American Journal of Respiratory and Critical Care Medicine

Rationale: Whether occupational exposure to asbestos causes airway obstruction remains controversial.

Objectives: This study evaluated lung function in relation to cumulative exposure to asbestos in a large cohort of retired or unemployed workers exposed to asbestos.

Methods: The study population consisted of 3,660 volunteer subjects. An individual cumulative exposure index to asbestos was calculated for each subject, and information was obtained on smoking status. Pulmonary function tests were performed in all subjects; high-resolution chest computed tomography was also performed in 3,335 subjects.

Measurements and Main Results: Values of FEV1/FVC and FEF25–75% did not differ between five classes (quintiles) of cumulative exposure to asbestos, and no significant correlation was observed between cumulative exposure to asbestos and pulmonary function parameters, after adjustment for sex, tobacco consumption, emphysema, and body mass index. Furthermore, the proportion of abnormal pulmonary function tests did not differ between the five classes of cumulative exposure to asbestos.

Conclusions: The results do not support a causal relationship between asbestos exposure alone and airway obstruction. However, the study sample may not be representative of all people occupationally exposed to asbestos, because a fraction of subjects with previously diagnosed asbestosis probably did not participate in this screening program.

Scientific Knowledge on the Subject

Whether occupational asbestos exposure can generate airway obstruction remains controversial.

What This Study Adds to the Field

This large-scale cross-sectional study, including information on individual cumulative exposure to asbestos and tobacco consumption, does not support a causal role of exposure to asbestos alone in the development of airway obstruction.

Occupational asbestos exposure is associated with the development of both nonmalignant and malignant respiratory diseases involving the pleura and the lung (1). It is also well known that small airways abnormalities develop as part of the pathophysiologic process of asbestosis (2).

Whether occupational asbestos exposure can generate airway obstruction is still a subject of debate. Functional impairment suggestive of obstructive disease has been described in cross-sectional studies (36), and high prevalences of radiologic emphysema (7, 8) have been reported in workers exposed to asbestos.

Although other epidemiologic studies do not support a causal role for asbestos exposure in airway obstruction (915), the 2003 official statement of the American Thoracic Society on diagnosis and initial management of nonmalignant diseases related to asbestos concluded that “epidemiological studies have demonstrated a significant association between exposure or asbestosis category and reduction in FEV1, FEV1/FVC ratio, and midexpiratory flow rates,” and that “asbestos exposure independently contributes to accelerated decline in airflow over time, whether or not exposure ceases” (1).

However, the role of asbestos exposure in inducing airway obstruction remains controversial. Several authors consider that the available studies are unable to support the conclusion that asbestos exposure may induce significant airway obstruction (1416). Arguments used to refute a causal relationship between present or past occupational exposure to asbestos and airway obstruction include the lack of dose–response and failure to control properly confounding factors, such as smoking, radiographic abnormalities, or coexposures to other mineral dusts.

The aim of the present study was to investigate, in a large cross-sectional study comprising information on individual cumulative exposure to asbestos, whether occupational asbestos exposure is associated with airway obstruction after controlling for other factors that impact lung function. This study is part of a large–scale pilot screening program for asbestos-related diseases organized at the request of the French Ministry of Labor and National Health Insurance between October 2003 and December 2005 in four regions of France: Aquitaine, Rhone-Alpes, Haute-Normandie, and Basse-Normandie (17). The program was initiated after a national consensus conference, held in Paris in 1999, on the clinical surveillance strategy for persons exposed to asbestos (18), which proposed periodic chest computed tomography (CT) scan and pulmonary function tests (PFTs) for workers with moderate to high exposure to asbestos. Some of the results of this study have been previously reported in the form of an abstract (19).

Study Population

The eligible population in the selected regions consisted of all retired or unemployed workers, previously occupationally exposed to asbestos. Different means were used to invite people to participate in the program, including letters; trade unions; and radio, television, and newspaper advertisements (17). Free examinations, including high-resolution chest CT scan (HRCT) and PFTs, were proposed to volunteer subjects with previous occupational exposure to asbestos.

