1 Division of Occupational and Environmental Health, Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands.
2 International Agency for Research on Cancer, Lyon, France.
3 Finnish Institute of Occupational Health, Helsinki, Finland.
4 Danish Working Environment Service, Copenhagen, Denmark.
5 Centre for Occupational and Environmental Medicine, Rikshospitalet University Hospital, Oslo, Norway.
6 Bremen Institute for Prevention Research and Social Medicine, Bremen, Germany.
7 INSERM U170, Villejuif, France.
8 National Institute of Occupational and Environmental Health, Raanana, Israel.
9 Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark.
Received for publication December 10, 2002; accepted for publication March 20, 2003.
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ABSTRACT |
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asthma; benzo(a)pyrene; bronchitis; coal tar; cohort studies; emphysema; polycyclic hydrocarbons, aromatic
Abbreviations: Abbreviations: ICD-9, International Classification of Diseases, Ninth Revision; PAH, polycyclic aromatic hydrocarbon; ROCEM, Road Construction Workers Exposure Matrix.
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INTRODUCTION |
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Fumes are emitted when hot asphalt is applied to surfaces during paving. During that process, exposures to small particles (35) containing polycyclic aromatic hydrocarbons (PAHs) occur (1, 5). Such particle-bound PAH exposure has been associated with increases in respiratory morbidity and mortality in several different environments: diesel exhaust (6), coke oven fumes (7, 8), and environmental air pollution (9, 10). Nonetheless, the agents responsible for these health effects have not been identified, because in these environments persons are exposed to different complex mixtures rather than to pure substances. At the same time, particle-bound PAHs and their oxygenated derivatives have been shown to exert proinflammatory and tissue-damaging effects, possibly contributing to respiratory morbidity and mortality (11, 12). These toxic effects are thought to be mediated by macrophages and epithelial cells in the respiratory tract, and they arise through the generation of reactive oxygen species (1214). Exposures to both PAHs and their oxygenated derivatives occur in work with coal tar (15) and, to a lesser extent, pure bitumen (16).
There is some prior indication that exposures in the asphalt industry may contribute to mortality and morbidity from nonmalignant respiratory diseases. A nonsignificant excess of mortality from bronchitis, emphysema, and asthma was reported among 679 Danish mastic asphalt workers heavily exposed to bitumen fumes and PAHs (17). However, the study (17) suffered from serious limitations and revealed elevated standardized mortality ratios for causes of death not likely to be related to PAHs (18). Highway maintenance workers in California were reported to have an excess mortality from emphysema (eight cases observed vs. 3.2 expected (19)), but this excess could not be attributed to any specific exposure. Registry-based studies showed for US roofers, who have been exposed to both coal tar and bitumen fumes, a twofold increase in risk of death from nonmalignant respiratory diseases (20, 21). Other studies of mortality among asphalt workers did not uncover elevated risks for obstructive lung diseases (2). Respiratory symptoms, including those indicative of chronic bronchitis, have been associated with exposure to bitumen fume in several cross-sectional studies (2225), but these studies did not adequately control for confounding by smoking and tended to have low power. Overall, evidence to date does not consistently link work in the asphalt industry to elevated risk of nonmalignant respiratory diseases.
The International Agency for Research on Cancer assembled a historical international cohort of employees from the asphalt industry. The analysis presented in this paper investigates mortality from nonmalignant respiratory diseases and its relation with occupational PAH exposure. (The issue of bitumen fume exposure and cancer mortality in the cohort has been addressed elsewhere (26, 27).)
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MATERIALS AND METHODS |
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Occupational histories were coded on the basis of information from personnel records according to classifications of jobs constructed for the study. A "job" in this classification scheme represented the primary activity of a worker in a given time period (e.g., asphalt paving or employment at an asphalt-mixing plant), but it does not reflect the specific tasks performed. These job classes formed the basis for the linkage between employment histories and the study-specific exposure matrix: the Road Construction Workers Exposure Matrix (ROCEM, see below). Complete individual occupational histories in the target companies were available for all cohort members.
