1 Department of Occupational Health, Stockholm County Council, Stockholm, Sweden.
2 Division of Occupational Health, Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden.
3 Division of Environmental Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
4 Department of Environmental Health, Stockholm County Council, Stockholm, Sweden.
5 Department of Epidemiology and Public Health, Imperial College, London, United Kingdom.
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ABSTRACT |
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air pollutants; asbestos; hydrocarbons, aromatic; lung neoplasms; occupational diseases; occupational exposure; polycyclic hydrocarbons; vehicle emissions
Abbreviations: CI, confidence interval; PAHs, polycyclic aromatic hydrocarbons
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INTRODUCTION |
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Occupational exposure to diesel exhaust is widespread, and the question of its carcinogenicity has been the focus of a large number of epidemiologic studies over the past 20 years. Although findings are contradictory, many evaluations seem to agree that occupational exposure to high levels of diesel exhaust for a prolonged period of time may be associated with an increased risk of lung cancer (48
). Studies incorporating quantitative or semiquantitative assessments of 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 of asbestos, there is considerable uncertainty about the magnitude of the lung cancer risk at low exposure levels. Dose-response assessments have been nearly entirely based on highly exposed occupational cohorts (10, 11
).
Welding of stainless steel is possibly associated with an increased risk of lung cancer, but the evidence for a carcinogenic effect of welding for other materials is weak (12, 13
). However, the potential confounding effect from asbestos exposure may not have been fully controlled in many studies (14
). The carcinogenic effect of certain polycyclic aromatic hydrocarbons (PAHs), especially benzo(a)pyrene, is well documented (15
). The lung cancer excess in occupations involving high exposure to combustion products is often attributed to exposure to PAHs, possibly in combination with exposure to particles (16
18
). While dermal exposure to low-grade mineral oils is carcinogenic to humans (1
), there is less evidence for a cancer hazard from inhalation of oil mist (19
).
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 of 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.
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MATERIALS AND METHODS |
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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 of inclusion (19851990). Technically, the referents were identified from computerized population registers for each of the years 19851990. Two referent groups were selected. The first group, "population referents," was selected with no restrictions among men who were alive at the end of the respective inclusion year. The second series of referents, "mortality-matched referents," was frequency-matched to the cases with regard to vital status as of December 31, 1990 (in addition to age and inclusion year) and was selected among men who were alive at the beginning of each inclusion year. The second referent group was included for evaluation of reporting bias which might arise from the imbalance in the proportion of persons alive at the time of data collection among cases and referents, due to the high mortality rate among lung cancer patients. The deceased referents were selected among persons who had not died from diseases related to tobacco smoking (as an underlying or contributing cause of death) (cancers of 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 of the liver, and external causes (20)).
A postal questionnaire was sent to the study subjects, or to the next of kin for deceased subjects. Next of kin were identified from the estate inventories for the deceased persons or from parish offices 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 of incomplete answers. The response rate was high for both cases (87 percent; n = 1,042) and referents (85 percent; n = 2,364). Selection of subjects, final numbers of respondents, and vital status at the time of data collection are presented in table 1. The cases were distributed over the age groups 4044, 4549, ... 7075 years, with the following percentages per age group: 1.8, 2.6, 4.3, 9.9, 17.4, 28.1, and 35.9. The corresponding percentages for the referents were 1.8, 2.5, 3.7, 9.6, 20.2, 28.8, and 33.3. Cases as well as referents were equally distributed over the calendar years 19851990.
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Exposure assessment
The questionnaire gathered information on lifetime occupational history, residential history since 1950, 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 of at least 1 year during the subject's lifetime. Occupations were coded according to the Swedish standard classification of occupations (21). The intensity and probability of exposure to seven specific occupational exposure factors were assessed case-by-case for every work period by an occupational hygienist (R. J.) who was blinded to the case/referent status of the individuals.
The assessments were based on published and unpublished reports of 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 of occupational hygienists, as a refinement of the criteria used in a recent case-referent study of 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 cutoff points used, as well as the estimated arithmetic mean within each intensity class, are presented in the two first columns of table 3.
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The probability of exposure for each work period and substance was assessed as 0, 20, 50, 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 of the intensity, the probability, and the duration of the exposure, summed over all work periods in the person's occupational history. The cumulative dose was categorized according to quartiles among exposed referents, and each category was represented by an indicator variable.
The number and proportion of referents ever exposed to each of the factors and the correlation of exposures among the referents 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 of 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.
