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813 Clinical, Radiological, and Physiological Findings in Asbestosis SI. KLEIXFELD, .MD; J. MESSITE, MD; AND J. SHAPIRO, MD. NEW YORK PLAINTIFF'S EXHIBIT /ASBESTOS is the name given to a group of minerals composed of fibrous silicates of magnesium and iron. The inhalation of significant amounts of asbestos dust over an extended period of time can produce a symptomatic form of pneumoconiosis. The principal symptoms are dyspnea and cough, the former being usually more prominent than the latter. Both symptoms increase in severity as the disease progresses. The major clinical signs are diminished breath .1 sounds, basilar crepitations, limited chest expansion, clubbing, and cyanosis. Clubbing and cyanosis are usually seen in the more advanced stages of this disorder. Chronic bronchitis and emphysema are associated with this disease, the emphysema being more of a localized than a diffuse obstructive type. Cor pulmonale is the major complica tion and the usual cause of death from asbestosis. There is also an increased inci dence of carcinoma of the lung in asbestosis. The most characteristic finding on the chest roentgenogram is a reticulonodular shadow ing of both lung fields especially in the lower parts together with pleural thickening and/or pleural calcification and a shaggy bonier to the heart (Fig l).1 Cardiac en largement, predominantly right ventricular, is seen late in the course of this disease. The most consistent pathological change is a dense fibrosis' containing macrophages with absorbed dust particles, which in many areas obliterate the pulmonary architecture. A pattern of endarteritis with intimal hyper plasia consistent with pulmonary hyperten sion and bronchiolectasia are associated major findings. Rather striking is the pres ence of elongated, terminally-clubbed bodies, both segmented and unsegmented, in the respiratory bronchioles or embedded in the fibrous tissue or both. The pleura often shows a dense fibrotic thickening (Fig 2).The clinical and pathological features are indicative of a pronounced dysfunction of the respiratory mechanism. This has been confirmed by studies of pulmonary function which show both a disturbance in ventila tory function and diffusion capacity.3 The main functional defect is asbestosis is a re duced diffusion capacity of the lungs. The purpose of the present study was twofold: (1) to make clinical, electrocardiographic, and physiological observations on 21 work ers who were exposed to asbestos dust for an extended period of time and who had radiological findings consistent with asbesto sis, and (2) to relate the changes in lung function in asbestosis to the clinical and radiological signs of the disease. Fig 1.--A 61-year-old asbestos insulator with a 36-year, exposure to asbestos dust. Reticulonodular shadowing predominantly in the lower lung fields. There is also obscuration of the left cardiac border. Received for publication Feb 1, 1966; accepted March 8. From the Division of Industrial Hygiene, New York. Reprint requests to 30 Centre St, New York 10013 (Dr. Kleinfeld). Arch Intern Med--I'd! 117. June 1966 ASARCO ALV 0005779 814 ASBESTOSIS--KLEINFELD ET AL 'T.St Table 1.--Clinical, Electrocardiographic, and Roentgenologic Case 1 o 3 4 5 6 7 8 9 10 11 12 13 11 15 16 17 16 19 20 21 Mean Are. Yr 45 64 72 54 39 41 57 40 57 47 45 63 52 52 40 68 63 54 53 61 54.5 Exposure, Coufh Yr (Yr) Dyspnea Abnormal Lung Findings 23 Pr (10) 55 0 40 0 54 NPr (5) 20 Pr (2) 18 0 IS Pr (5) 14 0 15 0 0 None E Distant breath sounds; basal rales 0 None 0 None 0 None 0 None 0 None E None 0 None 35 0 22 IS 35 ' NPr (6) 0 Pr (10) 25 0 0 Distant breath sounds: basal rales E Basal rales 0 None E Bhonchi, distant breath sounds 0 None 15 NPr (2) 0 None IS Pr (20) 0 None 46 Pr (10) E Basal rales 33 0 E Basal rales 32 0 0 Basal rales 37 NPr (30) 0 Basal rales 36 0 E Basal rales 29J3 Clubbing