Occupational Exposure and Lung Cancer Risk: A Population-based Case- Referent Study in Sweden

Transcription

1 American Journal Epidemiology Copyright 2 by The Johns Hopkins University School Hygiene and Public Health All rights reserved Vol. 52, No. Printed in U.S.A. Occupational Exposure and Lung Cancer Gustavsson et al. Occupational Exposure and Lung Cancer Risk: A Population-based Case- Referent Study in Sweden Per Gustavsson,,2 Robert Jakobsson,,2 Fredrik Nyberg, 3 Göran Pershagen, 3,4 Lars Järup, 4,5 and Patrik Schéele,2 This case-referent study investigated the lung cancer risk from occupational exposure to diesel exhaust, mixed motor exhaust, other combustion products, asbestos, metals, oil mist, and welding fumes. All cases lung cancer in males aged 4 75 years among stable residents Stockholm County, Sweden, were identified from 85 to 9. Referents were selected as a stratified (age, inclusion year) random sample. Information on lifetime occupational history, residency, and tobacco smoking was obtained from the study subjects or from next kin. Response rates 87% and 85% resulted in,42 cases and 2,364, respectively. Occupational exposures were assessed by an occupational hygienist who coded the intensity and probability each exposure. Risk estimates were adjusted for tobacco smoking, other occupational exposures, residential radon, and environmental exposure to traffic-related air pollution. For the highest quartile cumulative exposure versus no exposure, the relative risk was.63 (95% confidence interval (CI):.4, 2.33) for diesel exhaust,.6 (95% CI:.9, 2.34) for combustion products, and.68 (95% CI:.5, 2.46) for asbestos. Dose-response analyses indicated an increase in lung cancer risk 4% per fiber-year/ml for asbestos exposure. No increased risk was found for the other exposure factors. An overall attributable proportion 9.5% (95% CI: 5.5, 3.9) was estimated for lung cancer related to diesel exhaust, other combustion products, and asbestos. Am J Epidemiol 2; 52:32 4. air pollutants; asbestos; hydrocarbons, aromatic; lung neoplasms; occupational diseases; occupational exposure; polycyclic hydrocarbons; vehicle emissions A number occupations or occupational exposures are established or suspected risk factors for lung cancer. The International Agency for Research on Cancer has identified 2 occupational exposure factors as being carcinogenic to the human lung (aluminum production, arsenic, asbestos, bis-chloromethyl ether, beryllium, cadmium, hexavalent chromium, coke and coal gasification fumes, crystalline silica, nickel, radon, and soot). Diesel exhaust has been classified as probably carcinogenic to humans ( 3). Occupational exposure to diesel exhaust is widespread, and the question its carcinogenicity has been the focus Received for publication April 3, 99, and accepted for publication October 26, 99. Abbreviations: CI, confidence interval; PAHs, polycyclic aromatic hydrocarbons. Department Occupational Health, Stockholm County Council, Stockholm, Sweden. 2 Division Occupational Health, Department Public Health Sciences, Karolinska Institutet, Stockholm, Sweden. 3 Division Environmental Epidemiology, Institute Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. 4 Department Environmental Health, Stockholm County Council, Stockholm, Sweden. 5 Department Epidemiology and Public Health, Imperial College, London, United Kingdom. Reprint requests to Dr. P. Gustavsson, Department Occupational Health, Karolinska Hospital, S-7 76 Stockholm, Sweden ( per.gustavsson@smd.sll.se). a large number epidemiologic studies over the past 2 years. Although findings are contradictory, many evaluations seem to agree that occupational exposure to high levels diesel exhaust for a prolonged period time may be associated with an increased risk lung cancer (4 8). Studies incorporating quantitative or semiquantitative assessments historical exposure levels are needed for a risk assessment pertinent to present occupational as well as nonoccupational environments (9). While there is little controversy over the carcinogenic effect asbestos, there is considerable uncertainty about the magnitude the lung cancer risk at low exposure levels. Dose-response assessments have been nearly entirely based on highly exposed occupational cohorts (, ). Welding stainless steel is possibly associated with an increased risk lung cancer, but the evidence for a carcinogenic effect welding for other materials is weak (2, 3). However, the potential confounding effect from asbestos exposure may not have been fully controlled in many studies (4). The carcinogenic effect certain polycyclic aromatic hydrocarbons (PAHs), especially benzo(a)pyrene, is well documented (5). The lung cancer excess in occupations involving high exposure to combustion products is ten attributed to exposure to PAHs, possibly in combination with exposure to particles (6 ). While dermal exposure to lowgrade mineral oils is carcinogenic to humans (), there is less evidence for a cancer hazard from inhalation oil mist (). 32

