Document bBDeYKK4eKvxG34zakEvV884y

PLAINTIFF'S EXHIBIT UC-2392 PREVENTIVE MEDICINE 2,412-437 (1973) i - i f- p'oterte'' i k,C\.s j Widening Perspectives of Occupational Lung Disease' Irving J. Selikoff Environmental Sciences Laboratory, Mount Sinai School of Medicine of the City University of New York. Fifth Avenue and 100th Street, Sew York. New York 10029 Note. This paper is part of the "Forum on the Prevention of Pulmonary Disease" (Guest Editor: Dr. A. Fishman) which appeared in Vol. 2, No. 1, March 1973 of Preventive Medicine. It is something of a paradox that the basic concepts which helped establish much of our current knowledge concerning occupational and environmental lung disease are now often found to be inadequate and occasionally even inappropriate or misleading. At the turn of the century, there was general belief that dust, fumes, and vapors might cause lung damage. Agricola had written almost four hundred years before of lung disease in Saxony mines (1) [the very mines which, in our times, yielded the first knowledge of radiation lung cancer (101)], and the grinding shops of nineteenth century Britain demonstrably shortened the lives of their workers. Yet, little could be said definitely about this. Many dust-exposed workers --farm laborers, for example --lived long lives, while others, even with lungs blackened by dust in Scottish coal mines, suffered no evident ill health (84). Moreover, the widely prevalent lung disease, tubercu losis, was not seen to be related to dust or fumes; its frequent presence often confounded and overwhelmed other lung disease which might be present. It is, therefore, to the considerable credit of our predecessors that they were r.tlr -T".ke crier of this ccn.adietciy and diTase situation. If cue eon.ribction can be said to have provided clarity and definition it may be Collis' brilliant Milroy Lectury of 1916 (22), in which he established for the first time that a specific dust particle --crystalline silica (Si02) -- had a biologically unique effect. He did this, incidentally, by using what would now be labeled an epidemiological approach--workers exposed to dusts with high concentra tions of free silica (as, quartz) died much more frequently of tuberculosis than did workers exposed to dusts of other composition. Demonstrating this effect, he gave new meaning to the word "pneumoconiosis," introduced 50 years before (144). After Collis, it was no longer a specific disease but rather a generic term which covered a variety of dust diseases of the lung--and opened the way for its compartmentalization into many categories (silicosis, asbestosis, talcosis, beryllium lung disease, coal workers' pneumoconiosis, aluminosis, and others), all related by the presence of pulmonary reaction (primarily fibrosis) to dust in the lung parenchyma. ' These studies were supported by research grants ES 00358 of the National Institute of Envi ronmental Health Sciences, OH 00320 of the National Institute for Occupational Safety and Health, and by Contract UI272 of the Health Research Coj^n^ij of New York. 412 Copyright 1973 hy Academic Press, Inc. All rights of reproduction in any form reserv ed. UCC 015456 m se' .Guest Editor: irme. ed establish :vironmental ionally even a . fumes, and iur hundred which, in our 'll)], and the lortened the it this. Many ; lives, while suffered no use, tubercuesence often t be present, hat they were . one contribu;ay V Colbs' r the first time t biologically '\v be labeled igh concentraerculosis than ing this effect, hiced 50 years ! but rather a rhe lung--and i ies (silicosis. eumoconiosis. unary reaction i Institute of Enviitional Safety and iiy of New York. '*ir T' ': -V % '`c..A V: b' :k OCCUPATIONAL LUNG DISEASE 413 Two methodological perspectives seemed to flow from this discovery. In their time, they were reasonable. First, was the stricture that there should be a one cause/one effect relationship; indeed, this seemed a good biological prin ciple and consonant with observations then being rapidly made in infectious disease. Second, on the other side of the coin, specific lung changes were sought and often found after exposure to specific substances. When it was finally agreed, for example, that asbestos (without free silica) could cause lung disease (25), it was logical to find that the fibrosis it produced was diffuse rather than nodular (40). Moreover, the approach has in many ways been a productive one. With it, we have been able to determine that some metal particles as iron or tin (103) produce little pulmonary reaction. The sometimes serious consequences of beryllium exposure were found early although, at least in the United States, we were laggard in acting upon this recognition (47), in part because animal studies did not show an expected specific effect. Tungsten carbide, talc, nonfibrous silicates as kaolin (31), aluminum (41), titanium (77), and others were all discovered to have their own pathogenicity. Even today, it makes good sense to isolate a substance in the human environment, so far as is possible, to study its effects, and this technique is almost universally used in animal studies. Nevertheless, however well this concept has served us to this point, there has been a growing realization that these methods are incomplete and restric tive (116). As a result, wider perspectives have emerged, especially in the last ten years. Mixed dust exposures. While it makes good sense, for purposes of identifica tion and definition, to study isolated exposures, in industrial circumstances these are more often the exception than the rule. In mining, for example, ores are complex with a variety of minerals, and the dusts produced during extrac tion and