Pneumoconiosis

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Besides mixed dust pneumoconiosis, coal mining has been shown to be a risk factor for COPD. (1-5) It is recognized that silicosis is a risk factor for tuberculosis, (6,7) and there is a well founded suspicion that those subjects who do not present with silicosis, but have had long exposure to silica, have a greater risk of developing tuberculosis. (7,8) It has been reported (9) that the risk of tuberculosis does not increase in coal miners who do not have pneumoconiosis, nor does it appear that the presence of pneumoconiosis in coal mine workers increases the risk of infection by mycobacteria, as is the case with silicosis. (10) Mosquera et al (11) found an incidence of tuberculosis of 150 per 10 (5) person-years among coal miners in our region, both active or retired, which is a rate that is three times higher than that of the general population of the same area. More than half of the patients presented with complicated pneumoconiosis.

Silica has been classified by the International Agency for Research on Cancer as a carcinogen in humans, (12) although it does not seem that the incidence of cancer among coal miners is increased. (9,13,14) The different concentrations of silica in this kind of mining, which are related to the type of coal extracted and the rock work required to extract it, may help to explain certain persistent discrepancies and uncertainties about the risk posed by coal mine dust. In our region, coal is extracted from narrow vertical seams embedded in slates and sandstone. To access the coal seams, a great deal of rock work is required. The coal is bituminous, of low grade, and this fact has been associated with a lesser risk for pneumoconiosis than that posed by high-grade coal. (9)

The aim of the present work was to study the evolution of respiratory diseases in a cohort of coal miners in Asturias (Spain), some of whom have to do a great deal of rock work to extract the coal and, as a result, are exposed to relatively high concentrations of silica compared with coal workers. Rock workers were exposed to an average level of breathable dust of 2.5 mg/[m.sup.3] with 17.5% silica. Coal extractors were exposed to 3.4 mg/[m.sup.3] of dust with 8% silica, and other inside workers were exposed to lower dust levels. These figures refer to averages over the working day. In Spain, the permitted exposure limit (established in 1985) varies according to the percentage of silica from 6 mg/[m.sup.3] (with < 10% silica) to 2 mg/[m.sup.3] (with 30% silica).

MATERIALS AND METHODS

Identification and Characteristics of the Cohort

The cohort comprises 2,579 men who underwent a medical examination in the Institute National de silicosis (INS) prior to starting work inside the coal mines of Hulleras del Norte SA (Asturias, Spain) between 1972 and 1980. Their first follow-up examination took place between 1981 and 1986. There was a second follow-up examination between 1999 and 1993, in which 2,335 persons participated, and a third follow-up examination took place between 1994 and 1995, in which 1,966 persons participated. In the initial examination for entry into the mine, those candidates who showed radiographic or functional anomalies were rejected, as stipulated by law. Candidates who had residual lesions from pulmonary and/or pleural tuberculosis were not admitted to work in the mine, and neither were those whose functional spirometry values were below the normal lower limit. (15) Subjects who had worked in other activities that placed them at risk for pneumoconiosis before entering the Hulleras del Norte SA mine (eg, work in mines or quarries, and work with china clay, or iron and steel) were excluded from the study. The great majority of those who had undergone the initial examination attended the first cheek up, with the exception of 33 participants who did not join the enterprise, 35 who had left employment (voluntarily or through dismissal), and 45 who had retired before this first check-up.

