Document Dv0aQ5vad8LwKj0RmJZ4rv564

PLAINTIFF'S Is exhibit v GF.-814' DISTRIBUTION OF MINERAL PARTICLES AND FIBERS IN THE LUNG AFTER EXPOSURE TO ASBESTOS DUST J. F. KNOX, MB. AND J. BEATTIE, M.D. ROCHDALE, ENGLAND S THE result of experimental work on the production of asbestosis in animals, \ orwald and associates 1 concluded that typical peribronchiolar fibrosis was produced when the particle length of the inhaled asbestos dust lay between 20 and 50 p. The asbestos caused fibrosis by the mechanical action of the filler on the lung tissue. When the animals were withdrawn from the dusty atmosphere, the lesions did not progress hut rather tended to regress. Asbestosis bodies, formed around inhaled asbestos fibers, were found to lie inert as fibrogemc agents when they were injected into the trachea The length of exposure to dust necessary to induce typical fibrosis by inhalation was between one and two years. lrt the series of cases which we have studied and reported on before i Knox and Beattie7), we noted that the time interval between the first exposure to asbestos dust and the appearance of asbestosis in autopsy specimens was not less than 12 Vcars. It appeared to us that the long interval between first exposure and the appearance of typical fibrotic changes indicated that the mechanism for the pro duction of human asbestosis differed from that responsible for the experimental type, ll the mere presence of asbestos particles within a critical sire range was the essential factor in the production of human asbestosis. it would be difficult to explain why so many persons escapie any asbestotic change even when exposed for more than 30 tears. It is generally agreed that soon after inhalation the majoritv of the asbestos fibers become included m the asbestosis bodies The experiments of Vorwald ai d his co-workers suggested that these structures are inert hut the bodies do not remain as intact structures indefinitely. With the passage of tears thev become "weathered," eroded, segmented, anil finallv fragmented i C ooke,5 Mc Donald,` C,lo>ne.: Hegerd (iloyne7). It was thus possible that m man the fibrotic changes in the lung might be related to this process of disintegration of the asbestosis body. We have noted already that the degree of asbestosis appeared to t>e correlated more closely to the sum of the years of exposure to dust and the vears of survival after the last exposure than to the total mineral content of the lung piarenchyma l Knox and Beattie 7 i Thus finding suggested that, if disintegration ot the Tilt Directors of Turner brothers Asbestos Company. Ltd. supported this studv hv making a grant to meet the expenses involved Further assistance was rendered hv pathologists and personnel managers ^0 SOOTQIflO Si. sti- $ /. , PULMONARY DISTRIBUTION OF ASBESTOS PARTICLES asbestosis bodies was an essential factor in the production of fibrotic change, then there ought to be a change in particle-size distribution in the direction of a fall in the numbers of the larger particles as survival time increased. The formation of large numbers of smaller sized particles, however, might not be apparent in the counts, if the rate at which such particles were removed irom the lungs kept pace with their rate of production. On the other hand, if the rate of production were greater than the rate of removal, then it might be possible to determine if fibrotic change were correlated with a rise in the small particle-size counts. MATERIAL AND METHODS The series of cases studied was the same as that reported in our paper on mineral content of the lungs (Knox and Beattie2). There were 27 workers. 21 men and 6 women. The duration of exposure to asbestos dust varied between 5 and 33 years, and the length of time from the last exposure to death ranged from less than 1 year to 21 years. The cases have been arranged in order of increasing survival time. The exposure and survival times are given to the nearest year. Asbestosis has been graded into three degrees according to the pathological reports based on the histological appearances found in the lung parenchyma. Particle-size distributions were determined on the incombustible and acid-insoluble residues of lung parenchyma prepared by the method of King and Nagelschmidt.