Mortality follow-up
A follow-up for mortality, in which data were obtained on the primary causes of death, was conducted in all the participating countries (26, 3036). Subjects were followed beyond the period of employment in the companies studied. Data on the contributing or underlying causes of death were not available. The earliest follow-up started in 1953, and the latest ended in 2000. The average duration of follow-up was 17 years (standard deviation, 8 years). These data were similar for all the groups of workers and all the countries. The cohort accumulated 911,209 person-years of observation. Persons who were employed only in asphalt paving accumulated 189,484 person-years of observations. The subcohort never exposed to coal tar in the companies studied accumulated 529,067 person-years of observation. The loss to follow-up was 0.9 percent; an additional 0.3 percent of the total cohort members emigrated during the follow-up.
Causes of death were coded according to the International Classification of Diseases, Ninth Revision (ICD-9). Mortality from nonmalignant respiratory diseases was identified by ICD-9 codes 460519. Mortality from chronic bronchitis, emphysema, and asthma (ICD-9 codes 490493) was collectively classified as arising from obstructive lung diseases. Because of the poor ability of death certification in Europe to discriminate between asthma (ICD-9 code 493) and chronic obstructive pulmonary disease (chronic bronchitis and/or emphysema, ICD-9 codes 490492) (37, 38), no distinction was made in the current analysis between mortality from asthma and chronic obstructive pulmonary disease.
Exposure assessment
We estimated exposures to bitumen fume, coal tar, benzo[a]pyrene (marker for four- to six-ring PAHs), diesel exhaust, respirable silica, and asbestos in the cohort (39). These agents cover the major occupationally occurring chemicals and mixtures to which asphalt workers can be exposed (1). Exposures were reconstructed by using 1) information about changes in the production characteristics in each company over time, 2) the relations between production characteristics and exposure levels, and 3) job histories.
We gathered information about the companies enrolled in the study through a company questionnaire that ascertained temporal changes in the production characteristics and work organization. Among the production characteristics, the questionnaire ascertained the type of materials used (e.g., coal tar, asbestos), the asphalt application methods (e.g., mastic laying, hot mix paving), and the average time spent handling these materials or utilizing existing paving methods. The questionnaire was administered to knowledgeable company representatives. Questionnaires were checked for errors, omissions, and inconsistencies, and responses were entered into a common database. Experts from each country checked the quality of the company questionnaires and supplemented them, when required.
Quantitative estimates of exposure to bitumen fume and benzo[a]pyrene were obtained only for workers employed in road paving. Most of the personal exposure measurements from asphalt companies (in countries enrolled in the cohort), collected between the late 1960s and 1997, were assembled into a single database (40). The following contextual information was coded for each exposure measurement: job (using a classification similar to what was used in the company questionnaire), production characteristics within a job (using a classification similar to what was used in the company questionnaire), repeated measurements for a worker, and country. Quantitative exposure assessment was restricted to one job (road paving), and we attempted to correct for between-country differences but discovered that there were no systematic differences among countries that cannot be explained by the time period, type of paving, materials used, and exposure monitoring methods.
Analyzing the relations between measured exposure concentrations and contextual information identified determinants of exposure. Thus, we constructed mixed-effects models, with production characteristics as fixed effects and repeated measurements on a worker as random effects, to support quantitative exposure assessment to bitumen fume and benzo[a]pyrene among road pavers (41, 42). Use of coal tar was the strongest determinant of exposure to PAHs and benzo[a]pyrene. We demonstrated that, although the use of coal tar (yes/no) accounted for 20 percent of the variability in benzo[a]pyrene concentrations, there was still an independent relation between the total organic fume levels and benzo[a]pyrene concentrations (41). The time period, mastic laying, repaving, surface dressing, and oil-gravel paving were significant determinants of exposures to both bitumen fume and benzo[a]pyrene. The models were judged to be sufficiently valid for relative ranking of exposures in the epidemiologic study (43). We used the mixed-effects models of exposure to predict exposure levels for production conditions described by the company questionnaires, thereby producing modeled quantitative exposure intensity estimates in ROCEM (39).