2 Occupational Exposure and Lung Cancer 33 The present investigation was initiated to investigate the lung cancer risk from occupational as well as environmental exposures, using detailed individual exposure data. Occupational exposures were assessed in a quantitative or semiquantitative way in order to permit investigation dose-response relationships and interaction. Information on tobacco smoking, environmental air pollution, and proxies for residential radon exposure were included so the risk estimates could be adjusted for important possible confounders. This presentation is focused on lung cancer risk in relation to seven occupational exposure factors: diesel exhaust, mixed motor exhaust, combustion products, asbestos, metals, oil mist, and welding fumes. Results regarding environmental exposures will be published separately. MATERIALS AND METHODS Study base The study population comprised all men aged 4 75 years who were residents Stockholm County, Sweden, at any time between 85 and 9 and who had lived outside the county for no more than 5 years during the period 5 9. All cases lung cancer (International Classification Diseases, Seventh Revision, code 62.) diagnosed from January, 85 to December 3, 9 were identified from the regional cancer register Stockholm County. Referents were selected at random from the general population and were frequency-matched to the cases with regard to age (in 5-year groups) and year inclusion (85 9). Technically, the were identified from computerized population registers for each the years Two referent groups were selected. The first group, population, was selected with no restrictions among men who were alive at the end the respective inclusion year. The second series, mortality-matched, was frequency-matched to the cases with regard to vital status as December 3, 9 (in addition to age and inclusion year) and was selected among men who were alive at the beginning each inclusion year. The second referent group was included for evaluation reporting bias which might arise from the imbalance in the proportion persons alive at the time data collection among cases and, due to the high mortality rate among lung cancer patients. The deceased were selected among persons who had not died from diseases related to tobacco smoking (as an underlying or contributing cause death) (cancers the upper gastrointestinal organs, liver and biliary passages, pancreas, respiratory organs, and urinary bladder, as well as ischemic heart disease, aortic aneurysm, bronchitis and emphysema, peptic ulcer, cirrhosis the liver, and external causes (2)). A postal questionnaire was sent to the study subjects, or to the next kin for deceased subjects. Next kin were identified from the estate inventories for the deceased persons or from parish fices and were selected in the following order: spouse, sibling, child, other relative. Unless a subject declined to participate, up to three reminders were given, the final one by telephone. The questionnaires were completed by telephone interview in cases incomplete answers. The response rate was high for both cases (87 percent; n,42) and (85 percent; n 2,364). Selection subjects, final numbers respondents, and vital status at the time data collection are presented in table. The cases were distributed over the age groups 4 44, 45 49, 7 75 years, with the following percentages per age group:.8, 2.6, 4.3, 9.9, 7.4, 28., and The corresponding percentages for the were.8, 2.5, 3.7, 9.6, 2.2, 28.8, and Cases as well as were equally distributed over the calendar years The study was approved by the ethics committee the Karolinska Institutet. Exposure assessment The questionnaire gathered information on lifetime occupational history, residential history since 5, and smoking habits, as well as on some other potential risk factors for lung cancer. The occupational history was supplemented by detailed questions on work tasks, frequency, and location(s) for occupations involving potential exposure to motor exhaust. The occupational history included company name and location, occupation, and work tasks for each work period at least year during the subject s lifetime. Occupations were coded according to the Swedish standard classification occupations (2). The intensity and probability exposure to seven specific occupational exposure factors were assessed case-by-case for every work period by an occupa- TABLE. Selection male cases with lung cancer and and their vital status at the time data collection, Stockholm County, Sweden, 85 9 Cases Population Mortality-matched No. % No. % No. % Selected Nonrespondents Total included (response rate),6 54, ,44 67, , ,9 82 Vital status included individuals* Alive at time data collection Deceased at time data collection , * Percentages were calculated among included subjects.