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Smoking was controlled for by indicator variables indicating former smoking (2 years since stopping) and current smoking of, on average, 110, 1120, and >20 cigarettes/day (or the corresponding amount of tobacco). In addition, we adjusted for time since stopping smoking and intensity of smoking (within classes of 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 of nitrogen dioxide was used as an indicator of nonoccupational exposure to air pollutants from road traffic. The procedure for development of the exposure index is described in detail elsewhere (24). Briefly, all 11,000 addresses in the residential histories were transformed into geographic coordinates through the use of a regional address database. Nitrogen dioxide exposure levels since 1955 were modeled from a regional emission database reflecting exposure levels in 1993, by accounting for historical changes in the distribution of roads and road traffic intensity. The annual mean concentration of nitrogen dioxide was calculated by a dispersion model with a grid size ranging from 100 m x 100 m to 2,000 m x 2,000 m, depending on population density. The levels predicted by the model were within 20 percent (±20 percent) of measured levels of nitrogen dioxide. Finally, the air pollution data were linked to the address coordinates, and indexes of the cumulative dose and average exposure level of nitrogen dioxide were calculated for each person in the study over various time windows. The index of average exposure level, calculated with a lag of 20 years, was dichotomized at the 90th percentile and used in the regression model for control of confounding. Historical environmental level of sulfur dioxide (as an indicator of air pollutants from residential heating) had no influence on the relative risk of lung cancer and was not used for confounding control in the analysis of 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 9,002 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 30 years before the end of follow-up and 3 years before the end of follow-up. Cumulative exposure was dichotomized at the median value and used in the logistic regression analysis for confounding control.
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RESULTS |
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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 of lung cancer were noted in the highest quartiles of 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 of mixed motor exhaust, metals, oil mist, or welding fumes.
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The risk of lung cancer was positively correlated with duration of 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 of exposure in the middle or highest exposure intensity classes only, but this provided no additional evidence of an association for any of the exposure factors.
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DISCUSSION |
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Some methodological problems involved in the estimation of quantitative exposure-response relationships from population-based case-referent studies were recently reviewed in a discussion of a study on asbestos exposure and mesothelioma risk (26). The authors distinguished between diagnostic bias, information bias, and exposure assessment bias as sources of systematic error. To this may be added problems associated with the selection of referents, as well as selection of appropriate analytical methods.
In this study, bias in the identification of cases seems unlikely. The regional cancer register from which the cases were derived is part of the Swedish national cancer register, which has a high level of accuracy and completeness (27, 28
). Referents were selected from the population, and the response rates were high in both groups. The clinical diagnosis of lung cancer did not rely on information on the subject's occupation, and the diagnosis was based on histology for 78.3 percent of the cases and on cytology for 20.4 percent of the cases.
The reason for including the mortality-matched referents was to evaluate possible bias arising from obtaining occupational histories mainly from next of kin for the cases and mainly from the study subjects themselves for the population referents (29, 30
). We excluded smoking-related causes of death from the mortality-matched referent series, partly to obtain unbiased risk estimates of the effect of smoking (31
) but more importantly because several of the risk estimates for the occupational exposure factors otherwise may have been biased towards the null, since several of these factors may increase the risk of death not only from lung cancer but also from other forms of cancer and cardiovascular diseases, in analogy with tobacco smoking.
"Information bias" refers to the problem of study subjects' being aware of the association under study and thereby introducing differential misclassification, since the cases may "recall" more exposure than referents. In this study, the exposures were assessed by an occupational hygienist who was unaware of the case/referent status of the individuals. No questions on actual exposures were put to the study subjects. Selective overreporting of jobs involving exposure to diesel exhaust, combustion products, and asbestos but not of 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 of historical exposure levels, is probably the most significant methodological problem of the present study, with a possible bearing on the dose-response relationships found. Systematic underestimation of 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 of 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 of exposure data were available (see below). The precision of the risk estimates for nitrogen dioxide as a marker of exposure to diesel exhaust and benzo(a)pyrene as a marker of combustion products is lower because of sparse data on past exposure levels, and the risk estimates must be interpreted with caution.
The frequency matching used 42 strata (7 x 6) of age and selection year, and the numbers of cases and referents might consequently have been small in some strata, particularly for young subjects. The validity of 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 of 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 of relative risk in relation to cumulative dose indicated an increased risk of lung cancer in the highest dose group, and a dose-response trend was present in terms of cumulative dose. Previous data are not unequivocal but indicate that prolonged exposure to high levels of diesel exhaust may increase the risk of 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 of 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 of the 15.8 percent of exposed referents) of the male population in Stockholm County have experienced levels of diesel exhaust high enough to produce a risk excess of approximately 60 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 of mg-years/m3 of nitrogen dioxide in the highest cumulative dose group (table 4), for which a lung cancer excess was found, was 5.52. The average exposure duration in this group was 34.6 years, giving an average exposure level of 160 µg/m3. Caution is warranted in the interpretation of 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 of 2,000 µg/m3 of nitrogen dioxide will not protect workers from carcinogenic effects.