A similar algorithm was developed for semiquantitative exposure assessment for all workers and agents (39). Semiquantitative exposure estimates were calculated on the basis of assumptions about the relative exposure intensities between different jobs for each agent (e.g., the same bitumen fume exposure intensity during hot mix paving and asphalt mixing) that were developed by the authors in consultation with industry representatives. Company questionnaires provided information on whether a given job was performed and what materials were used in a particular time period. Some of the elements of the statistical models described above, such as declining time trends, were incorporated into the semiquantitative exposure assessment. However, in their simplest form, semiquantitative exposure estimates simply reflected the proportion of time that such materials as coal tar and asbestos were reported to have been used or the proportion of vehicles that were powered by diesel (diesel exhaust exposure index).
All exposure estimates in ROCEM were standardized to an 8-hour work shift, using information on the average work shift duration reported in company questionnaires. The resulting exposure matrix was time period, company, and job class specific. According to the exposure matrix, asphalt pavers were not exposed to asbestos; subgroups of asphalt pavers possibly exposed to different concentrations of respirable silica could not be identified. In ROCEM, jobs with a high PAH exposure also tended to have a high bitumen fume exposure (r = 0.96, p < 0.0001, semiquantitative exposure scores; r = 0.93, p < 0.0001, quantitative exposure estimates). The second main source of PAH exposure was coal tar, as witnessed by the correlation (r = 0.46, p < 0.0001) of semiquantitative exposure scores for PAHs and coal tar in ROCEM, the strongest correlation of coal tar exposure estimates to that of any other agent. For example, the correlation between exposure scores for coal tar and bitumen fume in ROCEM was 0.34 (p < 0.0001).
Exposure indices
In the analyses with ROCEM-based estimates of exposure, we derived the following indices of exposure: 1) duration, 2) cumulative exposure (product of exposure duration and intensity, integrated over work history), and 3) average exposure over the work history (ratio of cumulative exposure to duration of exposure). The estimates of duration of exposure were corrected for differences in duration of the working season between companies and countries. For each semiquantitative exposure index, unexposed subjects formed a separate reference category, and exposed subjects were divided into quartiles, each including approximately one fourth of the deaths from all nonmalignant respiratory diseases. Quantitative exposure indices were available for workers employed only in asphalt paving, all of whom were exposed to bitumen fume, and PAHs. Therefore, for quantitative exposure indices, there was no nonexposed group for bitumen fume and PAHs; the lowest exposure group was used as a reference in exposure response analyses. (Workers not exposed to PAH and bitumen fume were not used as a reference in the analyses with quantitative exposure indices, because we wanted to increase the chance that the reference groups did not differ in terms of confounders from exposed subjects. The majority of workers not exposed to these agents were employed in building or ground construction, where exposures to respirable silica, asbestos, and diesel exhaust were likely to be higher than those observed in asphalt paving.)
Exposure-response analyses
Relative risks and their associated 95% confidence intervals were estimated using Poisson regression (44). All Poisson regression models included an exposure index for each agent of interest, age (039, 4044, 4549, 5054, 5559, 6064, 6569, 70 years), calendar period of exit from the cohort (pre-1974, 19751979, 19801984, 19851989,
1990), total duration of employment (<1, 14, 59, 1014, 1519,
20 years), and country. Linear trends in log(relative risk) were estimated, assuming constant differences between exposure categories. Only the p values for these tests are reported. Poisson regression analyses were carried out in Stata version 6.0 software (Stata Corporation, College Station, Texas). Person-years were allocated in SAS version 6.12 software (SAS Institute, Cary, North Carolina), using an in-house computer program developed at the International Agency for Research on Cancer.
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RESULTS |
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DISCUSSION |
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Our findings provide additional evidence in support of hypotheses generated in previous studies, which linked elevated mortality from obstructive lung diseases to a high exposure to particle-bound PAHs (6, 10, 12), bitumen fume, and/or coal tar (7, 8, 17, 1921). This evidence is least convincing for pure bitumen fume, possibly because of the relatively low levels of PAHs in pure bitumen fume and the low power of the analysis of the tar-free cohort.
