra RL: Worldwide Asbestos Supply and Consumption Trends from 1900 28. Raffn E, Lynge E, Korsgaard B: Incidence of lung cancer by histological through 2003. Reston, Virginia: US Geological Survey Circular 1298; 2006:80. type among asbestos cement workers in Denmark. Br J Ind Med 1993, 50 3. United States Environmental Protection Agency: Airborne Asbestos Health (1):85–89. Assessment Update. Washington, DC: US EPA; 1986. 29. Clin B, Morlais F, Launoy G, Guizard AV, Dubois B, Bouvier V, Desoubeaux N, 4. International Agency for Research on Cancer: IARC Monographs in the Marquignon MF, Raffaelli C, Paris C, et al: Cancer incidence within a cohort Evaluation of the Carcinogenic Risk of Chemicals to Humans. Overall occupationally exposed to asbestos: a study of dose–response Evaluations of Carcinogenicity: An updating of IARC Monographs to Humans relationships. Occup Environ Med 2011, 68(11):832–836. Volumes 1 to 42. Lyon, France: IARC; 1987. 30. Yano E, Wang X, Wang M, Qiu H, Wang Z: Lung cancer mortality from 5. National Toxicology Program: Report on carcinogens. 1st edition. exposure to chrysotile asbestos and smoking: a case–control study Washington, DC: US Department of Health and Human Services; 1980. within a cohort in China. Occup Environ Med 2010, 67(12):867–871. 6. International Agency for Research on Cancer: IARC Monographs on the 31. Gustavsson P, Jakobsson R, Nyberg F, Pershagen G, Jarup L, Scheele P: Evaluation of the Carcinogenic Risk of Chemicals to Man, vol 14 Asbestos. Occupational exposure and lung cancer risk: a population-based case- Lyon, France: IARC; 1977. referent study in Sweden. Am J Epidemiol 2000, 152(1):32–40. 7. Ramazzini C: Asbestos is still with us: repeat call for a universal ban. 32. Bilello KS, Murin S, Matthay RA: Epidemiology, etiology, and prevention of J Occup Environ Med 2010, 52(5):469–472. lung cancer. Clin Chest Med 2002, 23(1):1–25. 8. 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Whitwell F, Newhouse ML, Bennett DR: A study of the histological cell types of lung cancer in workers suffering from asbestosis in the United Kingdom. Br J Ind Med 1974, 31(4):298–303. 45. Kannerstein M, Churg J: Pathology of carcinoma of the lung associated with asbestos exposure. Cancer 1972, 30(1):14–21. 46. Lee BW, Wain JC, Kelsey KT, Wiencke JK, Christiani DC: Association of cigarette smoking and asbestos exposure with location and histology of lung cancer. Am J Respir Crit Care Med 1998, 157(3 Pt 1):748–755. 47. Warnock ML, Isenberg W: Asbestos burden and the pathology of lung cancer. Chest 1986, 89(1):20–26. doi:10.1186/1471-2407-12-595 Cite this article as: Villeneuve et al.: Occupational exposure to asbestos and lung cancer in men: evidence from a population-based case-control study in eight Canadian provinces. BMC Cancer 12:595. 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Occupational exposure to asbestos and lung cancer in men: evidence from a population-based case-control study in eight Canadian provinces

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Biomedicine; Cancer Research; Oncology; Surgical Oncology; Health Promotion and Disease Prevention; Biomedicine general; Medicine/Public Health, general
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Abstract

Background: Asbestos is classified as a human carcinogen, and studies have consistently demonstrated that workplace exposure to it increases the risk of developing lung cancer. Few studies have evaluated risks in population-based settings where there is a greater variety in the types of occupations, and exposures. Methods: This was a population based case–control study with 1,681 incident cases of lung cancer, and 2,053 controls recruited from 8 Canadian provinces between 1994 and 1997. Self-reported questionnaires were used to elicit a lifetime occupational history, including general tasks, and information for other risk factors. Occupational hygienists, who were blinded to case–control status, assigned asbestos exposures to each job on the basis of (i) concentration (low, medium, high), (ii) frequency (<5%, 5-30%, and >30% of the time in a normal work week), and (iii) reliability (possible, probable, definite). Logistic regression was used to estimate odds ratios (ORs) and their corresponding 95% confidence intervals (CI). Results: Those occupationally exposed to (i) low, and (ii) medium or high concentrations of asbestos had ORs for lung cancer of 1.17 (95% CI=0.92 – 1.50) and 2.16 (95% CI=1.21-3.88), respectively, relative to those who were unexposed. Medium or high exposure to asbestos roughly doubled the risk for lung cancer across all three smoking pack-year categories. The joint relationship between smoking and asbestos was consistent with a multiplicative risk model. Conclusions: Our findings provide further evidence that exposure to asbestos has contributed to an increased risk of lung cancer in Canadian workplaces, and suggests that nearly 3% of lung cancers among Canadian men are caused by occupational exposure to asbestos. Keywords: Lung cancer, Asbestos, Cigarette smoking, Case–control, Occupational epidemiology Background describe six naturally fibrous minerals, and one of these, Lung cancer continues to be the leading cause of cancer chrysotile, accounts for 95% of the asbestos ever used among Canadian men, and in 2012, it was estimated that worldwide, and