238
particles. Baum and colleagues have found increased tracheal mucous velocity, in patients with cystic fibrosis, in the presence of airway inflammation. This is not inconsistent with our finding that the convalescent mucociliary clearance rates of the patients in our study are similar to normal control subjects at this laboratory who had a similar distribution of aerosol (1). In other words, the convalescent asthmatics have intact mucociliary clearance, even though mild asthmatics are likely to have residual significant mucosal inflammation (2). What is the pathophysiologic basis for the difference between our acute and convalescent results? That we do not know the answer to this question is reflective of the fact that we do not know preciselythe causes of severeexacerbations of asthma. The relationship between inflammation and mucociliary clearance has not been determined. It is possible that low levelsof inflammation may stimulate clearance of secretions while more severe inflammation may disrupt mucociliary structures. However, this is merely speculation and further studies need to be done to see if there is any substance to it, or whether other factors may be more important. ThOMAS G. O'RIORDAN M.B., M.R.C.P.I. MATTHEW S. MESSINA, M.D. GERALD C. SMALDONE, M.D., PH.D.
Pulmonary Disease/Critical Care Division Department of Medicine, State University of New York at Stony Brook Stony Brook, NY 1. Ilowite JS, Smaldone GC, Perry RJ, et al. Relationship between tracheobronchial particle clearance rates and sites of initial deposition in man. Arch Environ Health 1989; 44:267-73. 2. Djukanovic R, Roche WR, Wilson J, et al. Mucosal inflammation in asthma. Am Rev Respir Dis 1990; 142:434-57.
CELLULAR AND MOLECULAR BASIS OF THE ASBESTOS-RELATED DISEASES
To the Editor: Rom and colleagues (1) are to be commended for an excellent reviewof the cellular mechanisms of asbestosis. Nonetheless, the section concerning asbestosis and the pathogenesis of lung cancer seems to us to be poorly supported. The authors state that "asbestos-related bronchogenic cancer occurs on a background of alveolitis" and that "it is probably not possible to separate the process of carcinogenesis of the lung from inflammation and fibrosis in the asbestos worker with> 20 yr of exposure." We disagree. The authors cite four human studies, discussed here, as evidence for their conclusions: (1) In the first report, Doll (2) investigated the causal relationship of asbestosis and lung cancer. Cases wereselected by the coroner when he questioned asbestosis as a contributory cause of death; i.e., the cases were selected because they had asbestosis and thus cannot answer the question of whether asbestos causes lung cancer without asbestosis. Doll also noted that previous studies had shown a higher incidence of lung cancer in subjects with asbestosis than in those with silicosis, an observation inconsistent with the conclusion that carcinogenesis is related primarily to alveolitis and fibrosis rather than to asbestos exposure alone; (2) The second study (3) is based on data presented only in abstract form and has not appeared in a peer-reviewed journal; (3) The purpose of the third study, based on an abstract (4) as well as a peer-reviewed article (5), was to relate radiographic infiltrates to histologic manifestations of asbestosis (interstitial fibrosis) in heavily exposed insulation workers who had died of lung cancer. It was not designed to answer the question of whether the risk of lung cancer is increased by heavy asbestos exposure without asbestosis. Asbestos bodies were lacking in eight to 12 of their cases (depending on the series), and thus it is not clear that all of the fibrosis represented asbestosis. No cases of lung cancer without asbestos exposure were examined for the presence of fibrosis to control for fibrosis related to the tumor; (4) The purpose of the fourth study (6) was to relate type and
location of lung cancer in patients with elevated asbestos fiber burden to type and location in those with little burden. We were surprised to find that this study was used to support the hypothesis that asbestosis must precede an asbestos-related lung cancer. In this study there was an absence of gross and histologic fibrosis in 10 of 60 cases of lung cancer with moderate to high concentrations of asbestos fibers, i.e.,concentrations that caused asbestosis in some persons. Further, no significant difference in degreeof fibrosis could be found in persons with or without these moderate to high burdens of asbestos fibers. The lack of good correlation of fiber burden and fibrosis provides some evidence for differences in individual susceptibility to the fibrogenic properties of asbestos dust. It is our hypothesis, based on this study, that the same lung burden of asbestos fibers associated with asbestosis can cause lung cancer, even in the absence of asbestosis, given a sufficient latency period. Wethink that the evidence linking the process of alveolar inflammation and fibrosis to carcinogenesis is inconclusive. We believe that asbestos causes fibrosis, that it increases the risk of lung cancer, and that both fibrosis and lung cancer occur together in some individuals. Because of differences in host responses to asbestos, some persons will have an asbestos-related cancer without asbestosis. We believe that such cases must be evaluated individually using exposure history supported by lung asbestos fiber burdens. ANTHONY COSENTINO, M.D., MARTHA L. WARNOCK, M.D.