Etiologic agents
One of the difficulties of attributing the observed increased risk of obstructive lung disease to PAHs in bitumen and coal tar lies in the fact that fumes emitted during asphalt work are a complex mixture of both aliphatic and aromatic hydrocarbons. Based on our analyses, the main argument in favor of four- to six-ring PAHs as causative agents in the observed exposure-response relations is that the associations with measures of total organic fume (i.e., bitumen fume) are weaker than those observed for PAHs. In our earlier work, we explored the variability in types of PAHs present in fumes emitted during paving. We found little evidence of difference in PAH exposure profiles between different paving operations, except when coal tar was used, which increased the proportion of four- to six-ring PAHs, such as benzo[a]pyrene, in fumes (41). Nonetheless, we must accept the possibility that heterogeneity in the composition of fumes emitted during paving (e.g., differences in particle size distributions and chemical compositions) complicates the attribution of our findings to particle-bound PAHs.
Diesel exhaust is yet another source of PAH exposure among asphalt workers, but we observed no associations with diesel exhaust indices. Nevertheless, if different diesel exhaust levels were associated with specific types of paving, coal tar use, and time period, then it would be possible for PAH exposure indices to reflect changes in diesel exhaust exposure levels. The available data are not sufficient to test this supposition, because 1) we know little about the patterns of diesel engine use in the asphalt industry and 2) diesel exhaust exposure was not systematically monitored in asphalt companies in the countries studied.
Confounding
Tobacco smoking, a major cause of obstructive lung disease (45), is the principal uncontrolled potential confounder in our study. Analyses based on average exposure indices are most prone to confounding by smoking. The average levels of exposure in ROCEM decreased with time, as did the prevalence of smoking in many of the countries included in the study (46). As a consequence, workers in the highest categories of average level of exposure (but not necessarily of cumulative exposure) may have smoked more than workers in other categories, as suggested by analyses of the Dutch subcohort (34).
The weak positive association of bitumen fume with mortality from nonmalignant respiratory diseases and obstructive lung diseases could be an artifact of simultaneous exposure to coal tar. Cumulative exposure to coal tar was weakly yet positively correlated with both semiquantitative and quantitative bitumen fume exposure indices (Spearmans rank correlation coefficients in the range of 0.20.4). Adjustment for simultaneous exposure to coal tar reduced the association with exposure to bitumen fume. In the analysis of the subcohort not exposed to coal tar, relative risk estimates for obstructive lung diseases (table 4) were imprecise, being based on less than 10 deaths per exposure group. Overall, our data did not allow us to exclude the possibility that exposure to bitumen fume contributes to mortality from obstructive lung diseases.
Exposures to silica, diesel exhaust, and asbestos were not associated with mortality from obstructive lung diseases. This was due to low exposures to these agents, similar levels of exposure across the industry, or nondifferential exposure misclassification. Occupational exposures outside the asphalt industry were not assessed because we lacked complete occupational histories. Thus, the possibility remains that our findings were confounded by other occupational exposures from employment both within and outside the asphalt industry.
Bias
The methods used to assess occupational exposures may also have biased the outcome of this study. First, bias may have arisen in the sampling strategy used to collect exposure data that were the basis of the quantitative exposure models. This factor, however, was adjusted for in the statistical exposure models (41), which were deemed reasonably valid for application in the epidemiologic study (43). Second, information about production conditions in the companies recruited for the study could have been incomplete, inaccurate, or biased. In particular, company-reported use of coal tar may contain substantial errors. We attempted to limit this source of error by asking a panel of experts from each country to evaluate again the data collected via the company questionnaires. Nonetheless, it was impossible to validate most of the company questionnaire data. Company questionnaires were also used to estimate exposure duration, through corrections for workday and working season duration. The reported duration of workdays and working seasons was not validated. Duration of exposure was a key factor in the estimation of cumulative, rather than average, exposure indices. Therefore, the average exposure indices were the least prone to this source of error. Third, there may have been coding errors in job histories for cohort members. However, we are confident that such coding errors were the least likely in the subcohort of persons identified as having been employed only in paving (for whom quantitative exposure estimates were available).
