1423 airway hyperresponsiveness by decreasing enkephalinase. J Appl Physiol 1988; 64(6):2653-8. 10. Dusser DJ, Jacoby DB, Djokic TD, Rubinstein I, Borson DB, Nadel
JA. Virus induces airway hyperresponsiveness to tachykinins: role of neutral endopeptidase. J Appl Physiol 1989; 67:1504-11. 11. Tanaka DI; Grunstein MM. Mechanisms of substance P-induced contraction of rabbit airway smooth muscle. J Appl Physiol 1984; 57:1551-7.
From the Authors: We thank Drs. Jacoby and Fryer for their comments concerning possible mechanisms explaining hyperresponsiveness after airway virus infection. As these investigators point out, our original study on virus-induced hyperresponsiveness demonstrated that a muscarinic antagonist prevented the increase in airflow resistance after inhalation of histamine in infected subjects. At the time, various investigators challenged our interpretation that increased vagal motor activity could be involvedin virus-induced airway hyperresponsiveness. In the 1980s,a series of studies confirmed the presence of cholinergic mechanisms of hyperresponsiveness. Furthermore, therapy with muscarinic antagonists has found its place in regimens for bronchodilator therapy. The present study provides new and interesting evidence for the underlying mechanisms. LAURI A. LAITINEN, M.D. AB Draco Exploratative Clinical Research Lund, Sweden A. NADEL, M.D. School of Medicine University of California, San Francisco San Francisco, California JAY
CHRONIC AIRFlOW LIMITATION IN SOUTH AFRICAN GOLD MINERS
dust exposure (intensity x duration) was taken into consideration, in the analysis or by matching, then silicosis per se was not associated with a significant loss of lung function (4, 5). In the analysis by Cowie and Mabena (I) the effect of dust exposure was estimated by the duration of exposure and it is thus likely that the silicosis variable was acting as a surrogate for the level of dust exposure. To show our point, we related the FEY, to silicosis (converting ILO classification to an ordinal variable) in a regression model in which the age, height, smoking status, and cigarette pack-yr were adjusted and the precision of the dust exposure variable varied. The coefficient for silicosis, 13 ± SE, changed according to the dust variable used as follows: (l) when no dust variable was included 13 = - 0.0347 ± 0.0128 (p = 0.007); (2) when the duration of dust exposure was included 13 = - 0.0313 ± 0.0128 (p = 0.015); (3) when the cumulative dust exposure was included 13 = - 0.0206 ± 0.0130 (p = 0.11). Thus, as the precision ofthe dust variable increased, the magnitude of the coefficient for silicosis decreased. The p value of 0.11 may be due to silicosis having some effect on lung function or due to residual confounding. Their study design was basically a case-control study of silicosis. Most of the silicotics in the population were identified and matched by age with a set of controls who did not have silicosis in a ratio of 5:2. The results presented indicate that the controls were younger, had fewer years of mining exposure, and lower intensity of exposure, as would be expected because these are risk factors for silicosis. The study design could estimate the differences in lung function among the silicotics and non-silicotics, but unless a more precise measurement of silica dust exposure is used to adjust for the effect of dust itself on the loss of lung function, the esimated effect of silicosis may be overestimated. Whether this study design can provide an unbiased estimate of the effect of dust exposure on loss of lung function is questioned. We would like to commend the authors for addressing an important and difficult issue. The data on the white miners also indicate that silica dust exposure on South African gold mines has a potential to reduce lung function significantly; however, we think that the results on smoking and silicosis should be viewed with caution.
To the Editor: The paper by Cowie and Mabena (1) indicated that black South African gold miners "are exposed to a working environment that has a potential similar to, if not greater than, tobacco smoking to produce chronic airflow limitation." They estimated that the average loss of FEY, attributable to 25 yr of underground exposure was 200 ml, the loss attributable to smoking 25 pack-yr was 172 ml, and the loss attributable to silicosis (Category 2/2) was 320 ml. These results raise several points. To illustrate these points, we use results from a study of 2209 white South African gold miners who started gold mining in the early 1940sand had their lung function tests in 1970 when they were between 45 and 54 yr old (2). First, we suspect that the effect of smoking may have been underestimated by the regression model applied. In our data, the observed loss in FEY, in current smokers compared with never smokers (ex-smokers were excluded) was on average around 500 ml across all levels of dust exposure. A similar result was reported by Dockery and coworkers (3). The estimated effect of smoking on FEY, can change, however, according to the linear regression model applied. When smoking was represented by cigarette pack-yr only, the estimated coefficient (± SE) was -0.0091 ± 0.0009, and the loss of FEY, associated with 25 pack-yr was estimated as 228 ml. When an indicator (0/1) variable representing current smoking status was included in the model, in addition to pack-yr, then the estimated coefficients were -0.4352 ± 0.0593 and -0.0039 ± 0.0012, respectively. The estimated loss of FEY, attributable to smoking of 25 pack-yr was then estimated as 531 ml, which is close to the observed value. Second, we suspect that the effect of silicosis may have been overestimated by the analysis. It is known that silica dust can cause small airways obstruction and emphysema. Tho independent studies of white South African miners found that when the effect of silica
EVA HNIZDO, M.Sc.