University of California, San Francisco, CA 1. Rom WN, navis WD, Brody AR. Cellular and molecular basis of the asbestos-related diseases. Am Rev Respir Dis 1991; 143:408-22. 2. Doll R. Mortality from lung cancer in asbestos workers. Br J Industr Med 1955; 12:81-6. 3. Hughes JM, Weill H. Asbestos related cancer in relaxation to X-ray evidence of pulmonary fibrosis. Am Rev Respir Dis 1989; 139:A214. 4. Suzuki Y, Selikoff IJ. Pathology of lung cancer among asbestos insulation workers (abstract). Fed Proc 1986; 54:744A. 5. Kipen HM, Lills R, Suzuki Y, Valcuikas lA, Selikoff IJ. Pulmonary fibrosis in asbestos insulation workers with lung cancer: a radiological and histopathological evaluation. Br J Industr Med 1987; 44:%-100. 6. Warnock ML, Isenberg W. Asbestos burden and the pathology of lung cancer. Chest 1986; 89:20-6.
From the Authors: Drs. Cosentino and Warnock have challenged our judgment on one of the areas of asbestos-related disease that most observers would agree remains an issuethat is not completely resolved.Weare pleased to point out the difficulties in developing consensus on the concordance of fibrosis and lung cancer in asbestos-exposed workers and why we lean the way that we do (1). Doll reported several studies in his report (2) including necropsies of 18cases of lung cancer that had been referred to the coroner when, in the coroner's opinion, there was a question of asbestosis being a contributory cause of death. Fifteen had asbestosis and all were> 20 yr from onset of first exposure, except one who was 16 yr, and duration of exposure ranged from 13 to 32 yr with only three below 20 yr. Interestingly, three did not have asbestosis and none of these were exposed more than 10 yr and none were> 20 yr from onset (2, 12, 11 yr), Thus none met the "20 yr rule" of duration from onset characteristicof asbestos-related disease. All of those with asbestosis and lung cancer were heavily exposed (> 9 yr) prior to the 1931 asbestos hygiene regulations in Britain, and the three without asbestosis were first exposed after the mandated regulations drastically reduced exposure. The point is that a short-duration of exposure « 10yr) and a malignancy near the onset of exposure « 10yr) is unlikelyto meetthe standards oflatency causal in asbestosrelated disease. For example, a 47-yr-old asbestos-exposed individual with 2 yr of heavy exposure the previous 2 yr is likely to have many fibers in his lung tissue without fibrosis, and the etiology is certainly more likely to be his two pack per day cigarette smoking habit begun at age 11. Second, Doll performed an epidemiologic study on 113 men with> 20 yr asbestos exposure, and 11 lung cancer deaths
particles. Baum and colleagues have found increased tracheal mucous velocity, in patients with cystic fibrosis, in the presence of airway inflammation. This is not inconsistent with our finding that the convalescent mucociliary clearance rates of the patients in our study are similar to normal control subjects at this laboratory who had a similar distribution of aerosol (1). In other words, the convalescent asthmatics have intact mucociliary clearance, even though mild asthmatics are likely to have residual significant mucosal inflammation (2). What is the pathophysiologic basis for the difference between our acute and convalescent results? That we do not know the answer to this question is reflective of the fact that we do not know preciselythe causes of severeexacerbations of asthma. The relationship between inflammation and mucociliary clearance has not been determined. It is possible that low levelsof inflammation may stimulate clearance of secretions while more severe inflammation may disrupt mucociliary structures. However, this is merely speculation and further studies need to be done to see if there is any substance to it, or whether other factors may be more important. ThOMAS G. O'RIORDAN M.B., M.R.C.P.I. MATTHEW S. MESSINA, M.D. GERALD C. SMALDONE, M.D., PH.D.
Pulmonary Disease/Critical Care Division Department of Medicine, State University of New York at Stony Brook Stony Brook, NY 1. Ilowite JS, Smaldone GC, Perry RJ, et al. Relationship between tracheobronchial particle clearance rates and sites of initial deposition in man. Arch Environ Health 1989; 44:267-73. 2. Djukanovic R, Roche WR, Wilson J, et al. Mucosal inflammation in asthma. Am Rev Respir Dis 1990; 142:434-57.
