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were found with 0.8 expected. All had had necropsies and all had asbestosis as well. Furthermore, the incidences of both asbestosis and lung cancer associated with asbestosis declined as hygiene conditions improved post-1933. We would like to point out that Doll published this as a single author report because the medical director, who had gathered the data, of the company was not granted permission to publish, and the medical director was acknowledged anonymously. Moving forward to publish this classic article reflects the extraordinary integrity of Richard Doll who was later knighted. Cosentino and Warnock point out that silicosis has fibrosis plus alveolitis but a far lower incidence of lung cancer than asbestosis; however, idiopathic pulmonary fibrosis and scleroderma involving the lung have an increased incidence of lung cancer and both have fibrosis and alveolitis. In addition, lung cancers have been observed for years in areas of scar tissue from old tuberculosis. The active processes in alveolitis and fibrosis, however, may not lead invariably to lung cancer (most cases of asbestosis do not get lung cancer) suggesting that the genes induced in these two processes are likely different. Lastly, asbestos exposure alone is not likely to lead to lung cancer unless there is concomitant long-term cigarette smoking. References 3 and 4, we feel, provide the most convincing evidence of the presence of sufficient asbestos exposure to cause histologic fibrosis in order to have an asbestos-associated lung cancer. The North American insulators' study, extant for over 20 yr, is the largest prospective evaluation of a population with a significant occupational exposure to asbestos. Dr. Y. Suzuki, a pathologist with a lifetime's experience studying asbestos-related disease, investigated 544 consecutive lung cancer cases from this cohort. We quote, "we had material in 356 cases for evaluation of interstitial fibrosis and asbestos bodies. Histologically, all but a single case showed mild to severe interestitial fibrosis; indeed, 90.7070 (323 cases) ranged from moderate to severe. Asbestosis bodies were seen in slides of 344 (96.6%) cases" (3, 4). The last study (5) addressed two questions, the first stated by Consentino and Warnock, and the second, Is the presence of asbestosis helpful in designating a tumor as asbestos-related? The population in this study was radically different from that in the North American insulators' study since none of the 75 lung tumors were from asbestos insulators and the exposure was either nil (insurance sales, physicist, car salesman, bartender) or slight (bystander exposure in shipyard work). Despite this, they found 50/60 cases to have histologic fibrosis with> 105 fibers/g dry lung. The 10/60 cases without fibrosis unfortunately were not characterized as to smoking habit, duration of exposure, intensity of exposure, time since last exposure, or number of fibers/g dry lung (among these 10) to determine if the asbestos exposure was significant enough to contribute to the lung cancer versus smoking. A pathologicepidemiologic study including heavy (insulator) and bystander (shipyard) exposure might provide further information on lung cancer in asbestos-exposed without interestitial fibrosis; however, we predict that further study would only reinforce Suzuki's findings that we have relied upon in making our judgment. Lastly, Davis and Cowie retrospectively analyzed the relationship between fibrosis and cancer in experimental animals exposed to asbestos and found that animals with pulmonary tumors had almost double the amount of pulmonary fibrosis as animals of similar ages that did not (6). The mechanisms through which asbestos or any other inhaled materials cause lung cancer remain undefined. Until the mechanisms are elucidated we must rely upon associations of events to reach interim conclusions. The association between asbestosis and lung cancer remains intriguing. We do not dispute with Cosentino and Warnock who state "... some persons will have an asbestosrelated cancer without asbestosis ...". These, however, appear to be few, and it seems likely that the dose of asbestos sufficient to cause fibrosis may be enough of a dose to induce cancer, thus keeping the association obvious. WILLIAM N. ROM, M.D., M.P.H.
NYU Medical Center New York, NY
WILLIAM D. TRAVIS, M.D.
National Cancer Institute Bethesda, MD ARNOLD
R. BRODY, PH.D.
National Institute of Environmental Health Sciences Research Triangle Park, NC 1. Rom WN, Travis 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. Suzuki Y,Selikoff IJ. Pathology of lung cancer among asbestos insulation workers (abstract). Fed Proc 1986; 45:744A. 4. Kipen HM, Lilis R, Suzuki Y, Valcuikas JA, Selikoff IJ. Pulmonary fibrosis in asbestosis insulation workers with lung cancer: a radiological and histopathological evaluation. Br J Industr Med 1987; 44:96-100. 5. Warnock ML, Isenberg W. Asbestos burden and the pathology of lung cancer. Chest 1986; 89:20-6. 6. Davis JMG, Cowie HA. The relationship between fibrosis and cancer in experimental animals exposed to asbestos and other fibers. Environ Health Persp 1990; 88:305-9.