Epidemiology Research Unit Medical Bureau for Occupational Diseases Johannesburg, South Africa A. HESSEL, PH.D. Clinical Sciences Building University of Alberta Edmonton, Canada
PATRICK
GERHARD
K. SLUIS-CREMER, M.D.
Epidemiology Research Unit Medical Bureau for Occupational Diseases Johannesburg, South Africa 1. Cowie RL, Mabena SK. Silicosis, chronic airflow limitation, and chronic bronchitis in South African gold miners. Am Rev RespirDis 1991;143:80-4. 2. Wiles FJ, Faure MH. Chronic obstructive lung disease in gold miners. In: Walton WH, ed. Inhaled particles IV. Oxford: Pergamon Press, 1977:727-35.
3. Dockery DW, Spiezer EF, Ferris BG, Ware JH, Louis TA, Spiro A. Cumulative and reversible effects of life time smoking on simple tests of lung function in adults. Am Rev Respir Dis 1988; 137:286-92. 4. Irwig LM, Rock P. Lung function and respiratory symptoms in silicotic and non-silicotic gold miners. Am Rev Respir Dis 1978; 117:429-35. 5. Wiles FJ, Baskind E, Hessel PA. Silicosis and lung function. Poster presented at Inhaled Particles VI. Cambridge, September 1985.
From the Authors: We wish to thank Drs. Hnizdo, Hessel, and Sluis-Cremer for their interest in our paper. They are concerned that we have overestimated the effect of the working environment on FEY, by underestimat-
1424
ing the effect of smoking. They have suggested the addition of a dummy variable smoker:yes/no to the regression model and the exclusion of ex-smokers from the analysis. Rather than making an arbitrary addition of a dummy variable to our regression equation, we have eliminated the effect of smoking by examining the data collected from the 390 subjects, in our study, who had never smoked. In that group the effect on the FEV, of 25 yr of exposure to the underground environment is estimated to be 313ml (coefficient for 1 yr of underground exposure -0.0125 [liters], SE 0.0049) after controlling for age, height, and lung nodule profusion. This is larger than the effect of 200 ml per 25 yr underground exposure on the whole group of 1,197 men and might suggest that the effect of smoking was overestimated or that non-smokers are somehow more susceptible to the effects of that working environment. In any event, it is clear that smoking did not contribute to the loss of FEV, in the 390 miners who had never smoked and likely that the loss was, as suggested by the analysis, associated their working environment. The second concern that Hnizdo, Hessel, and Sluis-Cremer have relates to the association of silicosis with pulmonary dysfunction demonstrated in our study. It is clearly impossible to be sure that silicosis is not acting as a surrogate for small airways disease and emphysema. Nevertheless, the pattern of disturbance of lung function associated with silicosis differs from that attributed to the increasing duration ofexposure to the mine environment. In our original analysis, we used the models they have suggested, combining duration and intensity of exposure, and found that these did not alter the significant association of silicosis with pulmonary dysfunction, including loss of lung diffusion for carbon monoxide and reduction of vital capacity. No matter how the dust exposure data
is entered into the model, these changes remain significantly associated with silicosis and progress as the degree of nodule profusion increases. With regard to the nature of the study, we are not certain how this is relevant. However, we would not define it as a case-control study as the disease of interest is respiratory dysfunction and subjects were not selected on the basis of the presence or absence of that disease. They were selected for their category of silicotic nodule profusion, which was the "exposure" or determinant of interest. We would describe it as a cross-sectional study with the sampling of subjects designed to give the best possible contrast of silicosis. The rough matching for age was necessary to avoid having a representative group of the non-silicotics (the majority of miners) who have a mean age of 29 yr and would thus have not been comparable with the men with silicosis with their mean age of 47 yr. We believe that the subjects in our study differ from those studied by Hnizdo, Hessel, Sluis-Cremer, and their coworkers. This may be because the exposure to dust by black miners who provide the labor in the labor-intensive South African gold mines is more intense than that of the white miners who have been studied by the South African Medical Bureau for Occupational Diseases. R. L.