until recently was the only type produced 13,300 men would be diagnosed with lung cancer and in Canada [2]. All forms of asbestos have long been 10,800 would die of it [1]. While cigarette smoking is recognized as human carcinogens by the United States recognized as the leading cause of lung cancer, many oc- Environmental Protection Agency [3], the International cupational exposures, including asbestos, have also been Agency for Research on Cancer [4], and the National shown to increase risk. Asbestos is a term used to Toxicology Program [5]. This conclusion is based largely on unequivocal evidence assembled from epidemiological studies that have found excesses of lung cancer and meso- * Correspondence: [email protected] thelioma in highly exposed textile workers, miners, and Population Studies Division, Health Canada, Ottawa, Ontario, Canada cement factory workers [4,6]. Division of Occupational and Environmental Health, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada Full list of author information is available at the end of the article © 2012 Villeneuve et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Villeneuve et al. BMC Cancer 2012, 12:595 Page 2 of 10 http://www.biomedcentral.com/1471-2407/12/595 Today, more than 90% of the asbestos produced have suggested that the combined effects of smoking and worldwide is used to manufacture asbestos sheets and asbestos are more than additive but less than multiplica- pipes [7]. The World Health Organization has estimated tive. This conclusion is consistent with very recent work that approximately 125 million individuals continue to by Frost et al. that revealed interactions that were greater be exposed to asbestos in the workplace [8]. Occupa- than additive, although the multiplicative association tional exposure to asbestos in Canada has decreased dra- could not be rejected [18]. Apart from the studies by matically over the past two decades due to provincial Gustavsson et al. and Pintos et al., we know of no other re- occupational health and safety controls that have been search that has evaluated the joint relationship between implemented. While those involved in the mining of as- asbestos and smoking on lung cancer risk in the general bestos are at higher risk of developing asbestos-related population where exposure levels are much lower than in disease, the precautions offered to these workers to limit asbestos workers, yet with fewer precautions and protec- exposure are greater than those unwittingly exposed tions offered to reduce exposure. In the Gustavsson et al. through other trades. Overall, the mining of asbestos in study, the association between asbestos and smoking on Canada has decreased dramatically, and in 2011, for the lung cancer risk was found to be between additivity and first time in over 130 years, production was halted [9], multiplicativity [11]. In the Montreal study, the association Today, in Canada, the most common sources of asbestos was found to be sub-multiplicative [10]. To add to this exposure arise from the repair, renovation, and demoli- knowledge, we examined the joint relationship between tion of older (pre-1980) buildings. smoking and asbestos in this population-based case–con- Relatively few studies have examined associations be- trol study. tween workplace exposure to asbestos and lung cancer With this background, the primary objective of our using a population-based design. Population-based designs study is to build upon past research by reporting on the provide important features that include an ability to esti- association between occupational exposure to asbestos mate risks over a wider range of exposure levels than and lung cancer among Canadian men. The secondary ob- those typically reported in industry-specific studies. They jective of the study is to evaluate the combined effects oc- provide the opportunity to characterize the frequency and cupational exposure to of asbestos and cigarette smoking nature of exposures in the general population. Moreover, on the risk of lung cancer. because such studies cover diverse occupational groups, there is a reduced impact of confounders that may be spe- Methods cific to particular occupations. Recently, a population- Study population based case–control study in Montreal found that workers A case–control study design was used to address the re- with substantive exposure to asbestos had a greater risk of search objectives, and the data come from the lung cancer lung cancer, however, this finding did not achieve statis- case–control component of the National Enhanced Can- tical significance (odds ratio (OR) =1.78, 95% CI=0.94, cer Surveillance System (NECSS). The overall objective of 3.36) [10]. Cumulative exposure was positively associated the NECSS was to improve our understanding of both en- with lung cancer risk in a case–control study in Stock- vironmental and occupational determinants of cancer holm, Sweden [11], while a multi-center European case– [19]. The NECSS was a collaborative project between control study found no association between occupational the Public Health Agency of Canada and cancer regis- exposure to asbestos and lung cancer in six Central and tries in eight Canadian provinces (British Columbia, Eastern European countries, but a nearly twofold Alberta,Saskatchewan, Manitoba, Ontario, Nova Scotia, (OR=1.85, 95% CI=1.07-3.21) increased