3 34 Gustavsson et al. tional hygienist (R. J.) who was blinded to the case/referent status the individuals. The assessments were based on published and unpublished reports exposure levels specific for occupation, work task, and time period (if available), as well as on personal contacts and personal experience. The criteria for the exposure assessments were developed in collaboration with a group occupational hygienists, as a refinement the criteria used in a recent case-referent study head and neck cancers (22). Time-period-specific annual arithmetic average exposure levels were classified on a four-level scale (see below). The indicator substances and cutf points used, as well as the estimated arithmetic mean within each intensity class, are presented in the two first columns table 3. Nitrogen dioxide was used as an indicator for exposure to diesel exhaust (alone or in combination with gasoline exhaust). For mixed (diesel/gasoline) motor exhaust, both carbon monoxide and nitrogen dioxide were used as indicators. The scales and cutf points for the classification mixed exhaust were selected so that generally the same class number would apply for both nitrogen dioxide and carbon monoxide in occupations where diesel- and gasoline-fueled vehicles are used simultaneously. If this criterion was not met for a certain job task, the higher the classes indicated by the carbon monoxide and nitrogen dioxide scales was assigned. The average exposure intensity per class was expressed in units corresponding to the mean the carbon monoxide levels in each class. Benzo(a)pyrene was used as an indicator exposure to combustion products from organic material such as wood, coke, oil, and coal, not including motor exhaust. Metals were assessed as airborne metal dust (including all metals). Welding fumes were assessed in arbitrary units as low, medium, or high, with category averages assigned as, 5, and 5 units, where 5 units corresponded to full-time employment as a manual metal arc welder. The probability exposure for each work period and substance was assessed as, 2, 5, or 85 percent. The assessments were based on the estimated exposure prevalence within each occupation/job task. Cumulative exposure for each factor was calculated as the product the intensity, the probability, and the duration the exposure, summed over all work periods in the person s occupational history. The cumulative dose was categorized according to quartiles among exposed, and each category was represented by an indicator variable. The number and proportion ever exposed to each the factors and the correlation exposures among the are presented in table 2. Exposures to asbestos and combustion products were correlated, as were exposures to oil mist and metal dust. Furthermore, a large proportion individuals exposed to welding fumes had also been exposed to combustion products, asbestos, or metal dust. Not surprisingly, exposures to diesel exhaust and mixed motor exhaust were closely correlated, since persons exposed to exhaust from both diesel- and gasoline-fueled vehicles received a code for both exposures, although the intensity code would vary depending on the individual exposure situation. Data analysis The relative risks developing lung cancer (and their 95 percent confidence intervals) were estimated by unconditional logistic regression (23). All analyses were adjusted for the variables used for matching the (age group and year inclusion), through the use indicator variables. Vital status was used as a matching factor for the selection mortality-matched, which theoretically called for inclusion this variable in the analysis. However, it was not appropriate to include vital status in the model when the population were used, since subsequent death is very strongly associated with lung cancer. Adjustment for such a factor may yield biased risk estimates for an exposure factor (23). Exploratory analyses indicated that such bias did occur in these data; inclusion vital status when the population were used gave lower relative risks for most occupational exposure factors, whereas the relative risks were unaffected by inclusion vital status when the mortality-matched were used. No large differences in risk were noted for the occupational factors when risk calculation was based on population or on mortality-matched only, if vital status was not included in the model. Thus, we combined both referent groups in the final analyses in order to improve the precision through the use a larger number, and we did not match for vital status in order to minimize the bias the risk estimates (although the influence including vital status with the combined reference group was marginal). TABLE 2. Proportion ever exposed to any seven occupational exposure factors and correlation exposure factors, Stockholm County, Sweden, 85 9 Exposure factor No. exposed % exposed Diesel exhaust Motor exhaust % exposed also exposed to: Other combustion products Asbestos Metal dust Oil mist Welding Diesel exhaust Motor exhaust Other combustion products Asbestos Metal dust Oil mist Welding

