Document dYEnQO8RvEMNMn4wYzxNLjVBQ

S PLAINTIFF'S Asbestos and Airflow Limitation i EXHIBIT f Z. Mohsenifar, MD; A. J. Jasper, MD; T. Mahier, MD; and S. K. Koemer, MD To assess the effect of asbestos on the airways, researchers studied 45 shipyard workers who were lifelong nonsmokers and had asbestos-related abnormalities seen on their chest assess the effect of asbestos on the airways without the compounding influence of cigarette smoke. roentgenograms. Patients with interstitia/ lung disease, bron chial asthma prior to asbestos exposure, recurrent pneumo nias. or significant cardiovascular disease were excluded from Subjects and Methods the study. In addition to chest films, they had spirometry performed before and after bronchodilator inhalation, lung Patients were referred to us by the Department of volumes, diffusing capacity, and arterial blood gases. Forced vital capacity and forced expired volume in one second were normal in all patients. Maximum midexpiratory flow rates (MMFR) were abnormal (MMFR less than 75% of predicted) in 13 patients (29%). Therefore. 29% of lifetime nonsmokers with asbestos exposure exhibited evidence of small airways dysfunction. An abnormal MMFR in these workers may be due, in part, to asbestos exposure and could conceivably indi cate a population at risk for pulmonary fibrosis and/or ob structive airways disease. Labor. Most were exposed primarily to chrysotile as bestos while working in the shipyards of Long Beach, California. The following evaluations were done: (-1) a complete history and physical examination, including a detailed occupational history: (2) posteroanterior. lat eral. and bilateral oblique chest roentgenograms: (3) a 12-lead ECG: and (4) resting pulmonary function stud ies. The occupational history included a complete job his tory and industrial toxin exposure history. Asbestos >x-posure was classified according to (1) duration of Pulmonary function studies in asbestos workers with out parenchymal abnormalities are usually norraL exposure: (2) qualitative nature of exposure, which was either primary (worked directly with, asbestos-contain When abnormal they are characterized by a restrictive ing materials) or secondary (worked in same area, but pattern and a reduced diffusing capacity.' A few inves not directly with asbestos): (3) quantitative nature of tigators have suggested that airways obstruction, par exposure, which was either heavy (asbestos dust visible ticularly in small airways, is associated with exposure in air), moderate (asbestos dust visible on floor and to asbestos.2'5 However, past or current smokers were work surface), or light (no dust visible). not excluded, so the specificity of the abnormal physio Radiographic findings on the chest roentgenograms logic findings is unclear. A recent study reported that were categorized according to the International Labor seven of 17 lifetime nonsmoking asbestos workers had Organization/UC classification.7 The degree of pleural spirometric evidence of airflow limitation. However, this thickening was classified into three grades. Grade 1 was abnormality was associated with a restrictive ventila pleural thickening up to 5 mL in thickness which, alone tory defect, while workers without restrictive ventila or combined with similar shadows, did not exceed one tory defects had pulmonary function comparable to con half of the projection of one lateral chest wall. Grade 2 trol subjects. From 1980 until 1984, we evaluated was pleural thickening more than 5 mL in thickness and approximately 400 shipyard workers, of whom 45 were up to one half of the iateral chest wall or less than 5 mL lifetime nonsmokers. This allowed us the opportunity to in thickness if it extends over more than one half of the lateral chest wall. Grade 3 was pleural thickening more than 5 mL in thickness and extending over more than Division of Pulmonary Medicine. Cedars-Sinai Medical Center. UCLA School of Medicine. Box 48570, 8700 Beverly Blvd. Los Angeles. CA 90048 (address correspondence to Dr Mohsenifar). 