beneficiation reflect this diversity (66). Moreover, under some cir cumstances, the presence of sorer rrmprals may potentiate, or diminish, the effects of others; their concurrence need not be biologically neutral. Tr.us, while "pure" graphite can produce disease, its contamination with silica may add to the fibrogenic response (96). Similar effects are noted with coal dust and provide at least part of the explanation for the differences seen with anthracite and bituminous coal mining (92). Mixed dust exposures are also common in industrial practice. Insulation workers, for example, are called "asbestos workers" (indeed, they belong to the "Asbestos Workers Union"), yet the materials with which they work often contain only fractional amounts of asbestos and sometimes no asbestos at all (127). Merewether was aware of this when, 40 years ago, he sought to ascer tain the extent of the risk associated with the industrial use of asbestos (86). He sought out a "pure" asbestos trade, the manufacture of asbestos textiles. While this did provide clear information concerning the fibrogenic potential of asbestos, it also attracted scientific and medical attention to what has turned out to be a relatively uncommon use of asbestos, and several decades went by before concern was redirected to less well-defined but, in terms of workmen UCC 015457 402634 414 IRVING J. SEUKOFE involved, much more important uses, such as those in the construction in dustry (117,118). The frequency of mixed dust exposures in industrial practice makes it unwise to expect that "classical" X ray patterns will regularly be seen on roentgenograms in all cases. While silicosis will often show the expected nod ular infiltrations, linear and reticular shadows are also commonly seen. This is also true in coal workers' pneumoconiosis (95), and among iron miners (108), while in asbestosis, small nodular shadows may complicate the linear reticular pattern of diffuse interstitial fibrosis (11). The appreciation of this diversity has recently led to the modification of the International Classifica tion of Roentgenographic Appearances of Pneumoconiosis. Culminating an 8-year review of the problem by groups of experts, a new Classification was agreed upon in 1971 (57), and allows the description of the complexity of X ray changes that are commonly seen. Multiple factors in occupational lung disease. Just as complex dust ex posures are the rule, it has recently become apparent that there is a compara ble complexity in the total environment of the worker which must be consid ered. This includes both the occupational and nonoccupational setting. Of the two, it appears at the moment that personal factors have the greatest influence. Living conditions and style of life may play a role (54,55,105); their exact effect is not fully clear. Cigarette smoking, on the other hand, has great influence. The first well-defined report on the powerful effect of smoking on industrial lung disease was that of Sluis-Cremer (125). He demonstrated that the in cidence of bronchitis among gold miners depended upon whether or not they also smoked cigarettes; if they didn't, they had no greater risk than similar adult males in the same community. On occasion, it is even difficult to dif ferentiate an effect of an adverse occupational environment, as in S02-p]agued steel mills, because of the overriding influence of cigarette smok-'og (74). The same difficulty may be found in studying the influence of community air pollution (46), or industrial lung disease in the coke industry (141). In some circumstances, the cigarette smoking effect may be additive or may exaggerate or potentiate the influence of the occupational environment; this is seen in byssinosis (85) and in respiratory disease among coal miners (27). Recently, it has even been found that the existence of radiologically evident pulmonary fibrosis following asbestos exposure has such an association (142). With similar duration of work exposure, the smokers tend to have more radiological evidence of parenchymal fibrosis. One factor may have been the tendency for cigarette smoking itself to result in some pulmonary fibrosis (4); other mechanisms have been suggested. The metabolic status of the individual may be important: the subject has hardly begun to be studied (24). While hints have been available for some time [as, possible effects of concomitant infection (6,21)], the recent iden tification of the importance ofalpha^antitrypsin deficiency in the pathogenesis of some cases of emphysema (36,134) has attracted much-needed attention to this field of research. Indeed, such genetic defects may eventually explain UCC 015458 /)02S3h ;i i il l's it n on i nodi His is liners linear ! this 'sifica'insi an in was it X ray nst ex'inparavonsid- .'reatest their .s great Justrial the iniot they similar f to difilagued 74!. The lvt; ?;r or may t: this is rs (27). > evident ni (142). \ e more been the i i is is (4); 'iect has tor some eiit idenmenesis ntion to explain OCCUPATIONAL LUNG DISEASE 415 ninsual syndromes in occupational lung disease and some of the individual ..niations in response to apparently identical occupational exposures which , i-rplex us. Similarly, immunological (including auto-immune) response to pneumoconiotic dusts may explain not only such basic phenomena as the resulting fibrosis (16,137) but more esoteric observations including the occur rence of Goodpasture's syndrome following the inhalation of industrial sol vents (10,32). Physical interactions may also be significant. Thus, inert particles (as, arbon) may absorb and potentiate noxious gases (SOx, XOj.) (12) or car cinogenic materials (88, 109); little is known about interactions