ELEVATED BRONCHOALVEOLAR LAVAGE HISTAMINE IN ALLERGIC ASTHMATICS ASSOCIATED WITH INCREASED AIRWAY OBSTRUCTION
To the Editor: After the publication of our article (1) reporting the relationshipbetween bronchoalveolar lavage (BAL) fluid histamine levels and airway obstruction in asthma patients, Dr. R. Ingram was kind enough to bring to our attention that Pliss, Ingenito, and Ingram had previously reported similar findings (2). They investigated in 16atopic asthma and six normal subjects the relationships between changes of airway caliber after deep inspiration, the degree of baseline airway hyperresponsiveness, and peripheral airway inflammation reflected in cellular biochemical changes in bronchoalveolar lavage (BAL) fluids. BAL fluid was analyzed for histamine, leukotrienes, thromboxane B2, and prostaglandin E2. Among their findings were higher levelsof BAL histamine, leukotrienes, and proteins in asthmatics. Furthermore, they found an inverse correlation between the FEV, percent predicted and BAL levels of total protein, SRS-A, and histamine when both groups were combined. They did not investigate levels of tryptase as an indicator for mast cell activation. We would like to acknowledge their earlier contributions, which are in agreement with our reported findings, and, in addition, emphasize that in our study the lack of correlation between BAL fluid histamine and tryptase, and between BAL fluid tryptase and airway obstruction, suggested that basophils rather than mast cells are involved in the ongoing release of mediators in patients with chronic stable asthma. This has significant implications, particularly in view of recent evidence that basophils are increased in BAL fluid 19 h after instillation of ragweed antigen into the airway of patients with allergic asthma (3), suggesting that basophils are among the inflammatory cells contributing to the persistence of asthma.
NIZAR N. JARJOUR, M.D. Assistant Professor Pulmonary and Critical Care Medicine University of Wisconsin-Madison Medical School Madison, WI 1. Jajour NN, Calhoun WI, Schwartz LB, Busse WW. Elevated bronchoalveolar lavage histamine in allergic asthmatics is associated with increased airway obstruction. Am Rev Respir Dis 1991; 144:83-7. 2. Pliss LB, Ingenito EP, Ingram RH. Responsiveness, inflammation, and effects of deep breaths on obstruction in mild asthma. J Appl Physiol1989; 66:2298-304. 3. Liu MC, Hubbard WC, Proud D, Stealey BA, et al. Immediate and late inflammatory responses to ragweed antigen challenge of the peripheral airways in allergic asthmatics. Am Rev Respir Dis 1991; 144:51-8.
were found with 0.8 expected. All had had necropsies and all had asbestosis as well. Furthermore, the incidences of both asbestosis and lung cancer associated with asbestosis declined as hygiene conditions improved post-1933. We would like to point out that Doll published this as a single author report because the medical director, who had gathered the data, of the company was not granted permission to publish, and the medical director was acknowledged anonymously. Moving forward to publish this classic article reflects the extraordinary integrity of Richard Doll who was later knighted. Cosentino and Warnock point out that silicosis has fibrosis plus alveolitis but a far lower incidence of lung cancer than asbestosis; however, idiopathic pulmonary fibrosis and scleroderma involving the lung have an increased incidence of lung cancer and both have fibrosis and alveolitis. In addition, lung cancers have been observed for years in areas of scar tissue from old tuberculosis. The active processes in alveolitis and fibrosis, however, may not lead invariably to lung cancer (most cases of asbestosis do not get lung cancer) suggesting that the genes induced in these two processes are likely different. Lastly, asbestos exposure alone is not likely to lead to lung cancer unless there is concomitant long-term cigarette smoking. References 3 and 4, we feel, provide the most convincing evidence of the presence of sufficient asbestos exposure to cause histologic fibrosis in order to have an asbestos-associated lung cancer. The North American insulators' study, extant for over 20 yr, is the largest prospective evaluation of a population with a significant occupational exposure to asbestos. Dr. Y. Suzuki, a pathologist with a lifetime's experience studying asbestos-related disease, investigated 544 consecutive lung cancer cases from this cohort. We quote, "we had material in 356 cases for evaluation of interstitial fibrosis and asbestos bodies. Histologically, all but a single case showed mild to severe interestitial fibrosis; indeed, 90.7070 (323 cases) ranged from moderate to severe. Asbestosis bodies were seen in slides of 344 (96.6%) cases" (3, 4). The last study (5) addressed two questions, the first stated by Consentino and Warnock, and the second, Is the presence of asbestosis helpful in designating a tumor as asbestos-related? The population in this study was radically different from that in the North American insulators' study since none of the 75 lung tumors were from asbestos insulators and the exposure was either nil (insurance sales, physicist, car salesman, bartender) or slight (bystander exposure in shipyard work). Despite this, they found 50/60 cases to have histologic fibrosis with> 105 fibers/g dry lung. The 10/60 cases without fibrosis unfortunately were not characterized as to smoking habit, duration of exposure, intensity of exposure, time since last exposure, or number of fibers/g dry lung (among these 10) to determine if the asbestos exposure was significant enough to contribute to the lung cancer versus smoking. A pathologicepidemiologic study including heavy (insulator) and bystander (shipyard) exposure might provide further information on lung cancer in asbestos-exposed without interestitial fibrosis; however, we predict that further study would only reinforce Suzuki's findings that we have relied upon in making our judgment. Lastly, Davis and Cowie retrospectively analyzed the relationship between fibrosis and cancer in experimental animals exposed to asbestos and found that animals with pulmonary tumors had almost double the amount of pulmonary fibrosis as animals of similar ages that did not (6). The mechanisms through which asbestos or any other inhaled materials cause lung cancer remain undefined. Until the mechanisms are elucidated we must rely upon associations of events to reach interim conclusions. The association between asbestosis and lung cancer remains intriguing. We do not dispute with Cosentino and Warnock who state "... some persons will have an asbestosrelated cancer without asbestosis ...". These, however, appear to be few, and it seems likely that the dose of asbestos sufficient to cause fibrosis may be enough of a dose to induce cancer, thus keeping the association obvious. WILLIAM N. ROM, M.D., M.P.H.