The Follow-up of the cohort was prospective from the first check-up and retrospective between this examination and the one prior to starting work. All of the examinations included a clinical study, chest radiograph, and pulmonary function testing. The mean follow up time was 20.13 years (range, 9.35 to 24.47 years). Mean age on entry was 20 years (age range, 18 to 48 years), and at the third cheek-up it was 42 years (age range, 32 to 69 years). Those who did not respond to the first call to attend a cheek-up were invited to do so up to two other times. Six hundred thirteen subjects did not attend the third (final) check-up (23.7%), of whom 69 had died from a variety of causes (taken from death certificate records), as follows: accident (33 subjects); heart attack (5 subjects); cirrhosis of the liver (4 subjects); pnemnonia (2 subjects); and other nonrespiratory diseases (10 subjects). In 15 cases, access to death certificates was not obtained. It was impossible to contact 180 of the 613 subjects, as they had retired and changed their plate of residence. The causes of retirement, according to company archives, were as follows: accident (40 subjects); age (13 subjects); neurologic and/or muscular-skeletal diseases (52 subjects); other common nonrespiratory diseases (47 subjects); pneumoconiosis (1 subject); and unspecified common diseases (27 subjects). The remaining subjects (364) were asked to attend follow-up examinations on three occasions but did not come, probably due to the fact that an early retirement plan was to be implemented, affecting > 42 miners who had worked in the mine for a certain number of years. The case was that taking early retirement was markedly more advantageous, in economic terms, than taking retirement on the grounds of health.

Measurement of Exposure and Disease

In the Asturian coal mines the seams are narrow, and therefore there is a group of workers whose task consists of preparing access to the galleries. According to the estimates of the Technical Department of the INS, these rock workers were exposed to an average level of breathable dust of 2.5 mg/[m.sup.3] with 17.5% silica. Coal extractors were exposed to 3.4 mg/[m.sup.3] of dust with 8% silica, and other inside workers were exposed to lower dust levels. These levels refer to breathable dust (ie, particles < 5 [micro]m in size) reflecting the average level over a working day and were implemented as the rule for exposure in 1993. Prior to that date, working conditions were worse and, most likely, the levels of exposure were higher. Rock workers were defined as those workers who had carried out this type of work for the greater part of their time in the mine (ie, two thirds or more) and had never worked as coal extractors. Coal extractors were defined in a similar way. The relevant assistant workers were included in each category. The "other risk" category comprised other inside workers who were not included in the two aforementioned categories. For certain types of analysis, exposure was evaluated as the following binary variable: rock workers and others (this latter including all other workers).

Smoking was assessed at the first check up (as this was the first prospective follow-up). Those subjects who had never smoked were classified as nonsmokers, those who had not smoked in the last 6 months and had smoked at least one pack a year were classified as ex-smokers, and the rest were classified as smokers. For certain types of analysis, smokers were defined as those who smoked or had smoked in the past, as a binary variable.

Chest radiographs were performed in accordance with the prevailing International Labour Organization (ILO) standards (16,17) and were interpreted by three trained readers, with the intermediate value being taken as valid in the case of a discrepancy. With regard to compensation, in Spain pneumoconiosis is diagnosed if the opacities had an ILO profusion score [greater than or equal to] 1/1, or if there is evidence of lesions through another imaging modality or through histology. The histologic lesions that were evaluated for the purposes of diagnosing pneumoconiosis were characteristic nodules, as well as changes in the nodules that were consistent with progressive massive fibrosis. In our study, diagnosis was based exclusively on clinical findings and chest radiography. Given the small number of cases with ILO profusion score [greater than or equal to] 1/1, we included scores [greater than or equal to] 1/0, because in some countries this is the demarcation for the diagnosis of pneumoconiosis. Also, the number of eases in this shady with this profusion category allows reliable statistical analysis.

Pulmonary function was measured at the Respiratory Physiology Department of the INS. To carry out spirometry and to determine the predicted values, the recommendations of the Commission of the European Communities (15) were followed until 1993, and subsequently those of the European Respiratory Society were followed. (18) Given that the age, height, and FE[V.sub.1] of participants were known on their starting work, all predicted FE[V.sub.1] values were calculated in accordance with the European Respiratory Society equations (for those prior to 1993 applied retrospectively).

FE[V.sub.1] was the only measure of lung function employed in the analysis since it was the only test carried out in all cases on entry to the mine, thus permitting prolonged follow-up. Accelerated decreases in FE[V.sub.1] were calculated in accordance with the recommendations drawn up for worker assessment. An accelerated decrease was considered to exist if the FE[V.sub.1] (in liters) was < 85% of the baseline value, less 0.025 multiplied by the number of years between measurements. (19,20)

Chronic Bronchitis: Chronic bronchitis was defined in accordance with Medical Research Council criteria (21) (ie, coughing and expectoration for at least 3 months over 2 consecutive years).