with physical environments (heat, cold, radiation), although clinical suspicion exists that these may be important. There may be no such thing as an "inert dust," innoc uous in all circumstances. The total dust burden of the lung in respiratory disease among coal miners, for example, plays a pathogenetic role (106), perhaps by mechanical effect on lymphatic and bronchial clearance; even nepheline inhalation, if extensive enough, can produce fatal lung disease (7). Individual variations as a result of genetic, immunological, and metabolic (actors have been mentioned. Other causes are still obscure and may include physiological factors associated with age and nutrition (59). The spectrum of potential interactions is wide and provides fertile fields for critically needed research (71), since it may turn out that much occupational Jung disease--and environmental lung disease, in general--would not occur except with the ad ditive or even multiplicative effect of two or more agents. This has important useful connotations since, in some circumstances, it may be practical to focus on the elimination or control of one or another agent, least difficult to attempt. If there be a chain of pathogenetic events between initiation and clinical disease, all links in this chain may not be equally strong or inaccessible. Iden tification of one weak (ink may allow us to interrupt an otherwise inexorable progression of disease. Two initial proposals can be mentioned: the screening 'f new employees for alpha,-antitrypsin deficiency and for cigarette smoking, before their hiring for trades which in'.'uda risk of emphysema or pneumo coniosis (134). One could argue, correctly, that these industries should pro vide work environment without any risk. From a practical point of view, how ever, the best-controlled work environment is unlikely not to have some trace of the noxious agent, hazardous only to the specially susceptible individual. Compound and variable substances. Not infrequently, industrial exposures occur to multiple agents naturally. This is almost invariably the case with min eral dusts; the ores are complex mixtures of minerals, often varying from seam to seam. The extraction and beneficiation processes rarely result in uncon taminated, unique, single substances, except perhaps when laboratory grades are sought. Exposures, usually, are to more than one mineral component, the proportions varying with each step from mine to end use of the material. It is thus inadequate to speak of "exposure to coal dust" or to "asbestos" or to "talc." A miner may inhale varying amounts of quartz while quarrying tin (103), mica (52), or talc (124), and "rock dust" exposure frequently accom panies coal extraction. It is instructive to remember that the pathogenetic UCC 015459 416 1KVIXG J. SEUKOFF properties of coal dust per se were first isolated by demonstrating disease in coal handlers in transportation, away from the mines (23). It is likely that the spectrum of findings among coal miners relates at least to some extent to varia tions both in the rank of coal mined and its silica content (91), and disease with graphite also reflects contributions from both its carbon and silica con tent (96). Lung disease with cement may also reflect variability of the dust, and there has long been concern with the foundry environment (83). Failure to appreciate the potential effect of such admixture long delayed the recogni tion of the possible fibrogenic effect of bentonite (99) and hematite mining (37,132), while diatomaceous earth may give little trouble --unless its amor phous silica is altered to crystalline tridyrnite or cristobaiite by calcining. Shaver's Disease (123), too, has been studied not only in relation to aluminum ore, but to particle size and silica content, and hard-metal pneumoconiosis (19) is so named because of the varying materials involved in its causation. The possibility of complex agents exists even in industrial processes and agents. Several recent examples will point the problem. Abrasive soap mix tures may contain fine sand mixed with either acid (viz. oxalic) or with alkalies, potentially altering the effect of the fine silica in the ensuing abrasive soap pneumoconiosis. Printing pressmen may suffer lung disease --the matter is now under study--and both carbon black and oil mists in their environment are being investigated (72,89,94). Respiratory disease as a result of detergent enzyme exposure is another instance of exposure to variable substances (9,38). [To complicate the matter further, the particular substances under con sideration may vary in their effect not only by virtue of the chemical and phys ical nature, but also because of particle size and shape. Long known for par ticles of silica, it has recently been suggested that it may be true for some fibers as well, as fibrous glass (131).] Multiple effects of single agents. The obverse of the multiple factor coin is the fact that some agents, in and of themselves, may have more than one bio logical effech Asbestos can ~> oduce pulnu-ii .r fibiosis and cincer (vide infra). Both aluminum dust and diatomaceous earth may result in fibrosis and spontaneous pneumothorax. There is some evidence that cotton workers have not only reversible bronchial physiological effects but may have some "non specific" anatomical changes as well, and farmer's lung, as other varieties of extrinsic allergic alveplitis, may be marked both by bronchial disease and notable pulmonary fibrosis (113). Radiation can produce both fibrosis as well as cancer (63), manganese may produce Parkinsonism as well as pneumo nitis (128), while caisson workers are subject to lung as well as bone changes (81). Nonfibrotic