risk was observed Newfoundland, and Prince Edward Island). There were among UK workers [12]. no subjects (cases or controls) from the province of While both cigarette smoking and asbestos are recog- Quebec. Detailed information was collected from cases nized lung carcinogens, there remain uncertainties about and controls for a number of potential risk factors includ- how they operate together to increase the risk of lung can- ing: sociodemography, anthropometry, diet, smoking, expo- cer. Attempts to understand the joint effects of smoking sure to second hand smoke, and participation in physical and asbestos on the risk of lung cancer extend back to activities. Individuals were also asked to provide lifetime Selikoff et al.’s seminal work in the late 1960s [13]. A sub- residential and occupational histories. Questionnaires were sequent review of this literature suggested that the inter- administered between 1994 and 1997. active effects are multiplicative [14], which implies that The NECSS endeavoured to collect information for asbestos exposure increases the risk of lung cancer by the each incident cancer within three months of diagnosis. same factor in smokers and non-smokers alike. An addi- Among men, there were a total of 3,718 histologically tive relationship, on the other hand, would assume that confirmed lung cancer cases (ICD-9 rubric 162) identi- the effects of asbestos exposure and smoking are inde- fied between 1994 and 1997. Letters were sent to the pendent. Other reviews [15,16] and a meta-analysis [17] physicians of 3,033 (81.6%) of these cases to solicit their Villeneuve et al. BMC Cancer 2012, 12:595 Page 3 of 10 http://www.biomedcentral.com/1471-2407/12/595 participation. Physician consent was obtained and ques- sufficient information for exposure assessment. No tionnaires were mailed to 2,548 (69%) of the cases; phy- exposures were assigned for jobs that were self-reported sician consent was refused for 229 (6%) of all eligible to be retirement (n=185), disability (n=10), and un- cases and 653 (18%) were deceased at the time of the re- employment (n=8). quest and therefore excluded. Completed questionnaires Occupations and industry titles were assigned by one were returned by 1,736 of the 2,548 cases who were of two hygienists, who were blinded to case–control sta- mailed a questionnaire yielding an overall response rate tus, using the Canadian Classification and Dictionary of of 68.1%. Occupation codes (originally published in 1971 with The NECSS assembled a series of controls from the revisions up until 1986), and Standard Industrial Codes general population. For 5 provinces, controls were iden- [21]. The hygienist coded each job on the basis of expo- tified through provincial health insurance plans (Prince sure to known or suspected lung cancer carcinogens. Edward Island, Nova Scotia, Manitoba, Saskatchewan These exposures included: asbestos, diesel and gasoline and British Columbia). These insurance plans cover engine exhaust emissions, and crystalline silica. This as- more than 95% of residents in the province. Elsewhere, sessment was guided by the scientific and technical lit- either random digit dialing (Newfoundland and Alberta), erature, consultation with experts, and a review of or property assessment data (Ontario) were used as the existing databases of exposure assessment. The assign- sampling frame to recruit controls. Frequency matching ment of workplace exposures took into account the to the overall case grouping (19 types of cancers) was manner that asbestos was used over the years. For used to select controls with similar age and sex distribu- example, before 1976, drywall installers used dry-wall tion, such that there would be at least one control for joint cement that contained asbestos, while after 1980 every case within each sex and 5-year age group for any asbestos was banned in this cement. specific cancer site within each province. In total, ques- The assignment of occupational exposures was done tionnaires were mailed to 4,270 men identified as pos- according to three dimensions: concentration, frequency sible controls in the 8 provinces. Approximately 7% of and reliability. The frequency of exposure was assigned these (n=287) were returned because the address was in- based on the proportion of work time during a normal correct, and no updated address could be found through work week that the subject was exposed; this assignment publicly available sources. In all, 2,547 male controls took into account whether the work was part-time or returned completed questionnaires, representing 64% of seasonal in nature. ‘Low’ frequency corresponded to less those contacted and 60% of those ascertained. than 5% of the work time, ‘Medium’ between 5% and For the purposes of our analyses, we restricted the 30%, and ‘High’ represented more than 30%. Concentra- study population to only include men given that we tion was assessed on a relative scale. For each substance, expected few women to have been exposed to asbestos benchmarks were established and exposures were coded in the workplace. We used the same analysis file previ- with respect to these benchmarks. Non exposure was ously used to evaluate associations between diesel engine interpreted as exposure up to background levels found exhaust emissions and lung cancer which excluded indi- in the