0096.1736/86/2809-817*02.00/0 Copyright <c by American Occupational Medical Association one half of a lateral chest wall. The resting pulmonary function study included meas urement of lung volumes, forced expiratory flow rates, single-breath diffusing capacity for carbon monoxide, and arterial blood gases. Slow vital capacity (SVC), Journal of Occupational Medicine/Volume 28 No. 9/September 1986 817 forced vital capacity (FVC), and forced expired volume in one second (FEV,) were measured in duplicate using a 12-L dry rolling seal spirometer (Cardiopulmonary Instruments. Model 220). Flow rates were repeated after the inhalation of four puffs of isoetharine. We considered FVC or. FEVj/FVC abnormal if either was more than one SD below the predicted value.8 Lung volumes were measured by helium dilution.9 and pre dicted values were calculated using the data of Goldman and Becklake10 and Boren et al.n Arterial blood gases were measured using a blood gas analyzer (Corning Model 175). and the alveolar-arterial oxygen difference (A-a)POa was calculated. The single-breath diffusion capacity (DLco) was measured in the sitting position in duplicate by the single-breath method described by Ogilvie et al.ic Breath-holding times during DLco determi nations were 10 seconds and were measured by the method of Jones and Mead.13 Predicted values for DLco were calculated using the data of McGrath and Thom son.H When FEV,/FVC was normal, maximum midexpiratory flow rate (MMFR) was used to detect small airways obstruction. We expressed MMFR as a percent of predicted. Values of less than 75% of predicted were considered abnormal.15 Patients with interstitial lung disease, history of prior bronchial asthma, prior pneu monias or cardiac disease were excluded from the study. Patients with any history of smoking tobacco or any history of exposure to other toxins or fumes were ex cluded from the study. Statistical Analysis All data are presented as mean one SD of the mean. We compared patients with abnormal MMFR to those with normal MMFR by means of the Kruskal-Wallis test and the Mann-Whitney U test, which are nonparametric tests similar to the analysis of variance and Student's t test. We considered P values of less than .05 to be significant. Results All patients were make with a mean age of 53 11 years. All had been occupationally exposed to asbestos for a mean of 17 8 years. Nineteen gave a history of heavy exposure and 26 of moderate exposure. In nine patients, the exposure was primary and in 36. second ary. None of the workers had ever smoked tobacco in any form, and none were exposed to any other known fumes or toxins. All patients had a normal 12-lead ECG. All patients had pleural plaques, but none had intersti tial changes seen on their chest roentgenograms. Thirty-two patients had grade 1. ten patients had grade 2. and the remaining three had grade 3 pleural changes. Thirty patients complained of dyspnea with moderate exertion, whereas 22 complained of cough and sputum production. All patients had a normal FVC with a mean FVC of 98 14% of predicted. FEV,/FVC ratios were normal 818 in all patients with a moan ratio of 80 4`i. DL<V was normal in all patients with a moan value of 100 ]8% of predicted. Mean PaO and P(A-a)Ov were 82 7 and 15 9 mm Hg. respectively. Fourteen subjects had mild hypoxemia on room air and 12 had a slightly elevated P(A-a)Os difference (Table la). The MMFR was less than 75% of predicted in 13 patients (29%) of total (Tables lb and 2). Three of these 13 patients had heavy primary exposure. The remaining ten were exposed to asbestos on a moderate, secondary basis. Two of these 13 patients had a normal MMFR after inhaling two puffs of isoetharine. However, only one of the two had a significant change in isovoiume MMFR.16 When we compared the two groups by age. symptoms, degree of pleural thickening, duration of exposure, qualitative nature of exposure, total lung capacity. FVC, FEV,/FVC, Pa02, P(A-a)02 and DLco. patients with abnormal MMFR had significantly lower FVC and FEVj/FVC (F< .01). The two groups did not. however, differ with respect to any other parameters. The meaned data for the abnormal MMFR group and the normal MMFR group may be found in Tables lb and lc, respectively. Discussion We found evidence of small airways dysfunction in