pulmonary disease. The recognition of the importance of oc cupational factors in pulmonary disease other than that characterized by fibrosis was delayed, possibly by the fact that the findings resembled those which are noted in nonoccupational settings, as bronchitis and emphysema (53,107)2. This difficulty may be a real one, since tissues can respond to a vari ety of insults in a limited number of ways (39). However, careful occupational 2 The importance of the problem may be appreciated by recognition that chronic bronchitis and emphysema are currently more important than silicosis among white gold miners in South Africa (20) . A 028 3 7 UCC 015460 in i the ori.i- i conhist. .iliire ogni.iiiiug .HUMininp. Ainum miosis >ation. i*s and ip mix>r with nasive matter niment Urgent stances .ierconul phys(or paror some >r .ot. '; one bio.er (vide irosis and kers have me "non.ii ieties of case and -is as well pneumo1 as bone -. 4- ;i I I r t { i ^ j .nee of octerized by bled those mphysema ;.d to a varicupational nmchitis and South Africa OCCUPATIONAL LUNG DISEASE *117 ! -,ir>', especially that detailing work exposures two, three, or more decades i . ue, can help identify occupational factors, and we may anticipate that, so ...--ted, we will leam much more about specificity of "nonspecific" syn- .mes than we now appreciate. This is very likely to be the case with respirat n disease among cotton workers, now that its importance in the United - es has been recognized (13). "vonchial changes --functional or structural -- have been little studied, iough they seemingly underlie much disability in such conditions as bys... isis, bronchitis with physical and chemical agents, detergent enzyme exi-ure, and the variety of syndromes (largely in response to exposure to . i r.inic materials) gathered under the rubric of extrinsic allergic alveolitis 'll.97). These include such increasingly common categories as cork (su; :osis) (5) and farmer's lung (29,43), as well as esoteric varieties, as paprikalitter's, or smallpox-handler's lung, or maple-bark disease, or that associated > th redwood dust (sequoiosis). Sometimes, particles of the offending agent . l> be retained in the lung [furrier's lung (100)]; other times, the exposure is . anescent. Recently, particular attention has been paid to small-airway :i-ease in occupational lung syndromes, both those found with organic mater.ils, such as cotton dust, as well as with pneumoconiotic dusts, such as asi-stos or coal. This is likely to prove a very fertile field for research (78,104). Acute occupational lung disease, again largely resulting from bronchial .-actions, may be found in metal fume feveT and with isocyanates (114). , -ually short-lived in the former, they may be life-threatening with the latter, and their recognition important, since the affected individuals often should . vst a\oid further exposure. Death may also follow paraquat poisoning; here, progressive fibroblastic alveolitis is at fault (26). Uncommon pulmonary abnormalities observed in an occupational environ ment include cystic changes occuring following hyperbaric exposures, as with caisson aisease. Xo. infrequently, the roentgenological appearance is compli cated by concurrent pulmonary fibrosis. Since the workers 'nvolved often "have pneumoconiotic dust exposure as well, in tunnel and caisson work. Occupational lung cancer. The possibility that toxic inhalants in the work place could lead to lung cancer has long been considered, especially with regard to silicosis. There was a general consensus, however, that the in cidence of this neoplasm was not increased in such circumstances; indeed, die likelihood of its occurrence among coal miners was found to be less than expected. Against this background, data suggested an increased incidence among hematite miners (14,37). Within the past two decades, the clear demonstration that lung cancer and other intrathoracic neoplasms could occur in excess as a result of occupational exposures has turned the situation around. With some exposures, a neoplastic hazard now outweighs other pathological effects both in frequency and impor tance. This is true, for example, with fluoride mining (28), asbestos (30,117,121), uranium mining (75), nickel smelting (44,133), talc mining and milling (61), and chromate production (64). The forecast inherent in the 1879 observations (51) in Schneeberg have been borne out; perhaps this hazard un derlay Agricola's description of pulmonary disease in the same mines almost lour centuries before (1,56). 418 IRVING J. SELIKOFF Even coal mining is no longer without suspicion (90), and recent observa tions suggest that the question needs to be restudied. In such investigations, the possibility of multiple factor etiology will have to be taken into account, especially the potentiating effect of dust exposures on the lung cancer risk as sociated with cigarette smoking (75,121). A special circumstance of particular interest in recent years has been the occurrence of pleural neoplasms associated with occupational dust exposure (asbestos). Pleural mesothelioma has until recently been extraordinarily rare, with only infrequent cases being seen since the classic modem description of the tumor in 1931 (62). Its occurrence with asbestos exposure (139) --coupled with the wide use of this material --has made this a common problem in oc cupational lung disease practice (119). In several cohorts of asbestos workers studied by us, more than 5% of all deaths were the result of mesothelioma, j pleural and peritoneal (122). Two features of this complication of asbestos exposure have resulted in much concern. First, spreading rapidly over the en tire pleural surface, it has