general environment. The relative benchmarks for viduals under the age of 40, and those who had not concentration levels used by our team of hygienists were worked for at least one year [20]. In the NECSS, among ‘Low’ for welders and boiler operators, ‘Medium’ for all participating incident lung cancer cases only 0.7% boiler and pipe insulators and marine firemen and ‘High’ (n=13) were diagnosed before the age of 40; the cor- for miners and insulation workers (blowers and responding number of controls excluded to meet the age sprayers). It is very difficult to provide a reliable estimate requirement was 438. A total of 42 cases and 56 controls of the absolute number of fibres per unit of volume cor- were excluded because their reported length of employ- responding to the different exposure levels. However, as ment was less than one year. After applying these exclu- a crude indicator, we can suggest that our ‘Medium’ sion criteria we were left with a total of 1,681 cases and level corresponded roughly to the 1976 American Con- 2,053 controls. ference of Governmental Industrial Hygienists threshold limit values (TLV) given that these values were in force Occupational assignment of exposures in Canada in 1983 at a time when our study subjects Cases and controls were asked to provide information were working. Specifically, the TLV for chrysotile asbes- for each job held in Canada for at least 12 months from tos fibers over 5 microns was 5 fibres per/cc in these the time they were 18 years old until the time of inter- Quebec guidelines. Finally the third dimension of expos- view. Information sought for each job included: job title, ure, reliability, refers to the hygienists’ degree of confi- main tasks, type of industry, location, and the start and dence that the exposure was actually present in the job end dates of employment. A total of 15,646 jobs were under evaluation; ‘Low’ refers to a possible exposure, identified, of these 15,234 (97.4%) jobs contained ‘Medium’ to a probable exposure and ‘High’ to a certain Villeneuve et al. BMC Cancer 2012, 12:595 Page 4 of 10 http://www.biomedcentral.com/1471-2407/12/595 exposure. Estimates of the inter-rater reliability of the eight cross-classification categories, while the ninth ca- exposure assignment method, which were based on the tegory (no asbestos exposure, < 10 cigarette pack-years) work of chemists from the group that conducted the ex- was used as the referent. The joint effects of smoking posure assessment our study, lend credibility to the va- and asbestos on lung cancer risk were evaluated using lidity of the approach we used. Specifically, Goldberg two previously derived indices: the Synergy (S) [24] and et al. reported that the percent agreement among raters Multiplicativity (V) [25]. We followed a similar ap- was between 95% to 98% with a Cohen’s kappa from 0.5 proach that Frost et al. used to evaluate the relationship to 0.7 [22]. between asbestos and smoking and lung cancer in wor- kers in Great Britain [18]. We used our derived odds Statistical analysis ratios (ORs) to calculate the index S [24] as follows: We constructed several metrics to characterize occupa- OR  OR AS 0 tional exposure to asbestos. These metrics included: ever S ¼ OR þ OR  2OR A S 0 exposed, highest attained concentration (high, medium, low), as well as a duration of exposure. Given the small Where OR is the odds ratio of lung cancer exposed number of individuals that had high concentrations of to ‘medium or high’ levels of asbestos among those with exposure, we combined medium and high into one little to no smoking history (<15 pack-years), OR is the group. Those with a low reliability score (“possibly odds ratio of lung cancer among smokers (≥ 40 pack- exposed”) were assumed to have had no exposure. years) with no exposure to asbestos, OR is the odds AS Logistic regression was used to estimate the odds ratio of lung cancer among smokers (≥ 40 pack-years) ratios (OR) and their corresponding 95% confidence exposed to asbestos, where each odds ratio is estimated intervals (CI) for the various exposure metrics. Adjust- relative to the referent group of men who had accrued ments were made for the potential confounders: age, less than 10 cigarette pack-years and were not exposed cigarette smoking, socioeconomic status, exposure to to asbestos (OR ).The Multiplicativity index was calcu- second hand smoke, and occupational exposure to silica, lated as: and diesel exhausts. Occupational exposure to silica, and diesel engine exhausts were assigned to the cases and OR OR 0 AS V ¼ controls using the same methodology that was used for OR OR A S asbestos. Silica and diesel exposures were modelled as cumulative time-weighted measures. While gasoline en- A value that exceeds one for the S index suggests an gine emission exposure measures were also derived for interactive effect between smoking and asbestos expos- the cases and controls, they did not confound the risk ure on lung cancer that could imply a multiplicative ef- estimates for asbestos, and therefore, were not included fect. In contrast, a value of S near one suggests that the in the models as adjustment factors. Multivariable mo- two risk factors would operate in an additive fashion on dels were adjusted for cigarette smoking through the use the risk of lung cancer. For the V index, a value of one of a