Bronchial Asthma: The diagnosis of asthma was based on clinical data and changes in the FE[V.sub.1] of > 20% spontaneously, after the administration of bronchodilators, or provoked by methacholine. Asthmatic subjects were excluded from all FE[V.sub.1] analyses.

Pulmonary Tuberculosis: The diagnosis of pulmonary tuberculosis was made through bacteriologic confirmation. The check for lung cancer was based on clinical history, review of medical records, and chest radiography.

Statistical Analysis

To calculate the 95% confidence intervals (CIs) of the incidence rate ([lambda]) with fewer than 10 cases observed, exact methods were employed based on the [chi square] test distribution and in accordance with the following formulas for limit levels below [[lambda].sub.1] and above [lambda]u

[[lambda].sub.1] = [[chi square].sub.[alpha],[upsilon]]/2; [alpha] = 0.05; [upsilon] = 2x; [lambda]u = [[chi square].sub.1-[alpha], [upsilon]]/2; upsilon = 2(x + 1);

where X is the number of events. (22) If > 10 events were observed, the formula

SE = 1/[square root of (x)]

was employed for calculation of the SE of [lambda] in the logarithmic scale. (23)

Analysis of the relation among the binary variables (ie, round opacities, irregular opacities, chronic bronchitis, and FE[V.sub.1] < 80% of predicted values) with type of work and the smoking history (codified at three ordinal levels) was carried out using the [chi square] test. Linear tendency was assessed using Spearman lineal correlation. The Cox model was employed as the multivariable method to study round opacities, FE[V.sub.1] < 80% predicted, and accelerated decreases in FE[V.sub.1] related regard to rock work and smoking (as binary variables). Included in the analysis was the product of multiplying the two factors, which then was excluded because it was not significant. The appropriateness of the model employed was evaluated graphically. To evaluate the relations among FE[V.sub.1] percent predicted, kind of work, and tobacco use, a general linear model (CLM) multivariable analysis was employed for repeated measurements to control the correlation between repeated values measured in the same persons. In accordance with recommendations regarding the interaction evaluation, (24) this examination was carried out using an additive model. The following four subgroups were formed, based on rock work and tobacco use: 487 non-rock-worker nonsmokers ([R.sub.0][S.sub.0]); 1,456 non rock workers who smoked ([R.sub.0][S.sub.1]); 42 rock workers who were nonsmokers ([R.sub.1][S.sub.0]); and 122 rock workers who were also smokers ([R.sub.1][S.sub.1]). The occasional loss of certain data was put down to random factors, and the analysis was conducted on the basis of complete data. The analyses were carried out using a statistical software package (SPSS, version 8.0 for Windows; SPSS; Chicago, IL), and p < 0.05 was considered to he significant.