CELLULAR AND MOLECULAR BASIS OF THE ASBESTOS-RELATED DISEASES
To the Editor: Rom and colleagues (1) are to be commended for an excellent reviewof the cellular mechanisms of asbestosis. Nonetheless, the section concerning asbestosis and the pathogenesis of lung cancer seems to us to be poorly supported. The authors state that "asbestos-related bronchogenic cancer occurs on a background of alveolitis" and that "it is probably not possible to separate the process of carcinogenesis of the lung from inflammation and fibrosis in the asbestos worker with> 20 yr of exposure." We disagree. The authors cite four human studies, discussed here, as evidence for their conclusions: (1) In the first report, Doll (2) investigated the causal relationship of asbestosis and lung cancer. Cases wereselected by the coroner when he questioned asbestosis as a contributory cause of death; i.e., the cases were selected because they had asbestosis and thus cannot answer the question of whether asbestos causes lung cancer without asbestosis. Doll also noted that previous studies had shown a higher incidence of lung cancer in subjects with asbestosis than in those with silicosis, an observation inconsistent with the conclusion that carcinogenesis is related primarily to alveolitis and fibrosis rather than to asbestos exposure alone; (2) The second study (3) is based on data presented only in abstract form and has not appeared in a peer-reviewed journal; (3) The purpose of the third study, based on an abstract (4) as well as a peer-reviewed article (5), was to relate radiographic infiltrates to histologic manifestations of asbestosis (interstitial fibrosis) in heavily exposed insulation workers who had died of lung cancer. It was not designed to answer the question of whether the risk of lung cancer is increased by heavy asbestos exposure without asbestosis. Asbestos bodies were lacking in eight to 12 of their cases (depending on the series), and thus it is not clear that all of the fibrosis represented asbestosis. No cases of lung cancer without asbestos exposure were examined for the presence of fibrosis to control for fibrosis related to the tumor; (4) The purpose of the fourth study (6) was to relate type and
location of lung cancer in patients with elevated asbestos fiber burden to type and location in those with little burden. We were surprised to find that this study was used to support the hypothesis that asbestosis must precede an asbestos-related lung cancer. In this study there was an absence of gross and histologic fibrosis in 10 of 60 cases of lung cancer with moderate to high concentrations of asbestos fibers, i.e.,concentrations that caused asbestosis in some persons. Further, no significant difference in degreeof fibrosis could be found in persons with or without these moderate to high burdens of asbestos fibers. The lack of good correlation of fiber burden and fibrosis provides some evidence for differences in individual susceptibility to the fibrogenic properties of asbestos dust. It is our hypothesis, based on this study, that the same lung burden of asbestos fibers associated with asbestosis can cause lung cancer, even in the absence of asbestosis, given a sufficient latency period. Wethink that the evidence linking the process of alveolar inflammation and fibrosis to carcinogenesis is inconclusive. We believe that asbestos causes fibrosis, that it increases the risk of lung cancer, and that both fibrosis and lung cancer occur together in some individuals. Because of differences in host responses to asbestos, some persons will have an asbestos-related cancer without asbestosis. We believe that such cases must be evaluated individually using exposure history supported by lung asbestos fiber burdens. ANTHONY COSENTINO, M.D., MARTHA L. WARNOCK, M.D.
University of California, San Francisco, CA 1. Rom WN, navis WD, Brody AR. Cellular and molecular basis of the asbestos-related diseases. Am Rev Respir Dis 1991; 143:408-22. 2. Doll R. Mortality from lung cancer in asbestos workers. Br J Industr Med 1955; 12:81-6. 3. Hughes JM, Weill H. Asbestos related cancer in relaxation to X-ray evidence of pulmonary fibrosis. Am Rev Respir Dis 1989; 139:A214. 4. Suzuki Y, Selikoff IJ. Pathology of lung cancer among asbestos insulation workers (abstract). Fed Proc 1986; 54:744A. 5. Kipen HM, Lills R, Suzuki Y, Valcuikas lA, Selikoff IJ. Pulmonary fibrosis in asbestos insulation workers with lung cancer: a radiological and histopathological evaluation. Br J Industr Med 1987; 44:%-100. 6. Warnock ML, Isenberg W. Asbestos burden and the pathology of lung cancer. Chest 1986; 89:20-6.
From the Authors: Drs. Cosentino and Warnock have challenged our judgment on one of the areas of asbestos-related disease that most observers would agree remains an issuethat is not completely resolved.Weare pleased to point out the difficulties in developing consensus on the concordance of fibrosis and lung cancer in asbestos-exposed workers and why we lean the way that we do (1). Doll reported several studies in his report (2) including necropsies of 18cases of lung cancer that had been referred to the coroner when, in the coroner's opinion, there was a question of asbestosis being a contributory cause of death. Fifteen had asbestosis and all were> 20 yr from onset of first exposure, except one who was 16 yr, and duration of exposure ranged from 13 to 32 yr with only three below 20 yr. Interestingly, three did not have asbestosis and none of these were exposed more than 10 yr and none were> 20 yr from onset (2, 12, 11 yr), Thus none met the "20 yr rule" of duration from onset characteristicof asbestos-related disease. All of those with asbestosis and lung cancer were heavily exposed (> 9 yr) prior to the 1931 asbestos hygiene regulations in Britain, and the three without asbestosis were first exposed after the mandated regulations drastically reduced exposure. The point is that a short-duration of exposure « 10yr) and a malignancy near the onset of exposure « 10yr) is unlikelyto meetthe standards oflatency causal in asbestosrelated disease. For example, a 47-yr-old asbestos-exposed individual with 2 yr of heavy exposure the previous 2 yr is likely to have many fibers in his lung tissue without fibrosis, and the etiology is certainly more likely to be his two pack per day cigarette smoking habit begun at age 11. Second, Doll performed an epidemiologic study on 113 men with> 20 yr asbestos exposure, and 11 lung cancer deaths