proven invariably fatal (Fig. 1). Second, it may occur with no radiological evidence at all of asbestosis, indicating that the extent of exposure necessary for the development of asbestosis might be quite different from that needed to initiate mesothelioma, with very much less dust pro ducing the tumor. As a practical consequence, dust control measures, de signed to keep exposures low enough to prevent asbestosis, might be inade quate to prevent pulmonary and pleural neoplasms. Pleural disease. Pleural changes as an important accompaniment of occupa tional lung disease has been recognized for more than three decades but have gained prominence only within the recent past. A variety ofconditions may be seen, ranging from spontaneous pneumothorax complicating diatomaceous earth pneumoconiosis or aluniinosis to the fibrotic pleural plaques, diffuse pleural thickening and pleural calcification of asbestosis, talcosis, and mica pneumoconiosis (115,126). The importance of this appreciation is emphasized by tlit Tecent inch sio. of major categories o pleural disease ir the revi: ed classification of radiographs of pneumoconiosis of the International Labor Of fice (57). From the diagnostic and therapeutic points of view, also, this emphasis is well deserved. Pleural calcification can provide a most valuable "marker" for prior asbestos exposure (60), and fibrotic pleural plaques, especially on the diaphragm, can serve the same purpose. Such stigmata may be very limited in extent, often only a tiny fleck of calcification on the costal or diaphragmatic pleura. When fibrosis is diffuse and extensive, it may occasionally cause severe respiratory insufficiency (Figs. 2 and 3). If, in such circumstances, the pulmonary parenchyma is not unduly compromised, pleural decortication can be an effective therapeutic measure. Active intervention for the management of spontaneous pneumothorax in patients with diatomaceous earth pneumo coniosis or aluminosis (Fig. 4) can also be life-saving, especially since sponta neous pneumothorax is an important cause of death among workers with ex tensive diatomaceous earth pneumoconiosis. Reference has been made to neoplastic pleural complications associated with occupational asbestos exposure. This has also been observed among talc UCC 015462 A 0283 j observa. 'tigations, :> account, _er risk as- been the exposure . -iarily rare, 'C-ription of -i --coupled >lem in oc-:os workers thelioma, 4 of asbestos Aertheen.: may occur :he extent of te different -> dust prorasures, de_ ht be inade- -r , t :.t of occupa. :les but have :ions may be .atomaceous :ues, diffuse -is. and mica - emphasized :. the revised :.al Labor Of- ..... j k- j .-. y , .y. i -j emphasis is "marker" for - - tally on the r> limited in h.tphragmatic onally cause -[Stances, the rtication can management ,:th pneumo-ince spontarkers with ex- '"y ! . j ,?" . y. r" j rj h.. J as associated sjjjje. cd among talc if' Fic. Pleural mesothelioma in an asbestos insulation worker. Tumor characteristically envelopes entire lung, including costa), inediasu.ial, and diaphragmjt c aspects. --xt -iA isprecluded successful surgical approach. Chest X ray a year before had shown no evident disease, and right hemithorax of this film still demonstrates no asbestosis. Mesothelioma may occur as a result of exposure insufficient to produce pulmonary fibrosis (asbestosis). workers. Among them, too, mesothelioma may be the result of asbestos ex posure since asbestos contamination of the talc ores is a common occurrence. Experimentally, a variety of dusts, including fibrous glass, produce mesothe lioma (131), and the possibility that these might do so following occupational exposures is being studied. Extrapulmonary effects of occupational pulmonary disease. It has long been known that there can be extrapulmonary dissemination of inhaled dusts and chemicals. Pulmonary deposition of particles is largely of a size smaller than 5 pm diam, well within the capacity of tissue capillaries carrying 7-p.m red blood cells. Macrophage ingestion and transport is an important mecha nism. Further, systematic effects, especially those associated with im munological changes (16,137), need not depend on lymphohemotogenous dis semination. 40284c UCC 015463 t. H. >:fi! j I, i t ] `/ . ;j v- i UCC 015464 OCCUPATIONAL LL'NG DISEASE ; ! S Il 421 \ V I I 1 I a cuirass. recent past, >n and study lie appreci.'.s described and this -iici factor in evidence of >al workers iation with neoplasms - ! 140), coal a! mesothenrlication of h underlie that the Fic. 3. Death occurred of pulmonary insufficiency. Function was impaired both by the diffuse interstitial parenchymal fibrosis, also present, and the restrictive effect of the pleural thickening. Generally, parenchyma] disease has the more important bearing on the outcome. physical presence of inorganic microparticles plays an important part, dissem ination occurring either through the gastrointestinal tract (Fig. 5) or by lymphohematogenous dissemination (Fig. 6). In the former, the phenomenon of persorption may have pathogenetic significance (138). The demonstration that the surfaces of a number of inorganic particles, such as fibrous glass and asbestos, may alter Hageman factor metabolism (102) similarly opens a wide area for investigation. A surface effect may be responsi ble for the hemolytic properties in in vitro red cell systems of a large variety of inorganic particles of occupational importance. This, too, is now actively being investigated (112). Quantity and quality. It has long been well understood that there is no "allor-none" law applicable to occupational lung disease but that the likelihood of clinical change of consequence depends upon the level of exposure, modified by such variants as total duration of exposure and duration from &02b4? UCC 015465 it 422 IRVING J. SELIKOFF Fig. 4. Spontaneous pneumothorax in patient with aluminosis. This may be life-threatening complication. This complication may also occur in the course of diatomaceous earth pneumoco niosis, with the same significance. FlC. 5. Transmission electron micrograph of colonic tissue obtained from an asbestos worker. Small fibrils of chrysotile (arrows) and fragments of clay minerals (marked C) are observed Mag nification as marked. 