4 Occupational Exposure and Lung Cancer 35 Smoking was controlled for by indicator variables indicating former smoking ( 2 years since stopping) and current smoking, on average,, 2, and >2 cigarettes/day (or the corresponding amount tobacco). In addition, we adjusted for time since stopping smoking and intensity smoking (within classes intensity among current smokers) using two continuous variables. Data were missing on smoking intensity for two individuals and on time since stopping smoking for seven individuals. Historical environmental level nitrogen dioxide was used as an indicator nonoccupational exposure to air pollutants from road traffic. The procedure for development the exposure index is described in detail elsewhere (24). Briefly, all, addresses in the residential histories were transformed into geographic coordinates through the use a regional address database. Nitrogen dioxide exposure levels since 55 were modeled from a regional emission database reflecting exposure levels in 93, by accounting for historical changes in the distribution roads and road traffic intensity. The annual mean concentration nitrogen dioxide was calculated by a dispersion model with a grid size ranging from m m to 2, m 2, m, depending on population density. The levels predicted by the model were within 2 percent (±2 percent) measured levels nitrogen dioxide. Finally, the air pollution data were linked to the address coordinates, and indexes the cumulative dose and average exposure level nitrogen dioxide were calculated for each person in the study over various time windows. The index average exposure level, calculated with a lag 2 years, was dichotomized at the 9th percentile and used in the regression model for control confounding. Historical environmental level sulfur dioxide (as an indicator air pollutants from residential heating) had no influence on the relative risk lung cancer and was not used for confounding control in the analysis occupational exposures. Radon exposure for each residence was estimated from an equation predicting indoor radon levels from geographic data on ground radon, as well as data on building material and house type, obtained from the questionnaire. The regression equation was obtained by regressing radon measurements for 9,2 houses from a nationwide Swedish radon study (25) on these variables. The time-weighted cumulative radon exposure was calculated over all available residences in Stockholm County between 3 years before the end follow-up and 3 years before the end follow-up. Cumulative exposure was dichotomized at the median value and used in the logistic regression analysis for confounding control. RESULTS The relative risks lung cancer, in exposure categories determined by the highest intensity experienced for at least year during the subject s work history (considering only exposures with the highest probability code), are presented in table 3. High risk excesses were noted for high exposure both to asbestos and to combustion products. Slightly increased relative risks were observed in the highest dose class mixed motor exhaust and in the intermediate class diesel exhaust. There were very few cases in the highest dose class for diesel exhaust. Increased relative risks were also noted for welding fumes, but there was no evidence a dose response in terms maximum exposure level. The intensity exposure to oil mist or metals did not seem to affect the lung cancer risk. The relative risks associated with cumulative exposure to the seven occupational factors are presented in table 4. Risk estimates are presented with adjustment for matching factors only ( Crude ); with adjustment for smoking, residential radon, and environmental nitrogen dioxide level ( Adjusted (A) ); and with additional adjustment for diesel exhaust, combustion products, and asbestos when appropriate ( Adjusted (B) ) (see table footnotes). Increased risks lung cancer were noted in the highest quartiles cumulative exposure to diesel exhaust, combustion products, and asbestos. The risk associated with exposure to diesel exhaust was affected neither by adjustment for smoking habits nor by adjustment for exposure to combustion products and asbestos. The risk estimates for both combustion products and asbestos were attenuated when the two exposures were included