a group of nonsmoking asbestos workers. This was mot readily explained by or correlated with exposure history or other clinical, roentgenographic. or physiologic var iables. Review of pathologic data led us to suspect a priori that asbestos exposure may be associated with small airways dysfunction. The evolution of pathologic changes from initial asbestos exposure to fibrosing pa renchymal asbestosis is unknown. The process must be inferred from the study of animals exposed to asbestos.17 Asbestos fibers seem to be deposited first in respiratory bronchioles and alveolar ducts. A polymorphonuclear response is provoked, followed by a macrophagic peri bronchiolar alveolitis. Somewhat later, discrete foci of fibrosis develop in the wails of respiratory bronchi oles.18 The foci are associated with accumulation of asbestos bodies. Recent pathologic evidence in man has described lesions of the small airways in asbestos work ers which are different from lesions found in smokers, but which are similar to lesions seen in animals. The human asbestos lesions are characterized by fibrosis in and around the respiratory bronchioles and alveolar ducts, often accompanied by ferruginous bodies.19 These lesions are similar to those described by Churg et al80 in workers exposed to a variety of nonasbestos mineral dusts, and thus may not be specific to asbestos. There has been a reluctance to accept that asbestos exposure may cause an obstructive ventilatory defect because the workers are commonly also cigarette smok ers, and they may be exposed to other toxins as well. Founier-Massey and Becklake21 reported that FEV,/ FVC was reduced in workers exposed to asbestos, but some also had a reduced lung volume, suggesting inter stitial lung disease. Begin et al6 studied 17 lifelong Asbestos and Airflow/Mohsenifar et ai TABLE 1 Mean Pulmonary Function O.na (or All Patients, (or Group With Abnormal Maximum Midexpiraiory Flow Rate (MMFR) ano for Group v.'.tn Norma) MMFR' j) All patients N = 45 (b) Patients with abnormal MMFR N = 13 (c) Patients with normal MMFR N = 32 Age Exposure (Yr) (Yr) Mean SD 52 13 17 8 Mean 2; SD 53 12 15 + 8 Mean SD 52 12 17 + S TLC Predicted) 109 12 FVC (e Predicted) 98 14 FEV./FVC x 100 (%) 80 4 . MMFR (*<> Predicted) 91 -t- 29 Dl<o ("# Predicted) 106 18 PaO: mm H 82 -4- 7 108 91f 76f 6lt 104 82 + * 11 12 3 10 16 6 110 106 81 103 + + ++ 12 15 4 26 107 81 + 20 13 Abbreviations used are: TLC, total lung capacity; FVC. forced vital capacity; FEV,, forced expired volume in one second; DLco. diffusing capacity; Pa02, arterial oxygen tension, t Different from group C. P < .01. Patients TABLE 2 Pulmonary Function Data for Patients With Aonorrr.ai Maximum Midexoiratory Flow Rates (MMFR)* Age Exposure FVC FEV,,'FVC MMFR DLco (Yr) (Yr) (% Predicted) x 100 (%) (% Predicted) {% Predicted) PaO, mm Hg 1 63 19 86 78 2 55 2 80 81 3 51 28 97 74 4 48 8 109 76 5 60 22 84 72 6 40 11 109 71 7 77 20 77 76 8 54 11 98 73 9 39 19 93 80 10 33 7 92 77 11 61 17 112 76 12 46 6 83 79 13 65 22 75 79 74 73 54 66 46 48 64 54 73 54 74 64 61 109 76 99 84 103 83 139 79 104 82 125 86 . 105 85 89 90 82 63 108 76 120 94 86 72 90 78 ' Abbreviations used are; FVC. forced vital capacity; FEV,, forced expired volume m one second; Du- diffusing capacity; Pa02. arterial oxygen tension. nonsmoking asbestos workers. Seven had parenchymal asbestosis and ten did not. The workers with asbestosis had a restrictive ventilatory defect and also had in creased upstream resistance at low lung volumes. In the ten workers without asbestosis, MMFR did not differ significantly from control subjects; however, they had higher values for the helium iso-flow volume curves. Lung biopsies in three of the workers with asbestosis demonstrated that the airways were narrowed and dis torted, and that their walls were thickened. These two studies, therefore, suggest that airways pathology and airflow limitation occur in asbestosis. Hedenstierna et al2 found small airways dysfunction in workers exposed to asbestos, even in the absence of parenchymal disease. However, because many patients were ex-smokers. Hedenstierna's evidence of airway obstruction specifically related to asbestos