Asbestos Exposure

All subjects completed a standardized questionnaire to collect information on work history (17). A cumulative exposure index (CEI) was then calculated by industrial hygienists. All jobs of the subject's working life were taken into account. For each job suspected to be associated with asbestos exposure, the duration (number of years) was determined. The following weighting factors were attributed for the intensity of exposure: low level (passive exposure), 0.01; low-intermediate, 0.1; high-intermediate, 1; high, 10. The CEI was the sum of exposures calculated for each exposed job (duration × weighting factor). Because of the absence of atmospheric measurements and the lack of detailed information on the frequency of exposure (percentage of the working time), the CEI is not expressed in f/ml × years but rather in exposure units × years.

Pulmonary Function Tests

PFTs were performed by the chest physician of the subject's choice or in hospital physiology laboratories. These tests included at least flow–volume curves and, in a large number of cases, a measurement of residual volume (RV) (n = 3,104 [84.8%]) and TLC (n = 3,112 [85%]).

Parameters used for analysis of the flow–volume curve were FVC, FEV1, FEV1/FVC ratio, and forced expiratory flow between 25 and 75% of FVC (FEF25–75%). Results were expressed as percentages of predicted values, using equations published in 1993 by the European Respiratory Society (20).

Subjects with aberrant values (FEV1 >160% predicted or <10% predicted; FVC >150% predicted or <30% predicted) were excluded from the analysis. Results were also adjusted for the centers in which PFTs were performed by using a combination of status (private/public) and region.

HRCT and Conventional Chest Radiographs

Detailed HRCT procedures have been reported elsewhere (17). Radiologists who participated in the program received guidelines to perform HRCT for the diagnosis of nonmalignant asbestos-related diseases. In addition to recording asbestos-related diseases (pleural plaques and asbestosis), radiologists were also asked to report the presence of other pulmonary abnormalities, such as emphysema.

Conventional chest radiographs were also performed in a large number of cases, but readings according to the International Labor Office classification are not available in this study.

Body Mass Index and Tobacco Consumption

Body mass index (BMI) (weight [kg]/height [m2]) was calculated for each subject. Subjects were classified into three categories according to tobacco consumption: smokers, exsmokers, and nonsmokers. Exsmokers were defined as those who had quit smoking for at least 1 year.

The project was approved by the Cochin Hospital ethics committee in Paris, France. All patients received information on the study and gave their written informed consent.

Statistical Analysis

Personal characteristics, such as sex, age, BMI, and smoking habits, were described at baseline. Comparisons of PFTs according to dichotomized variables, such as smoking status, were tested using Student t test. Effects of cumulative exposure to asbestos on lung function were investigated in three ways: (1) comparison of lung function parameters in subgroups of increasing CEI, (2) correlation between CEI and pulmonary function parameters, and (3) comparison of the proportion of abnormal results in the various subgroups of increasing CEI.

According to these aims, CEI was classified in five classes, based on the distribution of values (i.e., quintiles). PFTs were then considered as outcome variables, in linear mixed models that included exposure as main predictor, sex, BMI, and tobacco as fixed terms and centers as random effect. Abnormal values for pulmonary function parameters were defined by comparison with the lower bound of predicted values using the European Respiratory Society equations (20). Comparison of the proportion of abnormal results was then performed using chi-square tests and Cochran-Armitage linear trend tests. Statistical analysis was performed using SAS software version 9.2 (SAS Institute, Inc., Cary, NC).

After exclusion of subjects with aberrant results or missing data for smoking status, BMI, or CEI, the study population consisted of 3,660 subjects, among whom HRCT of the chest was performed in 3,335 cases (91.1%) (Figure 1).