in the model ( Adjusted (B) ), but both relative risks remained statistically significantly elevated. No consistently increased risk was noted for cumulative dose mixed motor exhaust, metals, oil mist, or welding fumes. Dose-response relationships were investigated based on the categorized variables cumulative dose. Each exposure class was represented by the mean value the continuous cumulative exposure among all subjects within the class, in order to avoid undue large influence from a few very high exposures in the top category. A positive dose-response relationship was noted for diesel exhaust (relative risk.9; 95 percent confidence interval (CI):.2,.6) for an increase in the cumulative dose mg-year/m 3 nitrogen dioxide, adjusted for smoking, residential radon, environmental nitrogen dioxide, and exposure to other combustion products or asbestos. Dose response for combustion products and asbestos was investigated analogously, although both exposures were included in the same regression model to account for their interrelatedness. Both exposures showed a positive dose-response relationship: For combustion products, the relative risk was.6 (95 percent CI:.,.) for each increase in exposure by µg-year/m 3 benzo(a)pyrene, and for asbestos, the relative risk was.4 (95 percent CI:.4,.25) for an increase in cumulative exposure by fiber-year/ml. As an alternative, the continuous variables for cumulative exposure were included directly in the regression model, giving a similar risk estimate per exposure unit (for combustion products, relative risk.48 (95 percent CI:.7,.89) per µg-year/m 3 benzo(a)pyrene; for asbestos, relative risk.4 (95 percent CI:.6,.22) per fiber-year/ml). Thus, both models indicated an increase in lung cancer risk from asbestos exposure approximately 4 percent per fiber-year/ml. The risk lung cancer was positively correlated with duration exposure to mixed motor exhaust and possibly also diesel exhaust, but not the other exposure factors (table 5). Lung cancer risk was also estimated in relation to duration exposure in the middle or highest exposure intensity classes only, but this provided no additional evidence an association for any the exposure factors.

5 36 Gustavsson et al. TABLE 3. Exposure intensity classes used for exposure estimation and relative risks lung cancer, subdivided by the highest intensity class* exposure at least year s duration, Stockholm County, Sweden, 85 9 Exposure factor and exposure category Estimated mean level in class Mean duration exposure in class (years) No. cases No. Crude relative risk 95% confidence interval Adjusted relative risk 95% confidence interval Diesel exhaust (µg nitrogen dioxide/m 3 ) Motor exhaust (mixed gasoline/diesel) (mg carbon monoxide/m 3 ) Combustion products (µg benzo(a)pyrene/m 3 ) Asbestos (fibers/ml) Metals (mg/m 3 ) Oil mist (mg/m 3 ) Welding fumes Low Intermediate High 8 26, , , , , , , , * Considering work periods with the highest probability code only. Adjusted for age group and selection year. Adjusted for age group, selection year, smoking, residential radon level, and environmental exposure to nitrogen dioxide. See text for explanation classes ,.73.5, ,.57.4,.74.96,.85.4, ,.54.84,.72.29, , 2.2.2, , ,.57.85,.86.87,.88.5, 2..7, ,.3.2, , , ,.49.9, 2..6, ,.63.72,.47.78, 2..72,.6.89, 2..25, , 2.32., , ,.56.75,.8.92, , , ,.24.6, , , 2.3 DISCUSSION This study showed an increased relative risk lung cancer after exposure to diesel exhaust, other combustion products, or asbestos, while there was no consistent evidence for an increased risk after exposure to mixed motor exhaust, metal dust, oil mist, or welding fumes. Some methodological problems involved in the estimation quantitative exposure-response relationships from population-based case-referent studies were recently reviewed in a discussion a study on asbestos exposure and mesothelioma risk (26). The authors distinguished between diagnostic bias, information bias, and exposure assessment bias as sources systematic error. To this may be added problems associated with the selection, as well as selection appropriate analytical methods. In this study, bias in the identification cases seems unlikely. The regional cancer register from which the cases were derived is part the Swedish national cancer register, which has a high level accuracy and completeness (27,