402643 UCC 015466 OCCUPATIONAL LUNC DISEASE 423 FlC. 6. Chrysotile fibrils in liver of asbestos factory worker, demonstrating lymphohem.itongenous dissemination. The unit fibrils are 200--400 A in diameter and cannot be seen by optica! microscopy. Electron micrograph, x 10,000. onset of exposure (see below). Within limits, such dose-disease response rela tionships are consistent and underlie the concept of Threshold Limit Val ues (3). In some circumstances, however, the relationship is hardly straightline. UCC 015467 A02844 * *ST' I* ir- ft 424 IRVING J. SELIKOFF with few or no qualitative effects seen until one reaches a very marked quan titative shift. Quantity becomes associated with qualitative differences. One reason for this is that two different physiological and pathogenetic processes are involved. Clearance mechanisms ordinarily may be entirely adequate to prevent undue accumulations of dust, whatever their fibrogenic potential. When such clearance mechanisms are overwhelmed, however, the inhaled dusts may then produce significant changes. Such mechanisms have been in voked in coal workers' pneumoconiosis, nepheline lung, graphite pneumoco niosis, as well as with instances of lung disease with kaolin or talc exposures. Carbon black, increasingly used in industry, may also have such an effect. An analogous situation exists with exposures to irritating fumes and vapors. Here, the repair processes of bronchial and alveolar tissues can be out stripped. A world offine particles (135). The past two decades have seen consider able interaction between conceptual advances in biological research and the availability of new analytical instruments and techniques. This is true in the field of pneumoconiosis as well. Until recently, histopathological studies have been limited by the power of resolution of the optical microscope, capable of demonstrating particles 0.5-5.0 pm or larger. Inability to detect particles smaller than 0.5 pm was not considered a serious limitation, since aerody namic theory predicted that particles smaller in effective diameter were unlikely to be deposited in the lung, even if they should be present in the inspired air. It is now realized that this is an inadequate approach, and the availability of the electron microscope offers an exceedingly important new direction for research, with relevance not only to industrial lung disease, but to atmospheric pollution, as well. It may tum out that particles visible by light microscopy play a relatively minor role in human disease. Submicron particles almost invariably accompany them and may have much greater pathogenetic significance; for a given mass their surface area is very much greater. The sub ject is largely unstudied. In many instances, optically visible particles are ab sent, yet disease occurs v, ith the presence o- particles in the Angstrom range (87). New techniques allow not only the demonstration of such particles, but their unique identification as well (65-69). And recent aerodynamic consider ations indicate that a very significant proportion of submicron fibers are likely to be deposited in the lung (Figs. 7-8) (50). Community effects associated with occupational lung disease. It was not until the serious consequences of neighborhood beryllium disease were clari fied that the important potential of community exposure to pneumoconiotic dusts (and other industrial materials) was widely recognized (18,33). In the recent past, there has been growing interest in this problem, ranging from studies concerning the health effects on children of cement and similar dusts in Romania (76) and neighborhood byssinosis in Egypt (8) to environmental asbestos disease (120). The latter has been perhaps best studied and provides ample evidence of the growing potential importance of this accompaniment of occupational lung disease. The first hint that asbestos dust derived from industrial use of the material UCC 015468 A0284b ked quannces. One processes adequate to potential, die inhaled ve been inpneumococ exposures, ich an effect, s and vapors. can be out- j j ! cen considerearch and the - is true in the .1 studies have pe, capable of ctect particles . since aerodydiameter were present in the roach, and the important new ng disease, but , visible by light micron particles tei pathogenetic greater. The subparticles are ab- Angstrom range uch particles, but lynamic consider>n fibers are likely * J . | j -j '/4, i;;; p, ":K~-j > nvefl.se. It was not disease were clari > pneuinoeoniotic red (18,33). In the Jem, ranging from t and similar dusts to environmental udied and provides % accompaniment of ! u se of the material OCCUPATIONAL LUNG DISEASE 435 FlC. T. Transmission electron micrographs oflung tissue from individuals exposed to asbestos oust. .At Talc dust exposure. Chrysotile asbestos fibrils found throughout lung tissue. (B) Worker indirectly exposed to asbestos. These fibrils would not be detected by optical micros copy. Cl Chnic.i' distposis, interstitial fibrosis of unknosvn etiology. Large numbers of chryso::!e fibrils indicates probable intimate expou.ic. History ro` ovni'able. (D) High