pack-years variable which incorporated aspects of indicates a multiplicative interaction, whereas as values both smoking duration and intensity. Cigarette pack- greater and less than one indicate an interaction that is years were defined as the number of years of smoking an more or less than multiplicative, respectively. average of 20 cigarettes per day. For exposure to second- hand smoke, a composite measure was used that took Ethics approval into account lifetime exposures received both at home, The participating provincial cancer registries obtained and in the workplace [23]. It was derived as a function approval of the NECSS study protocol through their re- of the number of years of exposure that incorporated spective ethics review boards. All participants provided both the number of regular smokers that lived in each informed consent. residence, and the number of smokers who smoked regularly in the subjects’ immediate work environment Results The joint effect of smoking and occupational exposure Of the 15,234 occupations ever held by the study subjects, to asbestos was first examined by estimating the odds a total of 801 were coded as having either ‘probable’ or ratios for cross-classification categories of cigarette ‘definite’ exposure to asbestos. The most commonly pack-years (<10, 10 - <40, ≥40) and the highest attained reported exposed occupations were mechanics and repair- occupational exposure to asbestos (none, low, medium/ men, stationary engine and utility workers, pipefitters, and high). The small numbers of lung cancers among never construction workers (Table 1). Water transport operating smokers (n=34; 2% of all cases) precluded a separate occupations represented the only group deemed to have a evaluation of asbestos risks in this group. The odds high frequency of exposure to asbestos. Specific jobs ratios and 95% confidence intervals were estimated for included in this group that worked on ships included: deck Villeneuve et al. BMC Cancer 2012, 12:595 Page 5 of 10 http://www.biomedcentral.com/1471-2407/12/595 Table 1 Most frequent occupations among the 801 jobs held by subjects that were classified as having probable or definite exposure to asbestos SOC Number of jobs % Most common exposure coding Confidence Frequency Concentration Mechanics and Repairmen (except electrical) 8580 – 8589 214 26.7 Probable Low Low Stationary Engine and Utilities Equipment 9530 - 9539 124 15.0 Probable Medium Low Pipefitting 8791 89 11.1 Probable Low Low Construction 8733 79 9.9 Probable Low Low Metal shaping occupations 8330 – 8339 48 6.0 Probable Medium Low Fabricating, assembling electrical and electronics 8530 – 8539 34 4.2 Probable Medium Low Water Transport Operating Occupations 9151 – 9159 42 5.2 Probable High Low Firefighters 6111 31 3.9 Definite Medium Low Plasterers 8784 23 2.9 Probable Medium Low Total 801 84.5 A – defined by highest percentage. officers, engineering officers, deck crew, engine and boiler variable, the adjusted odds ratio of lung cancer for an in- room crew workers. crease in 10 years of exposure was 1.03 (95%% CI=0.94- A total of 233 cases and 224 controls, respectively, were 1.13). This risk increased to 1.13 (95% CI=0.84-1.52) when exposed to asbestos at some point during their lifetime oc- analyses were restricted to those who were only exposed cupational history (Table 2). Those who were ever exposed to medium or high concentrations; this result however to asbestos had a 28% increased risk of lung cancer rela- was not statistically significant (p=0.44). The frequency of tive to those who were not (OR=1.28, 95% CI: 1.02, 1.61). the jobs that were deemed to have ‘medium’ or ‘high’ con- The risks according to highest concentration of occupa- centrations of asbestos is presented in Figure 1. The most tional exposure ever attained were more pronounced. common of these jobs were pipefitters and boilermakers, Only two cases and one control reported working in a job and insulators. with an assigned ‘high’ concentration of exposure. As a re- None of the first-order interaction terms between sult, we combined ‘medium’ and ‘high’ concentrations into cigarette smoking pack-years and the three measures of one category. Those who had ever been exposed to asbestos exposure were statistically significant. The cor- medium or high levels had a more than twofold increase responding p-values for the smoking interaction terms in risk (OR=2.16, 95% CI=1.21-3.88). with ‘ever’, ‘highest attained’ and ‘duration’ asbestos ex- We found that duration of occupational exposure to as- posure were 0.33, 0.77, and 0.88, respectively. bestos was not related to the risk of lung cancer (Table 2). Stratified analyses of highest attained asbestos expo- When we modeled duration of exposure as a continuous sure across cigarette pack years categories are presented Table 2 Adjusted odds ratios of lung cancer in relation to occupational exposure to asbestos A B Occupational exposure Cases Controls Odds ratio and 95% CI Odds ratio and 95% CI Unexposed* 1448 1829 1.0 - 1.0 - Ever exposed 233 224 1.31 1.07 – 1.59 1.28 1.02 – 1.61 Highest attained exposure Unexposed 1448 1829 1.0 - 1.0 Low 194 200 1.22 0.99 – 1.51 1.17 0.92 – 1.50 Medium / High 39 24 2.02 1.20 – 3.97 2.16 1.21 – 3.88 Total 1681 2053 Duration of exposure (years) < 10 88 68 1.68 1.21 – 2.33 1.60 1.10 – 2.33 10 - < 20 46 50 1.08 0.74 – 