NYU Medical Center New York, NY
WILLIAM D. TRAVIS, M.D.
National Cancer Institute Bethesda, MD ARNOLD
R. BRODY, PH.D.
National Institute of Environmental Health Sciences Research Triangle Park, NC 1. Rom WN, Travis 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. Suzuki Y,Selikoff IJ. Pathology of lung cancer among asbestos insulation workers (abstract). Fed Proc 1986; 45:744A. 4. Kipen HM, Lilis R, Suzuki Y, Valcuikas JA, Selikoff IJ. Pulmonary fibrosis in asbestosis insulation workers with lung cancer: a radiological and histopathological evaluation. Br J Industr Med 1987; 44:96-100. 5. Warnock ML, Isenberg W. Asbestos burden and the pathology of lung cancer. Chest 1986; 89:20-6. 6. Davis JMG, Cowie HA. The relationship between fibrosis and cancer in experimental animals exposed to asbestos and other fibers. Environ Health Persp 1990; 88:305-9.
ELEVATED BRONCHOALVEOLAR LAVAGE HISTAMINE IN ALLERGIC ASTHMATICS ASSOCIATED WITH INCREASED AIRWAY OBSTRUCTION
To the Editor: After the publication of our article (1) reporting the relationshipbetween bronchoalveolar lavage (BAL) fluid histamine levels and airway obstruction in asthma patients, Dr. R. Ingram was kind enough to bring to our attention that Pliss, Ingenito, and Ingram had previously reported similar findings (2). They investigated in 16atopic asthma and six normal subjects the relationships between changes of airway caliber after deep inspiration, the degree of baseline airway hyperresponsiveness, and peripheral airway inflammation reflected in cellular biochemical changes in bronchoalveolar lavage (BAL) fluids. BAL fluid was analyzed for histamine, leukotrienes, thromboxane B2, and prostaglandin E2. Among their findings were higher levelsof BAL histamine, leukotrienes, and proteins in asthmatics. Furthermore, they found an inverse correlation between the FEV, percent predicted and BAL levels of total protein, SRS-A, and histamine when both groups were combined. They did not investigate levels of tryptase as an indicator for mast cell activation. We would like to acknowledge their earlier contributions, which are in agreement with our reported findings, and, in addition, emphasize that in our study the lack of correlation between BAL fluid histamine and tryptase, and between BAL fluid tryptase and airway obstruction, suggested that basophils rather than mast cells are involved in the ongoing release of mediators in patients with chronic stable asthma. This has significant implications, particularly in view of recent evidence that basophils are increased in BAL fluid 19 h after instillation of ragweed antigen into the airway of patients with allergic asthma (3), suggesting that basophils are among the inflammatory cells contributing to the persistence of asthma.
NIZAR N. JARJOUR, M.D. Assistant Professor Pulmonary and Critical Care Medicine University of Wisconsin-Madison Medical School Madison, WI 1. Jajour NN, Calhoun WI, Schwartz LB, Busse WW. Elevated bronchoalveolar lavage histamine in allergic asthmatics is associated with increased airway obstruction. Am Rev Respir Dis 1991; 144:83-7. 2. Pliss LB, Ingenito EP, Ingram RH. Responsiveness, inflammation, and effects of deep breaths on obstruction in mild asthma. J Appl Physiol1989; 66:2298-304. 3. Liu MC, Hubbard WC, Proud D, Stealey BA, et al. Immediate and late inflammatory responses to ragweed antigen challenge of the peripheral airways in allergic asthmatics. Am Rev Respir Dis 1991; 144:51-8.