Electrocardiogram 0 Normal + Normal 0 Normal 0 Normal + Normal 0 Normal 0 Normal + Normal 0 Lou* T waves in left precordial leads 0 Sinus arrythmia 0 Normal 0 Normal 0 Kt bundle branch block 0 T-waves inverted in left precordial leads 0 Normal f* Normal 0 Normal 0 Normal 0 Normal + Low T waves in left precordial leads + Coving of leads 1, AVL and left precordial leads consistent with digitalis effect 0 - none; -f " minimal: -f+ - moderate; -r-r-r - severe; E - on exertion; P - present; Pr productive; NPr - nonproductive; PI = pulmonary infiltration: OCB obliteration cardiac border; OCPS obliteration costopbrenic sinus; PL = plaques (pleural and diaphragmatic): Empb emphysema: and CE cardiac enlargement. Material and Methods Twenty-one persons employed as asbestos insula tors comprised the study group. Each had more than a ten-year history of exposure to asbestos dust and roentgenographic findings compatible with asbestosis. Each subject underwent a detailed medical, so cial, and occupational history, a clinical examination, a 12-lead electrocardiogram, a chest roentgenogram, and a battery of pulmonary function tests. The pul monary function tests included vital capacity (VC), one-second vital capacity (VCi), residual volume (RY), total lung capacity (TLC), and diffusion capacity for carbon monoxide (Di.co). The vital capacity and one-second vital capacity were meas ured by a Krogh spirometer and the volume changes of the spirometer were electrically recorded on a Texas Rectiriter recorder. The residual volume was determined by the nitrogen dilution method using the closed circuit technique as recommended by Wright and Gilford.4 AH lung measurements were determined at ambient temperature and pressure, saturated (ATPS). The values for residual vol umes were corrected for the dead space of the breathing tube and the phase of expiration in which the subject was connected to the spirometer. The Di.co was determined at rest by the single breath technique described by Ogilvie et al.' Normal values for vital capacity, residual volume, total lung capac ity, and the ratio of residual volume to total lung capacity were calculated using the best regression equations of Needham et al.' For Dlco the observed readings were used. The control group was com prised of 50 men whose occupations varied and who had no occupational dust exposures. The 95% confi dence intervals used in the study for all the lung parameters were based on the data obtained from the control group. Findings The predominant clinical, electrocardio graphic, and roentgenographic findings of the 21 asbestos workers are given in Table 1. The lung function data are shown in Table 2. The comparative clinical and physiological findings in control and asbestos worker groups are shown in Table 3. Clinical.--The asbestos workers ranged in age from 39 to 77 years, with a mean of 54.5 years. The mean age of the control groups was 49.2 years with a range of 35 to 63 years. The mean ages of the two groups were not statistically different. Ten of the asbestos workers had a chronic cough of be tween 2 and 30 years' duration. In six, the cough was productive and the remaining Arrh Intern Med--Vol 117. June 1966 i ASARCO ALV 0005780 ASBESTOSIS--KLEIXFELD ET AL 815 Findings in 21 Cases of Asbestosis pi + +++ + ++ ++ + ++ ++ + +++ +++ ++ ++ + + ++ ++ + J+-T +4**r Roentgenologic Findings OCB OOPS PL P p0 P p0 0 pp ppP p p0 p0 0 0 p0 0 pp p p0 ppp p p0 0 p0 0 p0 00p 0 p0 000 0 p0 pp0 0 p0 000 p0 0 Emph 0 0 0 0 0 0 0 0 0 0 p 0 0 0 0 0 p 0 0 0 0 four had a dry cough. Seven of the 21 had exertional dyspnea. Basilar crepitations were found in eight of 21 workers. Six individuals had clubbing. These clinical findings as shown in Table 3 were appreciably greater than those in the control group. A positive smoking history was obtained in 16 of the 21 asbestos workers (76.2%) whereas 21 out of SO (42.0%) in the control group gave a positive smoking