RESULTS

Pneumoconiosis

Round opacities with an ILO profusion score of [greater than or equal to] 0/1 were observed in 387 cases (15%), those with an ILO profusion score of [greater than or equal to] 1/0 were observed in 99 eases (3.8%), and those with an ILO profusion score of [greater than or equal to] 1/1 were observed in 3 cases (0.15%). Type p opacities (ie, diameter, [less than or equal to] 1.5 mm) were predominant at the first check-up (82%), and type q opacities (ie, diameter, 1.5 to 3 mm) were predominant at the third check-up (59%). Type r opacities (ie, diameter, 3 to 10 mm of diameter) were observed in only one case. Category 1 opacities began to appear after a minimum exposure period of 16 years, with an apparently exponential relation to the period of exposure (Fig 1). Irregular opacities with an ILO profusion score of 1/1 were found in two cases, and those with an ILO profusion score of [greater than or equal to] 1/0 were found in 20 cases. We would point out that there is a discrepancy between the number of cases with opacities that appear in Tables 1 and 2 due to the frequent changes in the kind of work performed occurring among these workers. The information obtained from the third survey of work history was thought to be the most reliable. This means that data are missing about the type of work performed, while other data previously obtained appear in other variables (ie, opacities and accelerated FE[V.sub.1] decline). The type of irregular opacities was s/t in 82% of cases and s/s in the rest (s denotes a width [less than or equal to] 1.5 mm, and t denotes a width of 1.5 to 3 mm). Round opacities are significantly related to work risk evaluated at three levels according to predicted exposure to silica, with a significant lineal trend (Table 1). The relation approaches significance in multivariable analysis including tobacco use (Fig 1). The presence of round opacities bear a significant relationship with tobacco use in the overall analysis, with a lineal trend, and also in multivariable analysis including type of work. The number of cases with category 1 round opacities was 9, 68, 0, and 11, respectively, in subgroups [R.sub.0][S.sub.0], [R.sub.0][S.sub.1], [R.sub.1][S.sub.0], and [R.sub.1][S.sub.1], and incidence for [10.sup.5] person-years was 97.4, 244.4, < 120, and 473.3, respectively. The incidence was noticeably greater in the [R.sub.0][S.sub.1] group, in which the two risk factors (ie, rock work and tobacco use) were combined, indicating a possible interactive effect. There is a potential reliability issue. This may indicate synergy, however, it may not be prudent to reach this conclusion as the [R.sub.1][S.sub.0] group consisted of only 42 persons. With regard to irregular opacities, a relation with tobacco use is suggested rather than with work risk, although, due to the small number of events, a valid statistical correspondence cannot be established.

[FIGURE 1 OMITTED]

The mean FE[V.sub.1] was 103.29% predicted, 100% predicted, 77% predicted, and 102.15% predicted, respectively, for the four groups in successive checkups, and only among heavy smokers was it slightly below the predicted value of 100% at the second and third check-ups (98.34% predicted and 99.63% predicted, respectively). The mean FE[V.sub.1] values among rock workers were 103.5% predicted, 100.2% predicted, and 101.4% predicted, respectively, in successive check-ups. The mean FE[V.sub.1] values for workers engaged in other inside tasks were 103.95% predicted, 101.67% predicted, and 103.1% predicted, respectively, for successive cheek-ups, always lower values in rock workers, and showing differences that tended to increase in successive check-ups but did not reach statistical significance.

FE[V.sub.1] < 80% predicted and accelerated FE[V.sub.1] decreases demonstrated a significant association with the consumption of tobacco. These phenomena were observed among rock workers, but statistical significance was not reached for kind of work (Tables 3 and 4). There is a discrepancy in Tables 3 and 4 in the number of workers, depending on whether classification is by type of work or the smoking history, for reasons previously indicated. In Table 4, the number reported is slightly lower as subjects who did not report for the final check-up and had not shown previous anomalies were considered to be lost to follow-up. This occurred with less frequency in cases of accelerated decline (Table 3), since they had been detected in greater numbers before the final check-up.

In the Cox model multivariable analysis, both FE[V.sub.1] < 80% and FE[V.sub.1] accelerated decrease were significantly related to tobacco consumption, while only FE[V.sub.1] was significantly related to rock work. In the GLM (repeated measurement) multivariable analysis, FE[V.sub.1] was significantly related to tobacco consumption but not to rock work, although there was the tendency toward a negative regression coefficient among rock workers that become more marked in successive cheek-ups (Table 5).

The relative risk of FE[V.sub.1] < 80% predicted, taking the [R.sub.0][S.sub.0] group as a reference, was 0.75 for the [R.sub.1][S.sub.0] group, 1.59 for the [R.sub.0][S.sub.1] group, and 2.67 for the [R.sub.1][S.sub.1] group, meeting the criteria for additive interaction. (24) Chronic bronchitis was significantly associated with tobacco consumption with regard to dose-response significance and with the kind of work, in which the trend test borders on significance. The incidence of the diseases studied can be seen in Table 6.