magnification d C. Lcnzth approximately 1500 A. might be of importance came many years ago when Haddow (45) found as bestos bodies in the lungs of a person living close by an asbestos factory. More recently, the finding of mesothelioma among individuals whose only con tact with asbestos was by virtue of residence within the household of an as bestos worker or by living within a half mile of an asbestos plant, has at tracted much attention (93,139). The practical importance of this question has r een emphasized in the past year by the recommendation by the Occupa tional Safety and Health Administration of the Department of Labor that, in specific circumstances, precautions are required to prevent household con`.amination from dust carried on work clothes or shoes (130). Similarly, the Env ironmental Protection Agency is now considering appropriate regulations to prevent environmental contamination from asbestos mines, mills, and fac tories, as well as from other industrial uses of asbestos. ucc 015469 H02b 426 IHVIXG J. SELIKOFF Fig. 8. Transmission electron micrographs of extrapulmonary tissues. A-D demonstrate par ticles observed in the pancreatic tissue of an asbestos worker with a primary tumor of the pan creas: (A and B) chrysotile asbestos fibrils, (C) diatomaceous earth fragments, (D) fibrous glass fragments, and (E) particles in tissue of ovary in which a malignant neoplasm was present. (F and G) Chrysotile asbestos fibrils obtained from the peritoneal fluids of an asbestos worker with perito, i j! oesrtheiior.ia 'coi.iinn.-d at autopsy). Epidemiological considerations. In general, there is a long-lapsed period between onset of exposure to occupational hazards and the appearance of clinical evidence of occupational lung disease. Sometimes, brief exposures, if followed by a long enough lag period, are sufficient to produce serious disease. In such instances, residence time in the lung is more important than the duration of exposure perhaps decades before (See below). There are ex ceptions, of course, especially with gases, fumes, and vapors causing acute disease; relatively rapid initiation of pneumoconiosis may also occur, as in acute silicosis (15) or abrasive soap pneumoconiosis. Beryllium disease may be associated with both acute bronchitic changes as well as long term fibrosis (79). Excessive exposure to calcined diatomaceous earth may also run a fairly short course, and we have seen death of pulmonary insufficiency following ex posure of sand blasters to high concentrations of quartz or of asbestos factory workers to similar exposures to asbestos, in less than ten years. Even neo plasms of the upper respiratory tract may occur, with at least one occupational substance, bis(chloromethyl)ether, in a relatively few years ^^ UCC 015470 i i icmstTate part of the panfibrous glass present. (F >> wo.vci v> iiii rjsed period oearance of xposures, if ice serious ivortant than here are ex cising acute occur, as in lisease may .'. rm fibrosis run a fairly illowingexfstos factory Even neooccupational '` ; r ( *. X < OCCUPATIONAL LUNG DISEASE 427 Nevertheless, by and large, decades usually elapse between onset of ex posure and evidence of significant disease, especially disabling disease. \ppropriate data are now available for asbestos lung cancer, for example, and t lias been found (122) that increased risk for both this neoplasm and pulmo nary mesothelioma is usually not evident much before 15 years from onset of \posure, with the greatest excess being seen 25-40 years from onset. This ring lag period sets important constraints on epidemiological investigations, -ince the passage of time often diffuses and obscures cause-and-effect rela tionships. Frequently, the worker is no longer employed at the site of original exposure and, equally often, not even in the same industry. The exposures themselves may have changed quantitatively or qualitatively, or have been eliminated. It is possible to mount'appropriate studies; they must, however, be care fully drawn, cover an adequate time period, and be meticulously, diligently, and completely carried out. Many of the lung changes which occur as a result of exposure to occupa tional agents are seen in other circumstances as well--bronchitis, emphy>ema, lung cancer, diffuse interstitial fibrosis, hypersensitivity lung disease. They are rarely unique to the exposure, although pleural calcification and progressive massive fibrosis approach that status. Definition of a risk of oc cupational agents depends, then, on the finding that such diseases are present more frequently among the occupationally exposed. This is no hardship when the excess risk is very great, but if the excess risk is modest, as with perhaps only twofold or threefold increase, its demonstration may be much more dif ficult and will involve the study of considerably larger populations of workers. When we add to this overriding consideration inclusion of such other vari ables as age specificity, relation to duration from onset or variable levels of ex posure, secular changes in the spontaneous occurrence of the disease in con trol populations, or possible efiects of no.icovnitanl or cr .rp^tmg factum, rrm can appreciate the epidemiological insecurities in the study of cause-andeffect relationships associated with some occupational exposures. Of con siderable value has been the demonstration in recent years that investiga tion oflarge exposed populations is entirely feasible. The detection of increased risks among employed populations can provide an important bonus. Many employed groups are exposed in inti mate circumstances and, at fairly high concentrations, to agents to which the general population is also exposed, albeit