The analysis of duration of exposure showed some evidence of a dose-response relationship for mixed motor exhaust. However, neither the analysis of maximum exposure level nor the analysis of cumulative dose showed any effect for mixed motor exhaust. A large proportion of those exposed to mixed motor exhaust were also exposed to diesel exhaust (table 2), and thus the evidence for a carcinogenic effect of motor exhaust other than diesel exhaust is weak in the present data.
Asbestos
As expected, exposure to asbestos was associated with an increased risk of lung cancer. Analyses of both maximum exposure intensity and cumulative dose supported the association, while the risk did not correlate with duration of 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 1 percent per fiber-year/ml, depending on asbestos type, length of follow-up, etc. (10, 33
). In this study, the relative risk increased by approximately 14 percent per fiber-year/ml, with adjustment for exposure to combustion products. A recent evaluation of occupational dose-response data showed that other population-based studies of occupational exposure (typically dealing with lower asbestos levels than those found in occupational cohorts) have similarly indicated a risk per fiber-year/ml that is higher than the 1 percent per fiber-year/ml predicted by the commonly applied linear extrapolation from highly exposed cohorts (10
). A previous Swedish case-referent study of 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 16 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 (11.6 percent and 8 percent, respectively) for occupational exposure to asbestos and lung cancer in men, but these studies gave no dose-response data in terms of fiber-years/ml.
There are two main potential sources of bias in the risk estimate of a 14 percent increase per fiber-year/ml. First, one could question whether the procedure of multiplying intensity and probability of exposure per work task is an unbiased estimate of 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 of exposure, this would tend to underestimate the true exposure levels and thereby overestimate the risk per exposure unit. To investigate the maximum possible magnitude of such bias, we recalculated the cumulative dose of asbestos for all individuals in the study, setting the probability to 1.0 for all asbestos-exposed work periods. This increased the doses by approximately 44 percent in the two upper quartiles of cumulative dose. Thus, even if the probability codes were totally disregarded, which would tend to overestimate the dose considerably, there is still an excess of about 10 percent (14/1.44 = 9.7) 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 of asbestos exposure levels (based on fiber counts) at Swedish workplaces that was performed in 19691973, involving over 2,400 samples at 35 workplaces, which is representative of 7075 percent of the total use of 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 of PAHs are carcinogenic, and the carcinogenic effect of fumes from coke and gas production, as well as of soot, is assumed to be mediated at least in part by PAHs (1517
). Benzo(a)pyrene is often used as an indicator of exposure to PAHs. During the past decade, exposure to fine particles has been in focus as an alternative explanation for the excess of lung cancer in occupational groups exposed to combustion products (18
). This study confirmed an excess risk of 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 of cumulative dose.
Welding fumes, oil mist, and metal dust
Two recent meta-analyses of epidemiologic studies of welders (13, 14
) arrived at different conclusions. One suggested an increased risk of lung cancer after welding of either stainless steel or mild steel (14
), while the other concluded that there is firm evidence of an increased lung cancer risk after welding of stainless steel only (13
). Exposure to welding fumes has been considered possibly carcinogenic to humans by the International Agency for Research on Cancer (12
), although no distinction was made with regard to welding of stainless steel or other materials. In a population-based case-referent study from Germany (38
), an excess of lung cancer was noted after a cumulative exposure of more than 6,000 hours of 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 of mild steel welding, which is the predominant type of 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 of an increased risk for skin cancer. The evidence for an association between inhalation of oil mist and lung cancer is weak (1). No effect of exposure to oil mist was seen in this study.
Some metals, such as hexavalent chromium, cadmium, nickel, and arsenic, are suspected or documented carcinogens (1, 12
, 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 of 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 of cumulative dose for diesel exhaust and combustion products and with the two highest quartiles for asbestos exposure ("Adjusted (B)" in table 4). The prevalence of the exposures in the population was assessed from the referents.
The attributable fractions in the population were: for diesel exhaust, 2.7 percent; for asbestos, 4.0 percent; and for combustion products, 2.2 percent. To assess the overall effect of these exposures, we considered an alternative model, introducing an indicator variable for any of these three exposures (40). The overall proportion of 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, 13.9).
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ACKNOWLEDGMENTS |
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The authors are indebted to Agneta Wahlbom and Ulla Klinga for conducting telephone interviews and to Cecilia Rudengren, Marcus Hugosson, Ewa Skarke, Camilla Bengtsson, Anna Boberg, Eva-Britt Gustavsson, and Kerstin Åström for managing data collection and database maintenance. The authors thank Drs. Nils Plato and Tom Bellander for valuable discussions regarding exposure assessment.
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NOTES |
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REFERENCES |
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