1.69 0.89 0.56 – 1.42 ≥ 20 87 103 1.05 0.78 – 1.42 1.18 0.84 – 1.66 A – Adjusted for age, province, B – Adjusted for age, province, cigarette pack years, occupational exposure to diesel and silica, exposure to second hand smoke. Villeneuve et al. BMC Cancer 2012, 12:595 Page 6 of 10 http://www.biomedcentral.com/1471-2407/12/595 Pipefitter Boilermaker Insulation Welder/sheet metal Other Construction Industrial mechanic Marine craft repair Miner Masonry Excavator Textile worker 0 5 10 15 20 25 30 35 40 45 Number of jobs Figure 1 Most common occupations among mean with medium or high concentration levels of asbestos, NECSS lung cancer case- control study. in Table 3. There was an approximate two-fold increase factors for lung cancer. The approximate 28% increased in risk among those with ‘medium’ or ‘high’ occupational risk observed among men ever exposed to asbestos is simi- exposure to asbestos relative to those with no such ex- lar to the finding of Pintos et al. [10]. In their Montreal posure in each of the three pack-year categories. This is based case–control study, those who were exposed to consistent with a multiplicative relationship between the asbestos had an odds ratio of 1.21, (95% CI=0.98-1.49) rela- two factors. Those who had at least 40 pack-years of tive to those with no exposures. The population attribut- smoking and were exposed to medium or high asbestos able risk (PAR) percent is often used to provide an levels had the highest risk of lung cancer; relative to estimate of the percentage of cases that be avoided if the those with no asbestos exposure, and less than 10 putative exposure was eliminated [26] . We calculated the cigarette pack-years, their risk nearly 38-fold higher PAR in our study using the odds ratio of 1.28 among ever (OR=38.59, 95% CI=10.78-138.08) (Table 4). The calcu- exposed, and an estimated prevalence of exposure of 11.3% lated values of the S and V indices were 2.10 and 0.99 (based on our control series). This yielded a PAR of 3.1% respectively, supporting the notion that the interaction which suggests that a relatively small percentage of Canad- between asbestos and smoking is multiplicative. ian male lung cancer cases are due to occupational expos- ure to asbestos. Based on an estimated 13,300 incident Discussion lung cancers among men in Canada in 2012 [1] this would This population-based study of men employed across a di- account for approximately 412 incident cases. verse range of jobs found that workplace exposure to as- Our study provided support for a dose–response rela- bestos was associated with an increased risk of lung tionship between asbestos exposure and lung cancer as cancer. This association persisted after adjusting for higher risks were observed among those who were ever cigarette smoking, second hand smoke, and other occupa- exposed to ‘medium’ or ‘high’ concentrations of asbestos. tional exposures previously implicated as possible risk Pipefitters accounted for nearly half of these cases and Table 3 Adjusted odds ratios* and 95% C.I. according highest occupational exposure to asbestos across cigarette pack- year smoking categories Cigarette smoking (pack-years) Highest occupational exposure to asbestos < 10 10 - <40 ≥ 40 N OR* 95% C.I. N OR* 95% C.I. N OR* 95% C.I. None 84 1.0 - 630 1.0 - 678 1.0 - Low 13 1.54 0.79 – 3.00 90 1.28 0.91 – 1.80 85 0.88 0.58 – 1.35 Medium or high 2 2.01 0.39 – 10.43 20 2.30 1.09 – 4.84 16 2.50 0.73 – 9.28 N = number of lung cancer cases. * adjusted for age, province, occupational exposure to diesel and silica, and second hand cigarette smoke. Villeneuve et al. BMC Cancer 2012, 12:595 Page 7 of 10 http://www.biomedcentral.com/1471-2407/12/595 Table 4 Synergy and multiplicative indices between asbestos exposure and cigarette smoking Cigarette smoking (pack-years) Asbestos exposure Label Cases Controls Odds ratio* 95% CI < 10 None R 84 745 1.0 - Low — 13 69 1.47 (0.77 – 2.81) Medium/High R 2 7 2.20 0.42 – 11.41) 10 - < 40 None — 630 778 5.28 (3.90 – 7.14) Low — 90 90 6.67 (4.41 – 10.10) Medium/High — 20 13 10.39 (4.83 – 22.36) ≥ 40 None R 678 266 17.68 (12.90 – 24.22) Low — 85 40 15.62 (9.72 – 25.09) Medium/High R 16 3 38.59 (10.78 – 138.08) AS Synergy Index 2.10 Multiplicativity Index 0.99 * adjusted for age, province, occupational exposure to diesel and silica, and second hand cigarette smoke. controls (41 of 87). While the limited number of sub- when compared to durations spent at lower levels sug- jects did not allow us to characterize risks for specific gests that time exposed above a threshold level may be a types of jobs, our results are consistent with a previously relevant marker of risk. However, this finding should be published study of Ontario pipe trade workers [27]. They interpreted cautiously as it based on a very small num- reported a 53% increased risk of lung cancer mortality ber of subjects who were exposed to either medium or among pipefitters who had been registered trade mem- high intensities. bers for at least 30 years, relative to the Ontario general It is well recognized that there is a lengthy latency population. However, their study was somewhat limited period between the time of first exposure to an environ- due to a lack of data on smoking. Our findings support mental carcinogen and the development of a solid tumour the hypothesis that asbestos and cigarette smoking