The problem of inaccurate death certification of obstructive lung diseases is widespread in the European Community (37). Thus, one of the weaknesses of our study was lack of information on contributing causes of death. This leaves open the possibility of nondifferential misclassification of cases of obstructive lung disease, which could have resulted in biased risk estimates (47, 48). However, obtaining such data was not feasible within the framework of the current cohort study. Furthermore, information on the contributing causes of death would still not address the issue of the incidence of nonfatal obstructive lung disease in the cohort.
Occupational hygiene intervention
Although the global burden of obstructive lung diseases is projected to grow, a reduction in occupational exposures could contribute to reducing this trend in industrialized countries (49). Our results suggest that mortality rates from obstructive lung diseases may have been effectively reduced in asphalt companies that discontinued use of coal tar in the binder. However, we cannot exclude the possibility that a small risk of mortality due to obstructive lung disease from bitumen fume exposure is still present. If so, it is probably attributable to the PAH content of bitumen fume (1, 42, 5052). Bitumen is a relatively minor source of PAH exposure when a mixture of coal tar and bitumen is used as binder in asphalt being paved. However, there are PAHs in bitumen fume, and their concentrations can be high (comparable to coal tar) in some paving operations (41, 42). Thus, it is not surprising that PAH exposures occurred in the absence of coal tar. The role of other additives to asphalt in respiratory disease cannot be excluded (53).
Conclusions
Our results support the notion that exposures to PAHs, derived primarily from coal tar and possibly bitumen fume, are risk factors for mortality from obstructive lung diseases among asphalt workers. However, confounding and bias cannot be definitely ruled out as an explanation for the observed associations. Nonetheless, our findings provide additional evidence that exposure to particle-bound PAHs contributes to mortality from obstructive lung diseases.
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ACKNOWLEDGMENTS |
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In addition to the authors of this report, many persons have contributed to the study. The following persons contributed to data collection, processing, and analysis in the collaborating centers: Pekka Ylöstalo, Anneli Ojajärvi, Raija Vuorela, Anja Savela, Heikki Koskinen, and Eero Pukkala (Finland); Djamilla Meguelatti and Dominique Margellin (France); Hiltrud Merzenich (Germany); Daan Bouwman, Jeroen de Hartog, Jean Pierre van Mulken, and Geurtje van Velsen (the Netherlands); Nils-Göran Lundström (Sweden); and Paul Brennan (International Agency for Research on Cancer). Collaboration with the European asphalt industry and trade union representatives was essential in the conduct of the study and, in particular, in the exposure assessment. The following persons are especially acknowledged for their valuable contributions: H. Fabiansen and C. Bisgaard (Denmark); S Lundgren, H. Jämsä, T. Salomaa, T. Blomberg, M. Ginman, L. Forsten, M. Marjasalo, M. L. Puranen, S. Heikkinen, J. Kylmänen, K. Thomssen, L. Koponen, S. Kauppinen, P. Tammi, and A. Taipale (Finland); F. Douarin (France); K. Kolmsee, G. Zoubek, and O. Harders (Germany); S. J. Veenstra and H. Roos (the Netherlands); T. Jørgensen and E. Lorentzen (Norway); and L. Ekholm, L. G. Ekström, and R. Tahvonen (Sweden). The representatives of the European industrial association, as well as members of the Study Liaison Committee, were instrumental in the starting of the project and very supportive during the whole duration of the study: M. von Devivere and P. Marsal (European Asphalt Paving Association); D. M. Lyall (Eurobitume); and B. Simpson and J. Urbanus (CONCAWE). Drs. Elsebeth Lynge (Copenhagen, Denmark) and Nils Plato (Stockholm, Sweden) served on the Study Advisory Committee. Drs. Bengt Järvholm and Ingvar A. Bergdahl (Umea University Hospital, Umea, Sweden) commented on early drafts of the paper. Pamela Cruise edited the manuscript.
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NOTES |
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REFERENCES |
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