was weak. MMFR has been cited as a sensitive test for early pulmonary disease.88 McFadden et al83 used MMFR to determine improvement of small airways defects after cessation of cigarette smoking. A recent study has cor related MMFR with pathologic abnormalities of small airways, ie, intraluminal inflammation and fibrosis of respiratory bronchioles.84 The definition of an "abnor mal" result is not perfectly clear; some authors compare observed values with predicted values,15 and others compare observed MMFR with observed FVC.85 Kuperman and Riker85 showed that the lower limit of normal for MMFR (twice the SR of estimate below the mean) was 65% of vital capacity. Even if we use this less sensitive criterion for abnormality, we found that nine of our 45 patients had evidence of small airways dys function. Furthermore, the mean FVC and FEVj/FVC were significantly lower in patients with an abnormal MMFR, even though these patients had normal FVC and FEVj/FVC. This difference in FEVj/FVC supports our suggestion that some asbestos workers have an early obstructive ventilatory defect unrelated to smoking. Airflow limitation in these patients may be due to asbestos. The deposition of inhaled particles and fibers depends on their velocity, diffusion coefficient, and fiber length. The site of initial deposition may be a nidus for a slowly progressive reaction or may merely be a way station, as the fibers migrate distally. The response to bronchodilators in one of our patients raises the possi bility that the inhaled agents may cause reactive bron- Joumaf of Occupational Medicine/Voiume 28 No. 9/September 1986 819 choconstriction. though of course the finding could be due to de novo development of "garden variety" bron chial hyperreactivity,"1' independent of asbestos expo sure. Follow-up studies may determine whether these early abnormalities progress toward more severe lung involvement. AH of our patients worked in the shipyards of Long Beach, so it is appropriate to compare our results to the general population data accumulated by Rokaw et al15 for residents of Burbank, which has a similar pollution level to Long Beach and is without any asbestos particles in the air. The prevalence of MMFR less than 75% predicted in the nonsmoking, asymptomatic subset of Rokaw's population is about 15%, less than our value of 29%. We found a high prevalence of mild airflow limitation in a group of 45 lifetime nonsmoking asbestos workers. We were careful to include only patients who had never smoked in their lifetime and who did not have histories of other pulmonary disease. Furthermore, they were not known to be exposed to industrial dusts other than chrysotile. It is possible that small airways dysfunction in asbestos workers is. at least in part, independent of smoking. Furthermore, it may indicate an increased risk for future parenchymal asbestosis and/or obstructive ventilatory defects. Acknowledgment The authors acknowledge the secretarial assistance of Ms Debra Craig. References 1. Murphy RL. Gaensler EA. Fenis 5G. et al: Diagnosis of asbes tosis: Observation from a longitudinal survey of ship-yard pipe coverers. Am J Med 1978:66:488-498. 2. Hedenstierna G. Alexanderson R. Kolmodin-Hedman B. et al: Pleural plaques and lung function in construction workers exposed to asbestos. Eur J Respir Dis 1981:62:111-112. 3. Rodrtquez-Roison R. Cochrane GM. Clark TJH: Asbestos ex posure and small airways disease. Scand J Respir Dis 1976:5?(6):318. 4. Menza LD. Ruff F. Bignon J. et al: Small airway obstruction with professional exposure to asbestos. Ann Anat Pathol 1976:21:261 268. 5. Jodoin G, Gibbs GW, Macklem PT. et al: Early effects of asbestos on lung function. Am Rev Respir Dis 1971:104:525-535. G. Begin R. Cnnlin A. 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Pare PD. et al: The detection of small airways disease. Am Rev Respir Dis 1984:129:989-994. 25. Kuperman AS. Riker JB: The predicted normal maximal midexpiratory flow. Am Rev Respir Dis 1973:107:231-238. 26. Boushey HA. Koltzmaa MJ, Sbelier JR. et al: Bronchial hyper reactivity (state of the art). Am Rev Respir Dis 1980:121:389-413. 820 Asbestos and Airflow/Mohsenifar et al