affect such as lung cancer. For example, the latency period asso- the risk of lung cancer in a multiplicative fashion. ciated with cigarette smoking and lung cancer has been In many occupational studies, duration of exposure is estimated to be several decades following the initiation of regarded as valid surrogate measure of cumulative ex- smoking [32]. By extension, the increased risks of lung posure due to the inherent difficulties in retrospective cancer due to exposure to asbestos observed in this study studies to precisely characterize exposure intensity. In are a reflection of workplace exposures many years if not their Montreal case–control study, Pintos et al. found a decades earlier. Indeed, among those classified has having higher risk of lung cancer among those exposed to as- ‘medium’ or ‘high’ concentrations to asbestos in the work- bestos for at least 20 years when compared to those place, the start date of employment was after 1980 in only exposed for shorter durations [10]. Duration of exposure 6% of these jobs. was also positively associated with lung cancer risk Participants in our study were asked to provide infor- in other industry-specific cohorts [28]. In contrast, mation for only those jobs that were held for at least we found that only intensity but not duration of expos- one year. The exclusion of these short-term jobs raises ure was associated with statistically significant increased the possibility that some exposure misclassification has risks of lung cancer. This observation is consistent been introduced. Previous analysis of 27.5 million work- with recently published findings on a cohort of work- ers found increased risks of lung cancer among those exposed to high levels of asbestos (20 to 40 fibers per ers employed in an asbestos reprocessing plant in the Calvados region of France [29]. In this study, Clin and cubic centimeter of air) for only a few months [33]. colleagues observed that the average exposure to asbes- Under a classical error model where the possible expo- sure misclassification error arising from excluding these tos expressed in terms of fibers per ml was associated with pleuro-peritoneal mesothelioma, lung cancer, and short term jobs is non-differential to case–control status, colorectal cancer (p<0.05), however, no statistically sig- our risk estimates would be understated. An important strength of this study was the availability nificant associations were evident with duration of ex- posure for any of these three cancer sites. Other studies of other risk factor data obtained through both the ques- of asbestos workers have also found associations with in- tionnaire, as well as expert-based coding of occupational histories. Unlike many other occupational case–control tensity but not duration of exposure [12,30,31]. Our finding of a stronger positive association between dur- studies, we had extensive data on cigarette smoking, ation of exposure at medium or high levels of asbestos most notably, exposure to second hand smoke. This Villeneuve et al. BMC Cancer 2012, 12:595 Page 8 of 10 http://www.biomedcentral.com/1471-2407/12/595 measure allowed our risk estimates to take into account it has been argued that these differences are not all that lifetime exposure to second-hand smoke incurred at important given that chrysotile is the most commonly both home and workplace settings. In addition, the in- used type of asbestos [40,41]. In our study, those who were dustrial hygienists also coded each job for possible ex- determined to have been exposed to asbestos were posure to other known or suspected lung carcinogens believed to have been exposed to chrysotile, however, it is including: crystalline silica, gasoline and engine emis- possible that some exposure to less prevalent yet more po- sions. We recently found that occupational exposure to tent types of fibers occurred and was unaccounted for. diesel but not gasoline engine emissions increased the Another limitation of our study was the relatively small risk of lung cancer; the risk of lung cancer was also number of study subjects who were ever exposed to increased among individuals exposed to crystalline silica medium or high levels of asbestos. In total, there were [34]. The addition of these two covariates (diesel and sil- only 39 cases and 24 controls exposed at these levels. ica) strengthened the association for asbestos by ap- These small numbers hindered our ability to characterize proximately 20%. the joint relationship between smoking and asbestos ex- Approximately 68% of eligible cases and 64% of eli- posure on the risk of lung cancer. It also limited our exam- gible controls completed a questionnaire. This raises the ination of the risks of lung cancer with exposure to potential to introduce some bias in our risk estimates, asbestos according to different histological subtypes. Se- and our results should be interpreted cautiously because veral studies have found associations that were most pro- of this possibility. However, for several reasons, we do nounced for adenocarcinoma subtypes [28,42-44], however, not believe this bias fundamentally changes our results. others did not [45-47]. The three most common histo- First, observed associations with known and suspected logical types of lung cancer in our study population were risk factors such as cigarette smoking, and exposure to