M.D., M.Sc. Foothills Hospital Calgary, Alberta, Canada S. K. MABENA, R.N. Ernest Oppenheimer Hospital Welkom, South Africa COWIE,
JA. Virus induces airway hyperresponsiveness to tachykinins: role of neutral endopeptidase. J Appl Physiol 1989; 67:1504-11. 11. Tanaka DI; Grunstein MM. Mechanisms of substance P-induced contraction of rabbit airway smooth muscle. J Appl Physiol 1984; 57:1551-7.
From the Authors: We thank Drs. Jacoby and Fryer for their comments concerning possible mechanisms explaining hyperresponsiveness after airway virus infection. As these investigators point out, our original study on virus-induced hyperresponsiveness demonstrated that a muscarinic antagonist prevented the increase in airflow resistance after inhalation of histamine in infected subjects. At the time, various investigators challenged our interpretation that increased vagal motor activity could be involvedin virus-induced airway hyperresponsiveness. In the 1980s,a series of studies confirmed the presence of cholinergic mechanisms of hyperresponsiveness. Furthermore, therapy with muscarinic antagonists has found its place in regimens for bronchodilator therapy. The present study provides new and interesting evidence for the underlying mechanisms. LAURI A. LAITINEN, M.D. AB Draco Exploratative Clinical Research Lund, Sweden A. NADEL, M.D. School of Medicine University of California, San Francisco San Francisco, California JAY
CHRONIC AIRFlOW LIMITATION IN SOUTH AFRICAN GOLD MINERS
dust exposure (intensity x duration) was taken into consideration, in the analysis or by matching, then silicosis per se was not associated with a significant loss of lung function (4, 5). In the analysis by Cowie and Mabena (I) the effect of dust exposure was estimated by the duration of exposure and it is thus likely that the silicosis variable was acting as a surrogate for the level of dust exposure. To show our point, we related the FEY, to silicosis (converting ILO classification to an ordinal variable) in a regression model in which the age, height, smoking status, and cigarette pack-yr were adjusted and the precision of the dust exposure variable varied. The coefficient for silicosis, 13 ± SE, changed according to the dust variable used as follows: (l) when no dust variable was included 13 = - 0.0347 ± 0.0128 (p = 0.007); (2) when the duration of dust exposure was included 13 = - 0.0313 ± 0.0128 (p = 0.015); (3) when the cumulative dust exposure was included 13 = - 0.0206 ± 0.0130 (p = 0.11). Thus, as the precision ofthe dust variable increased, the magnitude of the coefficient for silicosis decreased. The p value of 0.11 may be due to silicosis having some effect on lung function or due to residual confounding. Their study design was basically a case-control study of silicosis. Most of the silicotics in the population were identified and matched by age with a set of controls who did not have silicosis in a ratio of 5:2. The results presented indicate that the controls were younger, had fewer years of mining exposure, and lower intensity of exposure, as would be expected because these are risk factors for silicosis. The study design could estimate the differences in lung function among the silicotics and non-silicotics, but unless a more precise measurement of silica dust exposure is used to adjust for the effect of dust itself on the loss of lung function, the esimated effect of silicosis may be overestimated. Whether this study design can provide an unbiased estimate of the effect of dust exposure on loss of lung function is questioned. We would like to commend the authors for addressing an important and difficult issue. The data on the white miners also indicate that silica dust exposure on South African gold mines has a potential to reduce lung function significantly; however, we think that the results on smoking and silicosis should be viewed with caution.
To the Editor: The paper by Cowie and Mabena (1) indicated that black South African gold miners "are exposed to a working environment that has a potential similar to, if not greater than, tobacco smoking to produce chronic airflow limitation." They estimated that the average loss of FEY, attributable to 25 yr of underground exposure was 200 ml, the loss attributable to smoking 25 pack-yr was 172 ml, and the loss attributable to silicosis (Category 2/2) was 320 ml. These results raise several points. To illustrate these points, we use results from a study of 2209 white South African gold miners who started gold mining in the early 1940sand had their lung function tests in 1970 when they were between 45 and 54 yr old (2). First, we suspect that the effect of smoking may have been underestimated by the regression model applied. In our data, the observed loss in FEY, in current smokers compared with never smokers (ex-smokers were excluded) was on average around 500 ml across all levels of dust exposure. A similar result was reported by Dockery and coworkers (3). The estimated effect of smoking on FEY, can change, however, according to the linear regression model applied. When smoking was represented by cigarette pack-yr only, the estimated coefficient (± SE) was -0.0091 ± 0.0009, and the loss of FEY, associated with 25 pack-yr was estimated as 228 ml. When an indicator (0/1) variable representing current smoking status was included in the model, in addition to pack-yr, then the estimated coefficients were -0.4352 ± 0.0593 and -0.0039 ± 0.0012, respectively. The estimated loss of FEY, attributable to smoking of 25 pack-yr was then estimated as 531 ml, which is close to the observed value. Second, we suspect that the effect of silicosis may have been overestimated by the analysis. It is known that silica dust can cause small airways obstruction and emphysema. Tho independent studies of white South African miners found that when the effect of silica
EVA HNIZDO, M.Sc.