* Pooled samples of these residues were made from each lung and, after mixing, small aliquots were taken. After being moistened with a wetting agent, the aliquots were suspended in an appropriate volume of water, care being taken to prevent flocculation and the inclusion of air bubbles. A drop of the suspension was then placed on a microscope slide and a drop of polyvinyl alcohol added to the suspension. Fluid was then dried off on an electric hot plate. Five slides were prepared from each aliquot and four aliquots prepared from each pooled sample. The slides were placed in a microproiection apparatus and the image of the particles projected on a sheet of paper at a magnification of X 1.000. Light-field illumination was used. Fifty fields were counted on each slide. Care was : ,ken to obtain a suspension sufficiently dilute to ensure accurate counting. The number of particles in each of the following size ranges was counted: Less than 5 m Between 5 and 15 m Between 16 and 25 a Between 26 and 35 e Between 36 and 45 m Over 45 e Light-field illumination was chosen lo facilitate counting of large numbers of fields. It was realized that with this method very small particles would not be counted, and consequently the values given for counts in the smallest size range would be less than the true values. To facilitate comparison of the different particle-size distributions, the number of particles in each size range is expressed as a percentage oi the number of particles found in the size range 16 to 25 m in each lung specimen OBSERVATIONS The particle-size distributions in the residues from the luntjs of the 27 cases are given in the Table. As the residues from which the distributions were deter mined were pooled samples from different areas of the lung parenchvmn. it was possible that such pooling might introduce considerable errors if the particle-size distribution varied significantly from area to area. It was found from a study of particle-size distributions t'rnm samples representing different areas of the longs from tour cases that particle-size distributions did not van- significantly from area to area within the same lung. The mean distributions tpven in the Table are there fore representative of the distribution within the whoie lung. 50^01 *11 tXDVSTR/AL SIYGIESE AXD OCCL'PATIOSAL MEDICIS'E Particle-Sice Distributions Expressed as Percentages of Count in the 16 to 25 a Range Cttt So. 23 26 17 23 12 5 21 4 19 6 10 14 22 l 27 20 8 13 7 28 11 24 15 16 Total Suf. Exposure v | v A1 Ashestosis. P Time. Time. Sex Vr. Vr. 4- Th*n 3 m M. 26 0 U 23 0 M 20 0 M U,, 4-*-- _-r 364 456 .*10 612 M 12 0 4- 304 M a n __ 027 F 32 1 -- 501 M 27 2 1- 689 M 23 2 -r 433 F 33 2 -- 573 F 14 <> + 627 T 8 2 1- 522 M 40 3 4- 421 M 9 3 -- 510 M 27 4 4. 517 M 7 6 -- 486 M 23 7 610 M 21 8 +-r-- 786 M 23 8 -r++ 829 F 27 8 898 M 27 8 -- 496 F 69 611 M 5 11 -- 587 M 22 14 720 M 19 14 1.006 M 14 17 -- 529 M 10 21 4- 647 Mean Particle Count* 5-15 u 193 217 290 389 281 329 257 3S7 225 3S1 296 359 323 322 231 369 487 521 644 591 321 418 292 599 707 386 411 16-25 m 100 too 100 100 100 100 100 100 100 100 100 100 100 100 10ft 100 100 100 100 100 100 100 100 100 100 100 100 26-33 M 36 42 51 *2 79 38 48 33 50 14 62 41 51 50 46 31 0 22 11 4 0 0 0 0 0 2 36-45 M 21 18 9 17 0 0 17 20 ,8 25 20 18 12 0 2 4 1 0 2 0 0 0 0 0 45 m 0 0 11 2 21 17 9 8 6 5 7 17 0 2 0 0 0 0 l 0 0 0 0 0 0 0 No. at particlct 700 - JU 600- o 500f4001- $ icvtrt atbestasii JOOt200r- * no aiboto&is * minimal OJbcitoiii IOO|- o*- Chart 1.--Mean particle counts in the less than 5 u and the 5 to 13 m ranges in cases with no asbestosis and in those with minimal and severe asbestosts. The standard deviation for each mean value is given by the verticle line through this value. These counts were made on the incombust ible and acid-insoluble residue of lung parenchyma. 32 500^01.42 PULMONARY DISTRIBUTION OF ASBESTOS PARTICLES Relation of Particle Sice to Degree of Asbestosis.--In those cases which showed severe asbestotic changes in the lung parenchyma, the mean number ot particles less than 5 n in length was 791 (S. D. 134, S. E. 2: 55). In the size range 5 to 15 fi the mean count was 562 (S. D. 106, S. E. 43). Cases with minimal Particle count O no asbestosis 9 minimal . 