history. This difference in proportion was statistically significant. The criterion for positive smoking history was 20 cigarettes per day for a minimum of five years. Electrocardiographic. -- Electrocardio graphic findings were normal in 15 asbestos workers. Of the remaining six, one had sinus arrhythmia, one had a right-bundlebranch block, one showed abnormalities con sistent with digitalis effect, and three showed low or inverted T waves in left precordial leads. No individual demonstrated electro cardiographic findings consistent with the major criteria of cor pulmonale, including a deviation of the electrical axis of the QRS complex of more than 90, prominent R wave in AVR, rSR1 pattern in Vt, and prominent P waves in leads IT and III. Rocntgcnngraphic.--Tn eight individuals, the pulmonary infiltration was classified as grade 1, in nine as grade 2. and in four as grade 3. The criteria for classification are as follows: grade 1, a reticulated appearance in the lower lung fields: grade 2, a reticulonodular infiltration involving approximately 50% of the total lung area; and grade 3, a Table 2.--Lung Function Data in 21 Exposed Asbestos Workers VC VC i RV TLC HV-TEC Case %% Obs Pred Pred Obs VC % % % Oil# Obs Pred Pred Obs Pred Pred Ohs Pred Pred Obs 1 2900 4229 68.6 2045 70.5 1485 2C83 ru 4385 6561 66.3 33.9 33.0 102.7 27.3 2 1690 2573 65.7 1100 65.1 2170 2563 84.7 3860 5460 70.7 56:2 46.9 119.8 8.3 3 2385 2588 92.2 2025 84.9 1995 2221 89.8 4380 4950 88.5 45.6 43.0 106.7 19.3 4 1665 2528 66.9 1280 76.9 1240 2683 46.2 2905 5190 56,0 42.7 48.7 S7.7 20.7 3 2025 3254 62.2 1890 93.3 2030 2189 92.7 4055 5511 73.6 50.1 39.3 127.5 16.9 6 3195 4480 71.3 2700 84.5 2245 1736 129.3 5440 6680 81.4 41.3 27.6 149.6 41.7 7 3060 4245 72.1 2520 82.4 1715 16S4 101.8 4775 6420 74.4 35.9 28.2 127.3 21.7 8 ooon 3809 58.4 1980 89.0 2150 2411 892! 4375 6441 67.9 49.1 38.9 125.2 19.9 9 3105 4377 ;o.o 2025 65.2 2430 2268 107.1 5535 6571 84.2 43.9 34.4 127.6 19.6 20 2855 3740 76.3 1755 61.5 2150 2098 102.5 5005 6340 78.9 42.9 35.5 120.8 17.6 11 2025 3760 53.9 1755 86.7 1225 1818 67.4 3250 5960 54.5 37.7 32.3 116.7 13.3 12 3915 4215 92.9 3105 79.3 1865 1900 98.2 5780 6540 88.4 32.3 30.8 104.9 20,4 13 2395 3255 42.9 955 68.5 2820 2022 139.5 4215 5880 71.7 66.8 37.0 180.5 30.5 14 3215 3420 94.0 2790 86.8 1820 1598 113.9 5035 5670 ssa 36.1 31.3 115.3 24.4 IS 4230 4190 101.0 ' 2720 64.3 3035 2578 117.7 7265 6790 107.0 42.0 38.9 103.0 13d 10 3710 4280 86.7 3060 82.5 1475 1960 75.3 5185 6430 80.6 28.5 31.3 91.1 04 *1 17 1485 3438 43.2 1215 812 2260 2937 76.9 3745 6350 59.0 60.3 46.9 128.6 9.2 18 2385 3640 65.5 1620 67.9 2165 2652 81.6 4555 6440 70.7 47.7 42.5 112.2 13.0 19 1620 3323 48.8 1225 75.6 1200 1901 63.1 2320 5610 50.3 42.6 35.5 120.0 18.3 20 2700 3578 75.5 2115 78.3 1395 1607 87.4 4095 5940 68.9 34.1 30.6 uu 19.9 21 1530 3394 45.1 S85 572 2075 2417 85.9 3605 6000 60.1 57.7 41.1 140.4 11.6 Mean 69.2 76.3 91.5 73.4 120.2 19.6 Ohc ** observed: Pred predicted. Arch Intern Med--Vol 117, June 1966 ASARCO ALV 0005781 816 ASBESTOSIS--KLEIKFELD ET AL W- Fig 2.--Histological findings in a deceased 61-year-old asbestos insulator exposed to asbestos dust for 18 years: (A) Interstitial fibrosis with dust particles absorbed into the macrophages (X645). (B) Asbestos bodies located in the alveoli and interstitially (X645). (C) Bronchiolectasia (X52.5). (D) Endarteritis (X645). more diffuse reticulonodular infiltration in volving more than 50% of the total lung area. In addition to the pulmonary infiltra tion there was also a varying degree of ob literation of the costophrenic sinuses in 16 individuals and/or the cardiac borders in 10. Pleural calcification was observed in five instances. Two individuals showed emphy sema which was localized to the left upper lobe in one and the right lower lobe in the other. There was no cardiac enlargement found in any of the cases. Physiologic.