much more diffusely and at much tower concentrations. The experiences of such occupational groups can then often tell us whether or not the suspect agent might be a general environ mental hazard, as well. If an occupational group exposed at high levels shows a cancer risk, it need not mean that the population at large also has risk, but it would at least give some caution and provide direction to prevent the occupa tional hazard from becoming a general environmental one. On the other hand, if the heavily exposed occupational group has no evidence of excess disease hazard, it would make it much less likely that the general community is at risk. Treatment. In general, treatment for lung disease resulting from exposure to adverse occupational environments follows the precepts and techniques used UCC 015471 A02848 3- : i te .... > :ion: Since night, with ition of the nective de- sing the ef.nce it had leads, how'.roaches are r substance the experipossible that .ire observail properties Whether they FlC. 10. Film, July 2,1958. Shortness of breath had been noted. Patient denied any unusual oc~ CLpAl^Of.?] e::p>sures will also do this in vivo is not yet known, although the use of polyvinylpyridine-N-oxide is now being studied for the treatment of coal workers' pneumoconiosis (143) and in experimental silicosis in baboons (129). Delayed appearance of occupational lung disease. Four factors largely de termine the extent and severity of occupational lung disease: the nature of the agent, the duration and intensity of exposure, and the time from onset of ex posure. The last is particularly important in dust diseases, since exposure of the lung tissue is by no means synonymous with exposure of the individual. Intense exposure to pathogenic dusts by a worker for one day, one week, or one month may provide sufficient lung burden to result, years later, in disease, both fibrotic and/or neoplastic. In the interval, the retained dust, in completely eliminated or altered, exerts its effect on cellular elements with which it is in contact, often injuring a series of phagocytic cells, each unable to metabolize the inorganic particle and succumbing in the process. UCC 015473 r - 130 IRVING J. SELJKOFF Fig. 11. November 11, 1968. Lower lobe fibrosis and pleural calcification made diagnosis of asfce ;t' rir. fry likely. t\t bit ,'a, paFant r memberei hj-'ir.g worked as an asbestos weaver ia a brake lining plant for six months in 1934. Even when the duration of exposure is identical with the duration from onset of exposure (i.e., continuous employment), the biological effects of the lung dust burden of a worker are a composite. The first dust inhaled, let us say, thirty years before, has the effect of a thirty-year-in-residence dust, cap ping the inverted pyramid of its decades of damage. Dust inhaled 20 years before is having a twenty-year-in-residence dust effect, that inhaled 10 years before, a 10-year effect, and so on. Yesterday's dust, although perhaps most readily at hand, best measured and analyzed, is likely also the least related to the disease findings in the individual. Appreciation of this sequence of events leads to a number of conclusions. First, in many instances, disease now being seen is the result of work condi tions in the 1920's, 1930's, and 1940's. Since few environmental measure ments were made in those years, there is considerable difficulty now in de termining dose-disease response relationships for the setting of exposure A02851 UCC 015474 "inosi- nf *s> weave? m a ition from rets of the led, let us dust, capel 20 years el 10 years - haps most related to Delusions, ork condi measurenow in def exposure Fig. 12. June 25, 1971. Continued progression has resulted in pulmonary insufficiency and ret'ement because or disability. This sequence of films demonstrates the importance of progression u ijiout further exposure, decades alter brie.'ini : 2 cccuvitional exposure. standards for the workplace; one-half of the equation is uncertain. By the same token, exposures today will be reflected in disease in the year 2,000, stressing the importance of preventive measures at present. Although we can now undertake environmental evaluation, evaluation of their effectiveness is hampered by the absence of the other half of the equation. Second, from a practical point of view, seeking a possible occupational cause for lung disease is facilitated by investigating work exposures for the entire lifetime of the individual. What he did at age 16 may be much more im portant than his work at 60. A full, detailed occupational history (not merely job classifications) can be far more rewarding than tomograms or closing vol umes or serum protein fractionation (Figs. 9-12). Brief exposure followed by a long period of lung residence may be particu larly important in occupational lung cancer and pleural mesothelioma, since often much less exposure is required to induce neoplasms than pulmonary fibrosis. As a result, many instances of such neoplasms are seen without <hl |i 432 IRY1XG J. SELIKOFF roentgenological evidence of pneumoconiosis, and the relation of the neo plasm to prior occupational exposure may remain obscure unless work ex posures decades before are considered. ACKNOWLEDGMENTS I am grateful to my colleagues in the Environmental Sciences Laboratory for their generous cooperation in many research efforts reflected in the development of concepts expressed here. Particularly, thanks are due to Dr. Arthur M. Langerand his co-workers in the Physical Sciences Section of the Laboratory (Dr. William J. Nicholson, Dr. Arthur X. Rohl, Dr. Carl J. Maggiore, Mrs. Anne D. Mackler and Mr. Ivan B. 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