9 moderate ' sever* . Chart 2.--Mean particle count in the less than 5 m range for each case in the series plotted against the sum of the exposure and survival times. Particle count O no asbestosis minimal . moderate . severe - Chart J.-- Mean particle count in the 5 to 15 n range for each case in the series plotted against the sum of the exposure and survival times. asbestosis gave a mean count of 512 ( S. D. ar 85. S. E. at: 261 in the less than 5 M range and 311 i S. D. a: 57. S. E. a: 17) in the 5 to 15 ^ range. Cases with no asbestosis gave corresponding counts, as follows: less than 5 fi, 503 (S. D. a= 66, S. E. a= 23 i and from 5 to 15 n, 332 i S. D. aa 45, S. E. aa 16). The results are shown graphicallv in Chart 1. 500^014 INDUSTRIAL HYGIENE AND OCCUPATIONAL MEDICINE While there is a significant difference between the counts in botli size ranges from the cases of severe asbestosis and those with minimal changes, there was no significant difference between the counts from cases with minimal asbestosis and those with no asbestosis. When the mean counts in the less than a /j. range are plotted against combined exposure and survival times tor those cases which showed either no asbestosis or minimal asbestosis, there is a remarkable uniformity in the counts within tairiy narrow limits as time increases after the 12th year from the first exposure t Chart 2). On the other hand, the counts in the cases of severe asbestosis show higher values. When the counts for the size range 5 to 15 n are plotted in the same wav. the results are the same (Chart 3 I. There is again great uniformity in the counts over the combined exposure and survival times from the 8th to the 35th year for cases with minimal or no asbestosis. Cases of severe asbestosis showed higher counts. COMMENT It is remarkable that in the cases studied the number of particles witli a greatest length in excess of 26 p. should have disappeared almost completely from the lung parenchyma when the survival time was more than eight years. This finding sup ports Gloyne's 3 opinion that in long-standing cases of asbestosis the number and size of both the asbestos fibers and the asbestosis bodies seen in histological preparations were less than in those cases more recently exposed to asltestos dust. Gioyne, however, was not the first to express this opinion. Prof. M, J. Stewart,* in a private communication concerning one of Gloyne's cases, stated: There is no doubt also uout absorption of asbestos bodies and asbestos fibres going on in the lung. Indeed, it is only by the solution of the bodies that the ill effect is produced. I have no doubt that this process of solution of ihe asbesto- fibres will vary as to its rate of progress in different cases, and that in some cases asbestos fibres (and consequently bodies) may, after many years, disappear completely, leaving behind the rtbrouc lesion which they induced. If the cases of severe asbestosis be excluded, the particle counts in both the less than 5 p. range and m the a to 15 ^ range showed un significant change as the combined exposure and survival time increased. Moreover, there was no significant difference between the particle counts m either of these size ranges of cases with no asbestosis anti those with minimal changes. It would appear therefore over a long period of tune either that there was no movement of asbestos or asbestosderived particles from the lungs or that the rate at which small particles were produced from larger ones was almost epual to the rate at which thev were removed from the lungs. As we have produced some evidence that the mineral content of the lung tends to decline with increasing survival time, the latter alternative is the more probable. When the cases of severe asbestosis are considered, it is clear that the signifi cantly high counts in the small particle ranges must indicate either a much more rapid breakdown of larger particles nr a ia 11 m the rate at which the small particles are removed. Although it is more probable that the rise m the small particle counts in the cases of severe asbestosis is due to reduced rate of removal, there is no * Stewart. M. J.. Personal communication in the author- from Prof. M. f