6 Occupational Exposure and Lung Cancer 37 TABLE 4. Relative risk lung cancer by quartile cumulative exposure for seven exposure factors, Stockholm County, Sweden, 85 9 Exposure factor and exposure category Mean cumulative exposure in class No. cases No. Crude* Adjusted (A) RR 95% CI RR 95% CI RR Adjusted (B) 95% CI Diesel exhaust (mg-years/m 3 nitrogen dioxide) > Motor exhaust (mixed gasoline/ diesel) (mg-years/m 3 carbon monoxide) > Combustion products (µg-years/m 3 benzo(a)pyrene) > Asbestos (fiber-years/ml) > Metals (mg-years/m 3 ) > Oil mist (mg-years/m 3 ) > Welding fumes Quartile Quartile 2 Quartile 3 Quartile , , , , , , , ,.5.96,.9.84,.77.23, ,.79.83,.7.28, , 2..82,.68.87,.75.8,.66.3, ,.76.67,.53., , ,.47.85,.8.77,.67.95,.96.76, 2..53,.7.66,.95.72, 2..84, 2.3., ,.92.82, 2.7 * Adjusted for age group and selection year. Adjusted for age group, selection year, smoking, residential radon level, and environmental exposure to nitrogen dioxide. Relative risks for motor exhaust, metals, oil mist, and welding fumes were additionally adjusted for exposure to diesel exhaust, combustion products, and asbestos. Relative risks for diesel exhaust, combustion products, and asbestos were adjusted for exposure to each other. RR, relative risk; CI, confidence interval ,.8.77,.67.67,.53.3, ,.79.73,.64., 2..88,.82.86,.9.8,.73.8,.82.3, 2.7.8,.92.6,.5.9, , ,.75.72,.69.76,.76.89, 2..72, , 2..59,.95.54,.83.94, 2.69., ,.76.86, ,.4.77,.66.7,.6.4, ,.74.74,.65.92,.9.74,.6.8,.8.7,.57.69,.59.9, ,.89.56,.4., 2.7.5, ,.63.65,.54.63,.5.55,.37.7, , 2..55,.86.55,.88.83, , ,.36.46,.52 TABLE 5. Relative risk* lung cancer according to seven occupational exposure factors, by duration exposure, Stockholm County, Sweden, 85 9 Duration exposure (years) Diesel exhaust RR 95% CI RR Motor exhaust (mixed) 95% CI Combustion products Asbestos Metals Oil mist Welding fumes RR 95% CI RR 95% CI RR 95% CI RR 95% CI RR 95% CI > ,.3.88,.65.97, ,.99.85,.57.4, , 2..,.85.98, , 2..6,.92.7, ,.4.2, , ,.32.6, , , , ,.9 * Adjusted for age group, selection year, smoking, residential radon level, and environmental exposure to nitrogen dioxide. RR, relative risk; CI, confidence interval. Reference category.

7 38 Gustavsson et al. 28). Referents were selected from the population, and the response rates were high in both groups. The clinical diagnosis lung cancer did not rely on information on the subject s occupation, and the diagnosis was based on histology for 78.3 percent the cases and on cytology for 2.4 percent the cases. The reason for including the mortality-matched was to evaluate possible bias arising from obtaining occupational histories mainly from next kin for the cases and mainly from the study subjects themselves for the population (29, 3). We excluded smokingrelated causes death from the mortality-matched referent series, partly to obtain unbiased risk estimates the effect smoking (3) but more importantly because several the risk estimates for the occupational exposure factors otherwise may have been biased towards the null, since several these factors may increase the risk death not only from lung cancer but also from other forms cancer and cardiovascular diseases, in analogy with tobacco smoking. Information bias refers to the problem study subjects being aware the association under study and thereby introducing differential misclassification, since the cases may recall more exposure than. In this study, the exposures were assessed by an occupational hygienist who was unaware the case/referent status the individuals. No questions on actual exposures were put to the study subjects. Selective overreporting jobs involving exposure to diesel exhaust, combustion products, and asbestos but not jobs with exposure to metal dust, oil mist, or welding fumes seems very unlikely. Error in the exposure assessment, such as systematic over- or underestimation historical exposure levels, is probably the most significant methodological problem the present study, with a possible bearing on the doseresponse relationships found. Systematic underestimation exposure levels would tend to exaggerate the estimated risk per exposure unit, while overestimation would produce unit risk estimates that were too low. There is no way evaluating whether past exposures were over- or underestimated, since all available data on occupational exposures to the studied factors were used for the assessments. Precision would be expected to be best for asbestos, for which a large number exposure data were available (see below). The precision the risk estimates for nitrogen dioxide as a marker exposure to diesel exhaust and benzo(a)pyrene as a marker combustion products is lower because sparse data on past exposure levels, and the risk estimates must be interpreted with caution. The frequency matching used 42 strata (7 6) age and selection year, and the numbers cases and might consequently have been small in some strata, particularly for young subjects. The validity the unconditional logistic regression model could possibly be questioned. To