--The values within the nor mal range for each parameter of pulmonary function studied are indicated by the circles within the rectangles shown in Fig 3. Those circles above and below the rectangles for both the control and asbestos groups lie out side the 95% confidence interval. Low values for vital capacity (less than 74.0% predicted) were found in 14 of the 21 as bestos workers. None in the control group had a value below 74.0%. The low values in the asbestos group ranged from 42.9% to 72.1%. Five of the asbestos workers had a one-second vital capacity less than 65.7% with a range of 57.8% to 65.2%. Only one in the control group had a low value, namely ,f Arch Intern Med--Pol 117. June 1966 I 1 ASARCO ALV 0005782 ASBESTOSIS--KLEINFELD ET AL sir Table 2.--Clinical and Physiological Findings in Control and Asbestos Worker Groups Controls No. in group 50 Are tyr) Mean Range 49.2 35-S3 Clinical Vo. % Cough Dyspnea Lung crepitations Clubbing 3 6.0 5 10.0 0 0.0 0 0.0 Physiologic VC (% pred) VC i (% VC) RV t pred) TLC (% pred) RV/TLC (% pred) Dico (cc/mm ng/min) 101.1d=1.9 78.7=0.9 90.ti2.7 93.0t.6 93.62.0 31.6=1.0 Asbestos Workers 21 54.5 39-77 No. % 10 47.6 7 33.3 8 38.1 6 2S.6 69.23.S 76.32.2 9t.S4.9 ' 73.43.0 120.24.4 19.6l." Proba bility NS <0.01 <0.05 <0.01 <0.05 <0.01 NS NS <0.01 <0.01 <0.0t Expressed as mean values standard errors. 60.7%. Values for residual volume above 128.5% predicted were found in two of the asbestos group and in one individual of the control group. The two high values in the asbestos group were 129.3% and 139.5%. The single high value in the control group was 156.9%. Values for total lung capacity less than 69.8% predicted were found in eight of the asbestos workers. The low values ranged from 50.3% to 68.9%. Only one in the control group had a low value, namely, 69.4%. The ratio of residual volume to total lung capacity was above 122.2% pre dicted in eight of the asbestos group; the high values ranging from 126.2% to 180.5%. Two of the controls had abnormal values of 122.3% and 123.3%. Thirteen of the asbestos workers had a Dt,r,, less than 20.0 cc/mm Hg/min, and none of the controls had a value below this figure. Among the asbestos workers the low values ranged from S.3 to 19.9 cc/mm Hg/min. The differences between the control and the asbestos worker groups are statistically significant for VC, TLC, RV/TLC, and bLco, but not for VCt and RV. Environmental.--The asbestos dust to which these workers were exposed was chrysotile and amosite asbestos. The only exposure data available were those on the duration of exposure in each instance. The minimum exposure was 14 years (case 8) and the maximum 55 years (case 2). The mean duration of exposure for the group was 29.2 years. The data in Table 3 show that the asbestos workers as a group have a greater incidence of abnormal clinical and physiological find ings referable to the respiratory system than do the persons in control group. The clinical picture characterized by cough, dyspnea, lung crepitations, and clubbing, although not diag nostic, is consistent with sustained exposure to asbestos dust. The positive radiological changes in the chest roentgenogram, char acterized by reticulonodular shadowing, obscuration of the cardiac borders or costophrenic sinuses, or both, and the presence of pleural calcification are similar to what has been observed in previous studies of asbestos workers 1,3 and talc millers.7 It is of interest that none of the electro cardiograms or chest roentgenograms showed evidence of cor pulmonale even though a certain number of individuals had a long duration of exposure to asbestos dust, dyspnea, basal crepitations, and severe pul monary infiltration on chest roentgenogram (cases 2. 