Sicwart. formerly 1'roic^or of P.itliolnyy, ) ic<\- 500 y 01.4 1 PULMOSARY niSTKSBLTIOX OF ASBESTO PARTICLE* conclusive evidence that this i> >o. other than the fact that in these cases, as f have siiown already. both the hilar anti pleural and 'iiiipieural tissues contain much, mineral material i Knox and licattic - i. . The association of hitrh counts in the small particle ranges with severe ashestosis and the absence in three oi these cases of anv rihers with a greatest length in excess of 26 u suggest that human ashestosis. at least of the severe tvpe. is not due to the mere presence within the lung of particles with greatest lengths within a critical size range oi 20 to 50 fx. The high counts of such critical size rihers in many of the cases with no ashestosis or minimal fibrosis and with long exposure and short survival times would suggest that the mechanism for the production of clinically recognizable ashestosis (lifters from that which induces peribronchiolar rihrosis in experimental animals. - Our findings thus indicate that a rise in the numbers of small mineral particles derived presumably from the breakdown of ashestosis bodies is associated with severe fibrotic changes in the lung parenchyma. This implies that either these particles or some other product of the breakdown of the bodies can exert a fibrogenic erTect on lung tissue. If these products are removed as rapidlv as they are formed, then either no ashestosis develop.' or a minimal degree of change occurs. It is suggested above that a reduced rate of removal of these products may be due to partial blockage of the drainage routes from the lung, t. e., either toward the lung hiius or toward the pleural surface. It is conceivable that am pathological process which would cause any inflammatory change in the hilum or in the lymph nodes into which the pleural lymphatics drain might cause a further reduction in the drainage rate and might precipitate the onset of severe fibrotic changes. Cardiac decompensation too might be a factor in the precipitation of these changes. SUMMARY The particle-size distributions in the incombustible and acid-insoluble residues from the lungs of 27 persons who had been exposed to asbestos dust were determined. The number of particles with greatest lengths in excess of 26 ^ was considerable up to the eighth year after the last exposure to asbestos dust and then sharply fell. The number of particles within the size ranges of 5 fx and less and between 5 and la remained constant over a vert' long period m those cases which showed no sign of ashestosis or minimal fibrotic change. The cases of severe ashestosis showed a significant rise in the numbers of such particles. It is considered that the mechanism which is concerned with the production of human ashestosis is not the same as that which is responsible for the production of asbestotic changes in experimental animals exposed to high concentrations of asbestos dust. The appearance of such changes appears to be related to the break down of ashestosis bodies which mav liberate some librogeiiic agent. REFERENCES 1. \oruald A I ; Durkan. T. M. and Pratt. P C . Experimental Studies of A.sbe'tosis, A M. A. Arch Indust. Hye. 3: 1 --SJ. 1951. 2. Knox. J F., and Eeattie. J. Mineral Content of the I.tines After Exposure to Asbestos Dust, A. M A. Arcii. Indust Hye. tins issue, p. 2J. 35 500^01*1^ IXDL's l XI. IL IIYC.IXX,: "Li rrxnox.u. '//./'/L \ ! 3. Cooke. \V. E.: Pulmonary Asbestosis. Brit. M. J. 2:1034-1033. 1937. 4. McDonald. S.; Histology of Pulmonary Asbestosis, Brit. M. J. 2:1025-1026, 1927. 3. Gloyne. S. R.: Presence of Asbestos Fibre in Lesions of Asbestos Workers, Tubercle 10:404-407, 1929. 6. Beger, P. ]. : Cber die Asbestesiskorperchen, Virchows Arch. path. Anat. 290:280-353. 1933. 7. Gloyne, S. R., in Silicosis and Asbestosis, edited by A. J. Lanza, London, Oxford Uni versity Press, 1938, p. 225. 8. King, E. J., and Nagelschmidt. G.: Mineral Content of the Lungs of Workers from the South Wales Coalfields. Special Reports Series 250. Medical Research Council, London, Her Majesty's Stationery Office, 1945, pp. 3-4. " 9. Gloyne, S. R.: Pneumoconiosis: Histological Survey of Xecropsy Material in 1.205 Cases, Lancet 1:810-814, 1951. 36