DISCUSSION

The principal merit of this study is that it is a cohort study, and its principal defects are the loss of subjects to follow-up and the lack of individualized exposure measurements. Of the 613 subjects who did not attend the final check-up (23.7%), it was found that 207 were deceased or retired and that the cause was not respiratory disease. There remain, therefore, 406 subjects (15.75%) about whom there was no information at the end of the study, although they had been called for follow-up evaluations on three occasions. The principal reason for this was a proposed early retirement plan that was much more advantageous, in economic terms, than any form of retirement due to ill health. This may very likely be the reason why those who suspected they might be affected by some disease did not attend the follow-up evaluations. It may be supposed, therefore, that these losses could bear some relation to disease. We have analyzed the losses from the second follow-up review onward (ie, after 16.8 years and after the work survey) with regard to previous accelerated FE[V.sub.1] decline and type of work. Of 157 subjects (asthmatic subjects excluded) who had shown accelerated FE[V.sub.1] decline, 34 were lost to follow-up (21.6%), compared to 330 of 2,132 (15.4%) in the group without such decline, which is a significant difference (p = 0.041). Of 266 rock workers, 42 (15.7%) were lost to follow-up during the aforementioned period compared to 320 of 2,044 (15.6%) performing other tasks, which is a nonsignificant difference (p = 0.95). It appears that the losses of subjects to follow-up were at least related to accelerated FE[V.sub.1] decline. The losses of subjects to follow-up that were related to disease, in cases in which there existed an exposure-disease relationship, would tend to favor the null hypothesis and would not invalidate the positive findings of this study.

The INS, the hospital in which the study was carried out, is the reference point for miners with respiratory problems, both outpatients and those requiring hospital admission. The INS has a tuberculosis isolation unit available. It is unlikely, therefore, that this wastage has to do with respiratory diseases requiring study or treatment by the pneumologist (ie, for tuberculosis or lung cancer), and so should not significantly affect our findings.

Slightly profuse round opacities were developed by 3.8% of workers (category 1), a proportion that is in accordance with expectations among a young population with an employment rate of 76%. (9) It is to be expected that this proportion will increase with time, and perhaps at a faster rate, given the fact that the relationship between exposure (calculated according to time worked) and risk of disease is an exponential one (Fig 1), as has been demonstrated previously. (25) Furthermore, it is likely that, in a certain number of cases, pneumoconiosis may appear or progress once exposure has ceased, especially among those persons with the most exposure to silica (ie, rock workers), (26) while this evolution is less frequently observed among coal workers. (27) The minimum exposure time for the appearance of these opacities is approximately 16 years. The association between irregular opacities and smoking is well-known, (28-30) and is also suggested by our data, although it cannot be evaluated due to the small numbers involved. The relationship between round opacities and smoking is noteworthy. The role of tobacco as a causal agent in interstitial lung diseases has been emphasized in some studies. Many of these diseases reveal a nodular radiographic or ground-glass pattern. (31) A possible explanation for our findings may be that tobacco use favors the development of pneumoconiosis by impeding particle clearance (32) or by acting in synergy with dust (especially silica dust). The suspicion of additive interaction between rock work and tobacco use that was observed in our results may favor this hypothesis. Another possible explanation is that at least some part of the nodulation we have observed is not true pneumoconiosis but, rather, is due to one of the interstitial diseases that tobacco use may induce. (31) The findings of Hessel et al, (33) in histologic examinations, that there is a negative association between smoking and silicosis would seem to favor this hypothesis.

The decrease in FE[V.sub.1] was, as expected, related to smoking and was attenuated in ex-smokers. In all procedures that were used to evaluate the relationship between FE[V.sub.1] and type of work, rock workers were at a disadvantage, although this only became significant when the time up to the accelerated decrease was analyzed using the Cox multivariable model. It suggested that this method is the most appropriate for such situations and led to the conclusion that FE[V.sub.1] loss was greater among rock workers. The fact that the differences were small and difficult to detect may derive from the absence of a nonexposed comparison group, the comparison made being between those subjects who were more and less exposed. This supposes a bias against the null hypothesis and leads us to believe that the effect of exposure to silica may be greater than that observed in this study. The same occurs in the case of nodulation, with regard to functional loss. An additive interaction between rock work and tobacco use is indicated, but with the aforementioned limitation. Functional loss with respect to silica exposure is in agreement with the findings of other studies (1,3) that have reported a loss of ventilatory function related to work in mines, a relationship that is most marked among gold miners (supposedly due to greater exposure to silica).