11, and 21). In the absence of data on pulmonary artery pressures, cor pulmonale cannot be ruled out with certainty. Instances of high pulmonary artery pressure are found where the electrocardiogram is normal. It is noteworthy that Lavenne found no indications of cor pulmonale by electro cardiogram when there were no roentgenographic signs of cor pulmonale in coal workers pneumoconiosis.8 With regard to pneumoconiosis, cor pulmonale usually oc curs as a relatively late event. With respect to the lung function param eters, the data in Table 2 show that the ab normal values are indicative of a restrictive breathing disorder and impairment in dif fusion capacity. This is consistent with the observations reported by others in workers exposed for long periods of time to asbestos dust.3-9 Other diseases, including sclero derma, sarcoidosis, and the Hamman-Rich syndrome can cause a similar functional im pairment. The finding of such a functional lesion, coupled with a consistent chest roent genogram and history of sustained exposure to asbestos dust, is strong evidence of asbestosis. Although the mean values of the lung function parameters, with the exception of vital capacity and diffusion capacity for the group of asbestos workers, fall within the 95% confidence limits for the control group, it can be seen from Fig 3 that an ap- Arch Intern Med--VoI 117. June 1966 .1 ASARCO ALV 0005783 8X8 ASBESTOSIS--KLEINFELD ET AV ,190 iso 170 160 150 Fig 3.--The pulmonary function data observed in control and asbestos worker group are sum marized. The values within the 95% confidence interval for each param eter of pulmonary func tion are indicated by the circles within the rectan gles. Those circles above and below the rectangles represent abnormally high or low values respectively. The shaded circles iden tify the control group and the open circles the as bestos group. MO 130 120 110 100 90 BO 70 60 50 55 50 45 40 * 35 r * '* 30 $ 25 f t VC k PREDICTED vc. OF VC RV T LC RV/TIC % k 'U PREDICTED PREDICTED PREDICTED ml/mm Hg/min preciable number of asbestos workers fall outside these limits. This is particularly evi dent for vital capacity, total lung capacity, ratio of residual volume to total lung capac ity, and diffusion capacity. To a lesser ex tent, this is also observed in the one-second vital capacity. The high incidence of smok ers probably accounts for this finding. Relating the changes in lung function to the clinical and radiological findings it was observed that those with dyspnea and lung crepitations had a significantly lower mean vital capacity and total lung capacity than those in whom these findings were absent. The diffusion capacity was also appreciably lower in the group with lung crepitations. No relationship could be established between clubbing and changes in pulmonary function. It is of interest that Williams and HughJones 3 did find a good correlation between reduction in diffusion capacity and the grade of finger clubbing. These authors also noted a strong correlation between reduction in diffusion capacity and degree of pulmonary infiltration. Vital capacity and total lung capacity were also related to the severity in Arch Intern Med--I'ol 117, June 1966 ASARCO ALV 0005784 ASBESTOSIS--KLEINFELD ET AL radiological change but at lower levels of significance. Our study showed only a weak correlation between these lung function pa rameters and degree of pulmonary infiltra tion. In an extension of our study 16 of the 21 workers were compared with a group of 20 asbestos workers of statistically com parable mean and range of age and duration of exposure but having negative radiological findings. There were no significant differ ences in the clinical findings between the two groups, however, the lung function param eters showed an appreciably lower vital capacity, total lung capacity, and diffusion capacity in those with positive radiologic findings.10 Summary and Conclusions Clinical, electrocardiographic, and physio logical observations were made of 21 asbestos workers who had an average exposure to asbestos dust of 29.2 years and who had radiological findings