investigate this, we recalculated all results for diesel exhaust exposure by conditional logistic regression, using the strata age and selection year to define the risk sets. The risk estimates obtained in this way were very close to those from the unconditional regression model. Diesel exhaust The analysis relative risk in relation to cumulative dose indicated an increased risk lung cancer in the highest dose group, and a dose-response trend was present in terms cumulative dose. Previous data are not unequivocal but indicate that prolonged exposure to high levels diesel exhaust may increase the risk lung cancer (4, 6 8). Few previous studies have incorporated quantitative dose measures. Elemental carbon was used as an indicator for diesel exhaust in one study the US trucking industry (32). There was a positive relation between lung cancer risk and cumulative exposure to elemental carbon. Risk estimates were adjusted for smoking and asbestos exposure. The present findings add further evidence for an association between diesel exhaust and lung cancer, and they indicate that about 4 percent (one fourth the 5.8 percent exposed ) the male population in Stockholm County have experienced levels diesel exhaust high enough to produce a risk excess approximately 6 percent. The occupational titles that were most common for work periods assigned an intermediate or high intensity code for diesel exhaust were: machinery and motor repairer, miner/rock blaster, truck driver, bus driver, construction machine operator, and forklift truck driver. The average number mg-years/m 3 nitrogen dioxide in the highest cumulative dose group (table 4), for which a lung cancer excess was found, was The average exposure duration in this group was 34.6 years, giving an average exposure level 6 µg/m 3. Caution is warranted in the interpretation this quantitative risk estimate, since there were few representative measurements available from earlier periods. However, the present data indicate that the Swedish threshold limit value for motor exhaust 2, µg/m 3 nitrogen dioxide will not protect workers from carcinogenic effects. The analysis duration exposure showed some evidence a dose-response relationship for mixed motor exhaust. However, neither the analysis maximum exposure level nor the analysis cumulative dose showed any effect for mixed motor exhaust. A large proportion those exposed to mixed motor exhaust were also exposed to diesel exhaust (table 2), and thus the evidence for a carcinogenic effect motor exhaust other than diesel exhaust is weak in the present data. Asbestos As expected, exposure to asbestos was associated with an increased risk lung cancer. Analyses both maximum exposure intensity and cumulative dose supported the association, while the risk did not correlate with duration exposure. There was a statistically significant dose-response trend for cumulative dose. Most previous epidemiologic studies, which have been based predominantly on highly exposed occupational cohorts, have indicated that the relative risk increases by approximately percent per fiber-year/ml, depending on asbestos type, length follow-up, etc. (, 33). In this study, the relative risk increased by approximately 4 percent per fiber-year/ml, with adjustment for exposure to combustion products. A recent evaluation occupational dose-response data showed that

8 Occupational Exposure and Lung Cancer 39 other population-based studies occupational exposure (typically dealing with lower asbestos levels than those found in occupational cohorts) have similarly indicated a risk per fiberyear/ml that is higher than the percent per fiber-year/ml predicted by the commonly applied linear extrapolation from highly exposed cohorts (). A previous Swedish case-referent study lung cancer in Gothenburg supported the hypothesis that asbestos may be more potent per fiber-year/ml than is usually assumed, although no relative risk per fiber-year/ml was calculated. The population attributable fraction among men in Gothenburg was 6 percent (34). A prospective population cohort study from the Netherlands (35), as well as a population-based case-referent study from Germany (36), also indicated high population attributable fractions (.6 percent and 8 percent, respectively) for occupational exposure to asbestos and lung cancer in men, but these studies gave no doseresponse data in terms fiber-years/ml. There are two main potential sources bias in the risk estimate a 4 percent increase per fiber-year/ml. First, one could question whether the procedure multiplying intensity and probability exposure per work task is an unbiased estimate each person s exposure intensity. If the exposure probability