General characteristics of the study population are given in Table 1. The mean (SD) age was 63.2 (5.8) years (range, 37–85 yr); 3,519 subjects (96.1%) were male; and 2,741 (74.9%) were smokers or exsmokers. Mean (SD) duration of asbestos exposure was 27.7 (11.1) years (range, 1–36 yr). Among the 3,335 subjects in whom chest CT scan was performed, 224 (6.7%) exhibited interstitial abnormalities; 577 (17.3%) presented pleural plaques; and 339 (10.1%) had emphysema. After adjustment for sex, BMI, and the center in which PFTs had been performed, smokers and exsmokers had significantly lower values of FVC, FEV1, FEV1/FVC ratio, and FEF25–75% and significantly higher values of RV than nonsmokers (Table 2).

TABLE 1. CHARACTERISTICS OF THE STUDY POPULATION




N (N = 3,660)

%

Mean (SD)
Sex
 Male3,51996.1
 Female1413.9
Age, yr63.2 (5.8)
 <6081922.4
 60–742,70874
 ≥751333.6
Smoking status
 Nonsmokers91925.1
 Exsmokers2,42366.2
 Smokers3188.7
BMI, kg/m227.4 (3.8)
Duration of exposure, yr27.7 (11.1)
 1–93048.3
 10–1955615.2
 20–2997026.5
 ≥301,83050
Cumulative exposure index,   unit of exposure × yr
 0–3.365117.8
 3.4–13.668018.6
 13.7–3276921
 32.1–6478721.5
 >6477321.1
HRCT, n = 3,333
 Interstitial abnormalities2246.7
 Pleural plaques57717.3
 Emphysema
339
10.1

Definition of Abbreviations: BMI = body mass index; HRCT = high-resolution computed tomography.

TABLE 2. PULMONARY FUNCTION ACCORDING TO SMOKING STATUS



Nonsmokers

Smokers and Exsmokers


n
Mean
95% CI
n
Mean
95% CI
P*
FVC919103.6101.5–105.82,741101.499.4–103.40.001
FEV1919105.5103.4–107.62,741100.498.6–102.2<0.001
FEV1/FVC919108106.0–110.12,741104.9102.9–106.8<0.001
FEF25–75%8939792.9–101.12,67886.482.7–90.0<0.001
RV779104.999.7–110.12,325111.5106.6–116.3<0.001
TLC
781
101.6
99.4–103.8
2,331
102.6
99.4–103.8
0.15

Definition of Abbreviations: CI = confidence interval; FEF = forced expiratory flow, midexpiratory phase; RV = residual volume.

Data are percent predicted (20).

*Based on linear mixed model using pulmonary function parameters as outcomes, sex and body mass index as fixed terms, and center as random effect. Means estimates are based on least squares mean method.

There were significant (or borderline significant) differences between the five classes of CEI for FVC, FEV1, FEF25–75%, and TLC, but not for FEV1/FVC or RV (Table 3). However, when present, the differences in pulmonary function parameters between categories were small and without any signs of a dose–response relationship. In other words, there was no trend toward more signs of airway obstruction with increasing exposure category. The latter was confirmed when pulmonary function parameters were regressed, at the individual level, with the CEI adjusting for sex, smoking status, BMI, and center (Table 4). In the latter analysis, there was no significant correlation between cumulative exposure and FVC, FEV1, FEV1/FVC, or FEF25–75%, whereas the correlation with RV and TLC was significantly negative (i.e., suggestive of increasing restriction, not obstruction, with increasing cumulative exposure to asbestos).

TABLE 3. PULMONARY FUNCTION TESTS IN FIVE CLASSES OF CUMULATIVE EXPOSURE TO ASBESTOS



Increasing Classes of Cumulative Exposure (quintiles)


1
2
3
4
5
P*
FVC, n = 3,66099.6101.898.9100.799.50.01
FEV1, n = 3,66097.198.99698.696.30.01
FEV1/FVC, n = 3,660103.4102.9102.8103.6102.30.18
FEF25–75%, n = 3,57180.582.378.983.980.20.06
RV, n = 3,104111.7116.8116115115.60.12
TLC, n = 3,112
102.6
105.1
103
103.7
102.8
0.06

Definition of Abbreviations: FEF = forced expiratory flow, midexpiratory phase; RV = residual volume.

