Effects of asbestos and smoking on gas diffusion in people exposed to crocidolite

Exposure to asbestos causes not only cancers and frank asbestosis, but also more subtle changes in the structure and function of the lungs. Thickening of the alveolar-capillary membrane and fibrosis of the interstitium impair oxygen transport and reduce the compliance of the lungs.1,2 Further, some reports have suggested a positive interaction between smoking and asbestos exposure on the development of interstitial fibrosis.3,4

The single-breath carbon monoxide diffusing capacity (Dlco) test is clinically useful in diagnosing pulmonary vascular and interstitial lung diseases and in detecting emphysema. The measurement of Dlco is determined by the diffusing capacity of the alveolar-capillary membrane and the volume of blood in the alveolar capillaries, the former being predominantly affected by diffuse interstitial pulmonary fibrosis (as seen in asbestosis).2,5 The Dlco measurement is not substantially influenced by airway calibre. It is therefore an easy, non-invasive means of examining the integrity of the lung parenchyma in vivo and of monitoring the course of obstructive and restrictive lung diseases. Previous cross-sectional studies have shown that asbestos exposure reduces Dlco.6,7 In our study, we analysed the effects of crocidolite (blue asbestos) and tobacco smoking on changes in Dlco over time. To our knowledge, this is the first longitudinal study evaluating interactions between the effect of asbestos and smoking on gas diffusion.

There were 2980 measurements from 934 people who had at least one Dlco test. Apart from 146 participants who died during the observation period,19 279 (29.8% of all participants) dropped out of the study, without providing specific reasons. People who withdrew from the study had higher average levels of Dlco and tended to have had less exposure to asbestos.

Compared with women, men were exposed to higher cumulative amounts of asbestos (median, 6.6 f/mL per year; interquartile range, 2.1 f/mL–26.2 f/mL). A higher proportion of men had radiographic asbestosis, and a higher proportion of men were smokers or ex-smokers (Box 1).

During the observation period, participants had a varying number of Dlco determinations (median, 2; range, 1–17). As the vitamin A supplementation program initially enrolled people at higher risk of developing asbestos-related diseases, the follow-up for workers (mostly men) was more comprehensive than that for ex-residents (mostly women) (Box 2).

According to the mixed model, the estimated Dlco level at baseline was 24.8 units (Box 3). Women had lower Dlco levels than men (4.5 units); age was inversely associated with Dlco levels (0.35 units lower, on average, for each additional year of age) (Box 3).

The average rate of decline of Dlco over the follow-up period was 0.33 (95% CI, 0.31–0.35) units per year, plus an additional decrement of 0.22 (95% CI, 0.12–0.32) units per year if the participant had radiographic asbestosis at the beginning of the follow-up period (Box 3).

The random-effects model (Box 3) also demonstrated that the presence of radiographic asbestosis at baseline was significantly associated with lower baseline Dlco levels — 3.0 (95% CI, 2.2–3.8) units lower on average than people without asbestosis. Further, people exposed to asbestos at a younger age had significantly lower Dlco levels at baseline. However, number of years since last exposure, exposure category (worker or resident) and cumulative asbestos exposure were not significant predictors of change in Dlco over time. (Dlco fell non-significantly, by 0.006 units for each additional f/mL year of exposure at baseline.)

Compared with never-smokers, Dlco in current smokers was 5.1 (95% CI, 4.7–5.5) units lower, and Dlco in ex-smokers was 1.4 (95% CI, 1.1–1.7) units lower. Smoking status did not affect the change in Dlco over the follow-up period. There was no significant interactive effect of smoking and asbestos exposure on either the level of Dlco or its change over time.

Our study is the first to report that asbestos exposure (measured as radiographic asbestosis) is significantly associated with accelerated decline in Dlco. In our study population (unique in being exposed exclusively to crocidolite), the gas diffusion capacity fell by an average of 0.33 units of Dlco per year. This is within the range of that found in other studies (0.19–1.02 units decrement in Dlco per year).21-23 The average rate of decline of Dlco in people without asbestosis was about 1.3% per year (0.33/24.8), compared with about 2.2% per year (0.55/24.8) in people with asbestosis, a rate similar to the rate of decline in a small series of patients with chronic obstructive pulmonary disease (2.7% per year)24 and a small series of asbestos-exposed workers (2.5% per year).4

We also found that lower gas diffusing capacity of the lung was associated with radiographic asbestosis, especially in people exposed at a younger age. Furthermore, although smoking was associated with lower Dlco levels, it did not affect the level or the rate of change of gas diffusion in this population, although this has been suggested for spirometric measures.25 Our results suggest that the effects of tobacco smoking on the level or rate of change of gas diffusion are independent of those of asbestos exposure.

Other studies in different populations have also found that smoking is a significant predictor of Dlco at the beginning of follow-up.4,21-23 However, these studies differ as to whether smoking also affects rate of change in Dlco, with some finding, as we did, no effect4,22,23 and others finding that smoking results in a more rapid decrement with time.21 Whatever the biological mechanism underlying this latter observation, it suggests that the reduced Dlco associated with smoking is a stepwise phenomenon occurring before initial Dlco testing.

Sex, age and height at entry have been reported as significant predictors of Dlco level in previous reports.6,7 Our results confirmed this finding with regard to initial Dlco level, and further showed that the amount of change in Dlco over time is the same for men and women, regardless of their age and height. Others have reported different effects of demographic variables on the change of Dlco over time. For example, Burgess et al21 found steeper rates of decline in men, while Sherril et al26 and Viegi et al13 reported no difference between sexes, but accelerated decline in older people. The study of different occupational settings and the use of different analytical techniques may explain these conflicting results.

A particular strength of our study was the use of a random-effects model, which models individual measurements for each participant. Thus, although data from participants with only one measurement are not included in estimating the rate of change, they do increase the precision of the estimation of Dlco.19 Further, our longitudinal model included height, sex and age, accounting for the main sources of variability in alveolar volume.

However, a number of limitations should also be noted. The study sample may not be truly representative of the asbestos-exposed population at Wittenoom, as previous reports have shown that participants in the vitamin A program were younger and had higher asbestos exposures compared with non-participants.11

Furthermore, it was not feasible to meet the American Thoracic Society recommendation of stopping smoking for 24 hours before the test. This is likely to have affected Dlco measurements because of the presence of carboxyhaemoglobin,7 which would tend to accentuate differences between current smokers and ex-smokers or never-smokers.

Lastly, while survival bias (duration of disease influencing exposure measurements) is not a concern in cohort studies, the fact that there were missing data (due to withdrawals) may result in follow-up bias in our study.27

Our study confirms the deleterious effect of crocidolite on Dlco and shows, for the first time, that this damage not only persists but also worsens over time. Our results also show that smoking and asbestos exposure affect the level and rate of decline of Dlco in an additive, rather than synergistic, manner in this population.