squamous cell carcinoma (35%), adenocarcinoma (28%), second-hand smoke are similar in direction and magni- and small cell carcinoma (15.9%) [34]. When we restricted tude to risk estimates reported in other epidemiological analysis to adenocarcinoma, the odds ratio among those studies. Moreover, our published findings for other oc- exposed to medium or high levels of asbestos increased cupational exposures within the same study population from 2.16 to 3.14 (95% CI=1.50 – 6.58). However, the latter [34] are also consistent with the epidemiological litera- estimate was based on only 13 incident cases and therefore, ture. Lastly, the distribution of lung cancers by histology our study has very limited statistical power to make infe- in our study is remarkably similar to population-based rences by histological type. figures for North America [35] and provides some sup- port for the generalizeability of these results to incident Conclusions lung cancers in Canada. Unfortunately, the NECSS did In summary, the findings from this Canadian case–control not collect data from those diagnosed with mesotheli- study are consistent with the determination by inter- oma, and therefore, we were unable to investigate asso- national agencies that asbestos is a human lung carcino- ciations with this endpoint. gen. While chrysotile asbestos is the predominant type of We were unable to distinguish asbestos on the basis of asbestos in Canada, it is possible that some of the workers fiber type. Asbestos fibers can be described according to in our study were exposed to other types of asbestos fibers. two broad classes serpentines (phyllosilicates) and amphi- For this reason, and given the relatively small number of boles (inosilicates) that differ substantially with respect to individuals exposed to medium and high exposure where biopersistence and physical and chemical properties. Ser- the excess risks of lung cancer were found, we cannot con- pentines include chrysotile asbestos which is the predo- clusively attribute increased lung cancer risks to chrysotile. minant type of asbestos in Canada. The International Despite the limitation, our findings provide further sup- Agency for Research on Cancer has determined that there port that exposure to asbestos has contributed to an is sufficient evidence to conclude that all these forms of increased risk of lung cancer in Canadian workplaces. asbestos can cause cancer in humans [4,6]. There remains Abbreviations considerable uncertainty regarding differences in lung can- CI: Confidence interval; OR: Odds ratio; PAR: Population attributable risk; cer risk resulting from exposure to different types of asbes- NECSS: National enhanced cancer surveillance system; TLV: Threshold limit tos fibers. A review of cohort studies where quantitative value. measurements of asbestos exposure were available demon- Competing interests strated clearer and consistent associations between expo- The authors have no competing interests to declare. sure and lung cancer for crocidolite or amosite [36]. On the other hand, associations from cohorts exposed prima- Authors’ contributions PV contributed to the design of the study, conducted analysis of the data, rily to crysotile asbestos were less consistent [37,38]. It is and took the lead in preparing the manuscript. SH contributed to the design generally accepted that amphibole fibers are more harmful of the study, and assisted in the development of the manuscript. KJ is the than chrysotile fibers for mesothelioma [36,39]. However, principle investigator of the NECSS and oversaw the original collection of the Villeneuve et al. BMC Cancer 2012, 12:595 Page 9 of 10 http://www.biomedcentral.com/1471-2407/12/595 data, design of the questionnaire, and contributed to the writing of this asbestos and man-made vitreous fibres and risk of lung cancer: a manuscript. MEP oversaw the assignment of the occupational exposures for multicentre case–control study in Europe. Occup Environ Med 2007, this study, contributed to the design, and played a prominent role in the 64(8):502–508. writing of this manuscript. All authors read and approved the final 13. Selikoff IJ, Hammond EC, Churg J: Asbestos exposure, smoking, manuscript. and neoplasia. JAMA 1968, 204(2):106–112. 14. 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Saskatchewan Cancer Foundation; Shirley Fincham, Division of Epidemiology, Stat Med 2007, 26(5):1150–1169. Prevention and Screening, Alberta Cancer Board; and Nhu Le, British 18. Frost G, Darnton A, Harding AH: The effect of smoking on the risk of lung Columbia Cancer Agency. cancer mortality for asbestos workers in Great Britain (1971–2005). Ann Occup Hyg 2011, 55(3):239–247. Acknowledgements 19. Johnson KC, Mao Y, Argo J, Dubois S, Semenciw R, Lava J: The National We thank Benoit Latreille and Louise Nadon for their tireless efforts in Enhanced Cancer Surveillance System: a case–control approach to assigning the occupational exposures. We are also grateful to the helpful environment-related cancer surveillance in Canada. Envirometrics 1998, comments provided on earlier drafts of this manuscript by Paul Demers of 9:495–504. the Ontario Occupational Cancer Research Centre, and Michel Camus of 20. Villeneuve PJ, Parent ME, Sahni V, Johnson KC, Canadian Cancer Registries Health Canada. 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