Data are percent predicted (20).

*Based on linear mixed model using pulmonary function parameters as outcomes; sex, smoking status, and body mass index as fixed terms; and center as random effect. Means estimates are based on least squares mean method.

TABLE 4. SLOPE ESTIMATES* OF THE ASSOCIATION BETWEEN PULMONARY FUNCTION AND CUMULATIVE EXPOSURE TO ASBESTOS




Slope (SD)

P
FVC, n = 3,660−0.001 (0.003)0.67
FEV1, n = 3,660−0.004 (0.003)0.29
FEV1/FVC, n = 3,660−0.003 (0.002)0.15
FEF25–75, n = 3,571−0.003 (0.006)0.58
RV, n = 3,104−0.013 (0.006)0.03
TLC, n = 3.112
−0.008 (0.002)
0.01

See Table 3 for abbreviatons.

*Based on linear mixed model using pulmonary function parameters as outcomes; sex, smoking status, and body mass index as fixed terms; and center as random effect. Means estimates are based on least squares mean method.

Cumulative exposure is defined as a quantitative variable in this analysis.

Furthermore, the proportion of abnormal results did not differ between the five classes of cumulative exposure to asbestos (Table 5), except again for RV and TLC, pointing toward more restrictive impairment in the higher-exposure categories.

TABLE 5. PROPORTION OF ABNORMAL* PULMONARY FUNCTION RESULTS ACCORDING TO CLASSES OF CUMULATIVE EXPOSURE TO ASBESTOS



Increasing Classes of Exposure (quintiles)

1
2
3
4
5

n (%)
n (%)
n (%)
n (%)
n (%)
P
Abnormal FVC62 (9.5)47 (6.9)65 (8.6)59 (7.5)73 (9.4)0.29
0.84
Abnormal FEV163 (9.7)57 (8.4)83 (10.8)70 (8.9)74 (9.6)0.58
0.94
Abnormal FEV1/FVC39 (6)32 (4.7)41 (5.3)34 (4.3)43 (5.6)0.62
0.66
Abnormal FEF25–75%70 (11)74 (11.1)104 (13.9)73 (9.6)91 (11.9)0.12
0.99
Abnormal RV52 (9.8)46 (8.2)66 (10.1)66 (10.1)91 (13.1)0.06
0.02
Abnormal TLC55 (10.2)53 (9.4)85 (13.1)73 (11.1)96 (13.8)0.08






0.03

See Table 3 for abbreviatons.

*Abnormal test defined as being below the lower bound of predicted values using the European Respiratory Society equations (20).

Chi-square test.

Trend test.

This study did not demonstrate a relationship between estimated cumulative occupational exposure to asbestos and the lung function parameters FVC, FEV1, FEV1/FVC ratio, and FEF25–75% and consequently does not support the hypothesis of a causal role of asbestos exposure in the pathogenesis of airway obstruction.

These data are in agreement with several recently expressed opinions (1416, 21), but disagree with others (1, 22, 23). The strengths of our study are the large number of subjects and individual estimation of cumulative occupational exposure to asbestos.

However, this cross-sectional study also presents a number of limitations. The study population was selected for screening purposes and only volunteers were included. Consequently, this study sample is probably not fully representative of all people occupationally exposed to asbestos in that most of the participants selected had reached retirement age without severe respiratory disease. It is conceivable that subjects with previously diagnosed asbestos-related disease, particularly asbestosis, or respiratory insufficiency requiring care from chest physicians did not find it useful to participate in this screening program, which may explain the generally good results of PFTs and the fairly low rate of HRCT abnormalities consistent with asbestos-related benign diseases. Furthermore, the subjects in the higher classes of CEI could represent a survivor population of more resistant subjects.