is used more to express a general uncertainty in the intensity estimate rather than to adequately reflect a true low probability exposure, this would tend to underestimate the true exposure levels and thereby overestimate the risk per exposure unit. To investigate the maximum possible magnitude such bias, we recalculated the cumulative dose asbestos for all individuals in the study, setting the probability to. for all asbestos-exposed work periods. This increased the doses by approximately 44 percent in the two upper quartiles cumulative dose. Thus, even if the probability codes were totally disregarded, which would tend to overestimate the dose considerably, there is still an excess about percent (4/ ) per fiber-year/ml in these data. The second question is whether historical exposure levels were correctly assessed. The assessments were, to a large extent, based on a survey investigation asbestos exposure levels (based on fiber counts) at Swedish workplaces that was performed in 69 73, involving over 2,4 samples at 35 workplaces, which is representative 7 75 percent the total use asbestos in Sweden (37). This rather extensive survey would be expected to reflect actual working conditions in Sweden for that period reasonably well. Combustion products (other than motor exhaust) A number PAHs are carcinogenic, and the carcinogenic effect fumes from coke and gas production, as well as soot, is assumed to be mediated at least in part by PAHs (5 7). Benzo(a)pyrene is ten used as an indicator exposure to PAHs. During the past decade, exposure to fine particles has been in focus as an alternative explanation for the excess lung cancer in occupational groups exposed to combustion products (). This study confirmed an excess risk lung cancer after exposure to combustion products, both in the analysis by maximum exposure level and in the analysis by cumulative dose. A dose-response trend was present in terms cumulative dose. Welding fumes, oil mist, and metal dust Two recent meta-analyses epidemiologic studies welders (3, 4) arrived at different conclusions. One suggested an increased risk lung cancer after welding either stainless steel or mild steel (4), while the other concluded that there is firm evidence an increased lung cancer risk after welding stainless steel only (3). Exposure to welding fumes has been considered possibly carcinogenic to humans by the International Agency for Research on Cancer (2), although no distinction was made with regard to welding stainless steel or other materials. In a population-based case-referent study from Germany (38), an excess lung cancer was noted after a cumulative exposure more than 6, hours welding. However, adjustment for tobacco smoking and exposure to asbestos reduced this to a nonsignificant level. The present study gives no evidence for a carcinogenic effect mild steel welding, which is the predominant type welding in the Stockholm area. Untreated and mildly treated mineral oils are classified as carcinogenic to humans by the International Agency for Research on Cancer, on the basis an increased risk for skin cancer. The evidence for an association between inhalation oil mist and lung cancer is weak (). No effect exposure to oil mist was seen in this study. Some metals, such as hexavalent chromium, cadmium, nickel, and arsenic, are suspected or documented carcinogens (, 2, 39), whereas aluminum and iron are not. No effect on lung cancer risk was seen for exposure to metals in the present study. Attributable fraction The proportion cases in the population that could be prevented if the respective exposures were eliminated, i.e., the attributable fraction in the population (23), was calculated based on the relative risks associated with the highest quartiles cumulative dose for diesel exhaust and combustion products and with the two highest quartiles for asbestos exposure ( Adjusted (B) in table 4). The prevalence the exposures in the population was assessed from the. The attributable fractions in the population were: for diesel exhaust, 2.7 percent; for asbestos, 4. percent; and for combustion products, 2.2 percent. To assess the overall effect these exposures, we considered an alternative model, introducing an indicator variable for any these three exposures (4). The overall proportion lung cancer cases that could be prevented if occupational exposure to diesel exhaust, asbestos, and combustion products were reduced to the safe levels suggested by this study was estimated to be 9.5 percent (95 percent CI: 5.5, 3.9). ACKNOWLEDGMENTS This study was financially supported by the Swedish Council for Work Life Research (grant ), the

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