compatible with asbestosis. Ten of the 21 workers had chronic cough, and seven evidenced exertional dyspnea. Basilar crepitations were found in eight, and six had clubbing. Electrocardio graphic findings were abnormal in six but in none of these were the abnormalities con sistent with the criteria of cor pulmonale. In eight individuals the pulmonary infiltra tion was minimal, in nine it was moderate, and in four it was classified as severe. Varying degree of obliteration of the costophrenic sinuses was observed in 16 and/or cardiac borders in 10. Pleural calcification was observed in five. Two individuals' showed emphysema which was localized. Theabnormal lung function findings were consistent with a restrictive breathing and diffusion capacity impairment. This was char? acterized by low values in vital capacity (14 persons), in total lung capacity in (8), and in diffusion capacity (13). The workers with dyspnea and lung crepitations had a significantly lower mean vital capacity and total lung capacity than those without these clinical findings. In addition, the group with pulmonary crepitations had a lower mean Dt,co. There was a poor correlation between clubbing and vital capacity, total lung capac ity, and diffusion capacity. There was a weak correlation between these lung function parameters and the degree of pulmonary infiltration. When 16 of the 21 asbestos work ers were compared with a group of 20 as bestos workers of similar age and duration of asbestos exposure, but having negative radiological findings, there were no signifi cant differences in the clinical findings be tween the two groups. There was, however, a significantly lower vital capacity, total lung capacity, and diffusion capacity in the group with positive radiotogical signs as compared with the group with negative roentgenograms. Dr. Emanuel Levin of Maimonides Hospital of Brooklyn and the State University of New York, Downstate Medical Center, Brooklyn, NY, reviewed the chest roentgenograms. Dr. Harold Lepow of Lincoln Hospital and Albert Einstein College of Medicine, Bronx, NY interpreted the histological data. Mr. Jay Sarfaty of this Division assisted in the technical aspects of the program. REFERENCES 1. Oosthuizen, S.F.; Theron, C.P.; and SluisCremer, G.K.: Calcified Pleural Plaques in Asbestosis: An Investigation Into Their Significance, Med Proc (Mediese Bydroes) 10:496-501, 1964. 2. Heard, B.E., and Williams, K-: The Pathology of Asbestosi3 With Reference to Lung Function, Thorax 16:264-281, 1961. 3. Williams, R., and Hugh-Jcmes, P.: The Signifi cance of Lung Function Changes in Asbestosis, Thorax 15:109-119, 1960. 4. Wright, G.W., and Gilford, S.R.: A Method for the Simultaneous Measurement of Maximum Breath ing Capacity, Pulmonary Volumina and Effective Lung Ventilation, J Thorae Cardiov Surg 38:643651, 1959. 5. Ogilvie, C.M., et al: A Standardized Breath Holding Technique for the Clinical Measurement of the Diffusing Capacity of the Lung for Carbon Mon oxide. J Clin Invest 36(pt 1) :1-17, 1957. 6. Needham, C.D.; Rogan, M.C.; and McDonald, I.: Normal Standards for Lung Volumes, Intrapulmonary Gas Mixing and Maximum Breathing Ca pacity, Thorax 9:313-325, 1954. 7. Kleinfeld, M., et al: Effect of Talc Dust Inhala tion on Lung Function, Arch Environ Health 10:431437, 1965. 8. Lavenne, F.: "Correlation Between E.C.G". Cri teria, Clinical Manifestations and Necropsy Findings in Coal Miners' Pneumoconiosis," in Orenstein, A. J. (ed.): Proceedings of the Pneumoconiosis Confer ence, University of Witwatersand, Johannesburg, Feb 9-24, 1959, Boston: Little, Brown & Co., 1959, pp 237-241. 9. Bader, ME.; Bader, RA.; and Selikoff, I.J.: Pulmonary Function in Asbestosis of the Lung, an Alveolar-Capillary Block Syndrome, Amer J Med 30:235-242, 1961. 10. Kleinfeld, M., et alt The Effect of Asbestos Dust Inhalation on Lung Function, unpublished data. Arch Intern Med--Val 117, June 1966 ASARCO ALV 0005785