PFTs were performed in many different locations by many different chest physicians or technicians. To avoid erroneous results caused by inadequate forced expiration maneuvers or errors in transmission of the results, we excluded 68 subjects with clearly “aberrant” results from the analysis. The results were also adjusted for the center in which PFTs were performed. We also performed a posteriori a quality control for PFTs on a random sample of 20% of subjects from each of the four regions. All tests were examined by one of the authors. Among the 698 PFTs selected, the pattern of the flow–volume curve could not be evaluated (only figures were available) in 82 cases (11.7%). In the 617 remaining examinations, 327 (53%) were considered to be “perfect,” 262 (42.5%) were considered to be “satisfactory,” and only 27 (4.4%) were considered to be “unsatisfactory,” based on the pattern of the flow–volume curve and similarity between FVC and slow VC. Statistical analysis performed on the 589 “perfect” or “satisfactory” PFTs confirmed the results found in the overall population (i.e., no correlation between cumulative exposure to asbestos and airway obstruction). The credibility of our pulmonary function data is also reflected by the fact that smokers and exsmokers had significantly more obstructive impairment than nonsmokers.

Another potential limitation is the inaccurate assessment of cumulative exposure to asbestos. Evaluations of individual occupational exposures to asbestos were exclusively based on assessments by industrial hygienists (who were blinded to the medical information). Because of the absence of actual measurements of fiber counts in the air and the lack of detailed information on the frequency of exposure (percentage of the working time), the CEI is expressed in exposure units × years. This cannot easily be converted into fiber-years (f/ml × years), but the relevance of our index is supported by its very strong relationship with the prevalence of pleural plaques found by HRCT: 7.7, 11.3, 13.6, 16.4, and 33%, in the increasing quintiles of exposure, respectively (unpublished data). The percentage of 33% in the highest quintile indirectly indicates a high level of exposure. We also tried to correlate PFTs with interstitial abnormalities on HRCT, but this was not possible because of excessive variability in the reading of these abnormalities.

Several explanations can be proposed for the discrepancies between our results and those of some published studies. As emphasized by Ohar and coworkers (6), a standardized definition of airway obstruction has not been used in all published studies. Some investigators have defined airway obstruction on the basis of decreased FEV1 with no reference to FEV1/FVC ratio; other authors defined airway obstruction on the basis of decreased midexpiratory flow (2426).

Another plausible explanation concerns the recruitment of study populations and differences in cumulative exposure to asbestos and other dusts between studies. Lung function impairments suggestive of, or consistent with, airway obstruction have been reported in studies based on populations exposed to high concentrations of asbestos and other dusts: workers from an asbestos–cement plant (27), insulators (3, 28), and construction and shipyard workers (5). It has been suggested that conditions affecting the major airways, such as chronic bronchitis or chronic airflow limitation, observed in some subjects occupationally exposed to asbestos might be caused by nonspecific effects of exposure to total pollutant burden, including asbestos and other dusts, gases, or fumes, in the workplace (29).

The association observed in some studies between asbestos exposure and airway obstruction might also be caused by confounding factors, such as smoking or exposure to other occupational agents responsible for airway obstruction, such as silica (1).

Conclusion

The results of this study did not demonstrate a dose–response relationship and do not support a causal relationship between asbestos exposure and airway obstruction. However, the study sample may not be representative of all people occupationally exposed to asbestos because a fraction of subjects with previously diagnosed asbestosis probably did not participate in this screening program.

The authors thank all members of the asbestos postexposure program for their contribution to this survey: E. Abboud, B. Aubert, J. Baron, J. Benichou, A. Caillet, P. Catilina, S. Chammings, B. Clin-Godard, G. Christ de Blasi, E. Guichard, N. Lestang, M.F. Marquignon, M. Maurel, B. Millet, L. Mouchot, M. Pinet, A. Porte, J.L. Rehel, P. Reungoat, A. Sobaszek, F.X. Thomas, and L. Thorel.

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Correspondence and requests for reprints should be addressed to Jacques Ameille, M.D., Unité de Pathologie Professionnelle, Hôpital Raymond Poincaré, 104 Boulevard Raymond Poincaré, 92380 Garches, France. E-mail:

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