Epidemiology Research Unit Medical Bureau for Occupational Diseases Johannesburg, South Africa A. HESSEL, PH.D. Clinical Sciences Building University of Alberta Edmonton, Canada
PATRICK
GERHARD
K. SLUIS-CREMER, M.D.
Epidemiology Research Unit Medical Bureau for Occupational Diseases Johannesburg, South Africa 1. Cowie RL, Mabena SK. Silicosis, chronic airflow limitation, and chronic bronchitis in South African gold miners. Am Rev RespirDis 1991;143:80-4. 2. Wiles FJ, Faure MH. Chronic obstructive lung disease in gold miners. In: Walton WH, ed. Inhaled particles IV. Oxford: Pergamon Press, 1977:727-35.
3. Dockery DW, Spiezer EF, Ferris BG, Ware JH, Louis TA, Spiro A. Cumulative and reversible effects of life time smoking on simple tests of lung function in adults. Am Rev Respir Dis 1988; 137:286-92. 4. Irwig LM, Rock P. Lung function and respiratory symptoms in silicotic and non-silicotic gold miners. Am Rev Respir Dis 1978; 117:429-35. 5. Wiles FJ, Baskind E, Hessel PA. Silicosis and lung function. Poster presented at Inhaled Particles VI. Cambridge, September 1985.
From the Authors: We wish to thank Drs. Hnizdo, Hessel, and Sluis-Cremer for their interest in our paper. They are concerned that we have overestimated the effect of the working environment on FEY, by underestimat-
1424
ing the effect of smoking. They have suggested the addition of a dummy variable smoker:yes/no to the regression model and the exclusion of ex-smokers from the analysis. Rather than making an arbitrary addition of a dummy variable to our regression equation, we have eliminated the effect of smoking by examining the data collected from the 390 subjects, in our study, who had never smoked. In that group the effect on the FEV, of 25 yr of exposure to the underground environment is estimated to be 313ml (coefficient for 1 yr of underground exposure -0.0125 [liters], SE 0.0049) after controlling for age, height, and lung nodule profusion. This is larger than the effect of 200 ml per 25 yr underground exposure on the whole group of 1,197 men and might suggest that the effect of smoking was overestimated or that non-smokers are somehow more susceptible to the effects of that working environment. In any event, it is clear that smoking did not contribute to the loss of FEV, in the 390 miners who had never smoked and likely that the loss was, as suggested by the analysis, associated their working environment. The second concern that Hnizdo, Hessel, and Sluis-Cremer have relates to the association of silicosis with pulmonary dysfunction demonstrated in our study. It is clearly impossible to be sure that silicosis is not acting as a surrogate for small airways disease and emphysema. Nevertheless, the pattern of disturbance of lung function associated with silicosis differs from that attributed to the increasing duration ofexposure to the mine environment. In our original analysis, we used the models they have suggested, combining duration and intensity of exposure, and found that these did not alter the significant association of silicosis with pulmonary dysfunction, including loss of lung diffusion for carbon monoxide and reduction of vital capacity. No matter how the dust exposure data
is entered into the model, these changes remain significantly associated with silicosis and progress as the degree of nodule profusion increases. With regard to the nature of the study, we are not certain how this is relevant. However, we would not define it as a case-control study as the disease of interest is respiratory dysfunction and subjects were not selected on the basis of the presence or absence of that disease. They were selected for their category of silicotic nodule profusion, which was the "exposure" or determinant of interest. We would describe it as a cross-sectional study with the sampling of subjects designed to give the best possible contrast of silicosis. The rough matching for age was necessary to avoid having a representative group of the non-silicotics (the majority of miners) who have a mean age of 29 yr and would thus have not been comparable with the men with silicosis with their mean age of 47 yr. We believe that the subjects in our study differ from those studied by Hnizdo, Hessel, Sluis-Cremer, and their coworkers. This may be because the exposure to dust by black miners who provide the labor in the labor-intensive South African gold mines is more intense than that of the white miners who have been studied by the South African Medical Bureau for Occupational Diseases. R. L.
M.D., M.Sc. Foothills Hospital Calgary, Alberta, Canada S. K. MABENA, R.N. Ernest Oppenheimer Hospital Welkom, South Africa COWIE,