The incidence of tuberculosis in the general population of Asturias was between 18.6 and 50.3 per [10.sup.5] person-years in the period from 1980 to 1994, and in Spain as a whole the incidence was between 12.9 and 34.4 per [10.sup.5] person-years, according to the data of the Health Authority of the Principality of Asturias, with the higher values being among adult men. (34) We have found an incidence of 8.29 per [10.sup.5] person-years (range, 2.28 to 21.15 per [10.sup.5] person-years), which is within or even a little below the expected limits, perhaps due to the healthy worker bias. In a previous study of tuberculosis among Asturian basin coal miners that was conducted between 1971 and 1985, Mosquera et al (11) reported an incidence of 150 cases per [10.sup.5] person-years, an incidence that is three times greater than that of the general population in the same area, which was attributed to socioeconomic circumstances and the delay in diagnosis and treatment. An additional factor was that the majority of the subjects presented with complicated pneumoconiosis and that, given the type of mine working taking place in this region, they could well be true silicosis cases. The finding in our study of an incidence within expected limits, in contrast to the that of previous study of miners in this area, may have been due to the fact that our data corresponded to a working population with only incipient pneumoconiosis. Earlier studies, (6,7) on the other hand, included retired persons, many with pneumoconiosis, and sometimes complicated pneumoconiosis. It is well-known that silicosis triples the risk of tuberculosis.

The incidence of asthma in our cohort was 141 cases per [10.sup.5] person-years. The incidence of asthma estimated in Spain, as a whole, in adults (ie, persons 26 to 50 years of age) is 553 cases per [10.sup.5] personyears, a value that falls to 150 depending on the definition of who was free of asthma at baseline. (35) This difference may be derived from a variety of causes. On the one hand, the definition of asthma in our study is based on medical diagnosis through clinical and functional data, while in the study of Spain as a whole, the diagnosis of asthma was a result of a positive answer to the question "Have you ever suffered from asthma?" The Spanish study refers to the period from 1998 to 1999, and ours to the period from 1972 to 1995, and it is possible that the incidence has changed over time. The principal factor may well be the healthy worker bias. In any case, there is nothing to suggest that work in the mine is a risk factor for asthma.

There were no lung cancers identified in the cohort. Considering the size of the population under review and the number of relatively young subjects included, one or two cases were to be expected, especially among those persons who had the most exposure to silica. We cannot discount the possibility of cases of lung cancer among the 406 subjects for whom no information was available at the end of the study. This would reduce the validity of the negative finding. If it is indeed certain that there were no cases of cancer, our results would be in agreement with those of other authors, (13,14,36) who have not observed a significant incidence of lung cancer among coal miners.

In conclusion, our data show that round opacities are more frequent in smokers, and probably also among rock workers, and that declines in FE[V.sub.1] are related to tobacco use and the performance of rock work. There was no identified increase in the number of cases of tuberculosis or lung cancer in this group.

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* From the Services of Neumology (Drs. Isidro Montes, Rego Fernandez, and Martinez Gonzalez) and Radiology (Dr. Anton Martinez), Instituto Nacional de Silicosis, Hospital Central de Asturias, Oviedo, Span; and the Service of Medicine (Dr. Reguero, Cosio Mir, and Garcia-Ordas), Hulleras del Norte SA, Oviedo, Spain.

This research was supported by European Coal and Steel Community grant No. 7280-03/003.

Manuscript received December 10, 2002; revision accepted January 23, 2004.

Reproduction of this article is prohibited without writtin permission from the American College of Chest Physicians (e-mail: permission@chestnet.org).

Correspondence to: Isabel Isidro Montes, MD, C/ Bellmunt s/n, Hospital Central de Asturias, Instituto Nacional de Silicosis 33006, Oviedo, Spain; e-mail: iisidro@hcas.sespa.es

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