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State of the Art Asbestos-Related Diseases of the Lung and Other Organs: Their Epidemiology and Implications for Clinical Practice'a MARGARET R. BECKLAKE1 Contents Introduction The Asbestos Minerals Physical Characteristics and Fiber Types Uses of Asbestos: Occupations at Risk Indirect Exposure (Domestic, Neighborhood, En vironmental) Pathology Pathogenesis Clinical Features Radiographic Changes Lung Function Diagnosis Prognosis, Complications, and Medical Manage ment The Fate and Biologic Effects of Inhaled Asbestos Particles ' Deposition in the Lung Pulmonary Clearance ;; ; Penetration, Retention, Distribution, and Mobil- iution of. Uncoated Asbestos Particles within 1; the Lung V- Coated Asbestos Fibers (Asbestos Bodies) '. Cellular Effects - Bose Relationship of Biologic Responses to Asbestos _ Exposure Significance of Uncoated and Coated Fibers in Cliniy: cal Material Pleural Plaques, Hyaline or Calcified , Thickening of the Parietal Pleura) Pathology * t. Epidemiolo--g.y and Pathog-enesis Qinical and Radiologic Manifestations (Fibrotic iVv^ktiral Effusion (Benign) . Bifiuse Interstitial Pulmonary Fibrosis (Asbestosis) definition the Departments of Epidemiology and and of Experimental Medicine, McGill Uni* ari<^ ^TOrB the Department of Medicine, Royal SaC^voona Hospital, Montreal, Quebec, Canada. Requests for reprints should be addressed to De l of Epidemiology and Health, McGill Unih 3/75 University Street, Montreal, Quebec, iate of the Medical Research Council of Malignant Mesothelioma of the Pleura and Peri toneum Pathology Epidemiology: Association with Asbestos Exposure Pathogenesis Clinical Features ' Diagnosis and Treatment Carcinoma of the Lung Associated with Asbestos Exposure Other Asbestos-Related Cancers The Influence of Fiber Type and the Nature of Ex posure on Biologic Response Clinical Implications of the Epidemiologic Findings Introduction Although the fire-resistant qualities of asbestos have been recognized since ancient times (1, 2), its commercial exploitation was modest until the latter part of the nineteenth century, when as a result of the industrial revolution, the need arose to develop the means of insulating the steam engine (2). The discovery in 1877 and subsequent development in the 1880s of the ex tensive chrysotile deposits in eastern Quebec was followed by further exploitation of the al ready known and extensive deposits in the Ural mountains in Russia and of the more limited deposits in Italy and Cyprus (2, 3). The existence of blue asbestos deposits in the Cape (South Africa) was recorded in the early nine- REVIEW OF RESPIRATORY DISEASE. VOLUME 114, 1976 187 I ^>-1 > ;--' ! 1 : ' 188 MARGARET R. BECKLAKE teenth century, but large scale mining only be gan in the past decade. Amosite, discovered in the Transvaal in 1907, was first commercially ex tracted in 1908 (2). Milling of the fiber to re Wtir it t v4 ASBESTOS Whr H I* lAtond Cftrywtil* { lease it from the ore is usually done at the mine- head, and the fiber is then bagged and exported to the factories of the industrialized world, in ttsW particular Britain, other European countries, and the United States. Southern Africa The world sources of production and use of this mineral are shown in figure 1 in a way that underlines the need for worldwide appreciation Otfmartj USSR of its potential threat to health; figure 2 traces the history of medical recognition of its health effects in relation to the commercial exploita tion of the mineral. Thus, adverse effects on health were observed in the early 1900s and first reported in 1907 (1), and it is now recognized that exposure to asbestos may lead to the patho USSR logic conditions listed in table 1. These include fibrosis of varying degrees and virulence of the lungs and pleura; and neoplasms of the lung, pleura, peritoneum, gastrointestinal tract (5 9), and, possibly, the larynx (11-14), ovary (15), and breast (16). Despite legislative action aimed at controlling the health effects in Eu rope and North America (Gilson, 5, p. 696), de leterious effects on health continued to be re ported. Indeed, asbestos-related lung disease has been called "the occupation illness of the 60s," Slut Croeidolife ) SAfrico Anlhophytlilt V; Finland Fig. 1. [From Smither (4); reprinted by permission V;.s of publisher.] Asbestos: where it is mined and where it is used. This figure was based on world consump tion for 1970, estimated at 3,000,000 tons. The fig- ??' ure for 1974 is estimated at 5,100,000 tons, with % ; Russian production now surpassing the production^ . of the western world. purpos< rent ir from ej cations a description that also reflects the extent of cur rent public concern for this health hazard (1). Although recognition of the association be tween asbestos exposure and the various health effects listed in table 1 was made initially by Nevertheless, the practicing physician is often ;,, the first source of medical help for the exposedT?:. person whose health is affected, particularly xf,$the exposure is related to the use, rather than Y': erals to tained York C Asbesto shrewd clinical, pathologic, and epidemiologic production of, asbestos products, or if exposure' V observation, exploration of the nature of the is nonoccupational, i.e., by neighborhood .''or.'? association with asbestos exposure has subse household contact. quently been made by epidemiologic studies. It has been said by Weiss (17) that "thedin^.. Results of such studies are frequently found in ician sees the sick patient against his memories^..: journals of epidemiology, public health, and of individuals with a similar constellation of ah\'- environmental health, rather than in clinical normalities half-buried in his apperceptive^ journals, and in reports of international con background and in relation to what he retails,-.? ferences not covered by the usual clinical refer ence systems, such as the Cumulative Index (5-9). The published proceedings of these con from the literature, usually written by peers the same small field of vision" and thatjb* "founders into erroneous conclusions becati#J*4i ferences, all internationally supported, in keep looks only at the people directly in front of ing with the international nature of asbestos use, By contrast, the epidemiologist sees "the siti provide excellent source material to which ex tient as an impersonal unit in relation to apopj^z.v , tensive reference is made in this review. For this lational universe" and "misses a truth reason, the proceedings of each conference are it is buried in a mass of data." Perhaps^the^ cited only once, in references 5 to 9. Individual remarks apply only to the bad clinician presentations are subsequently identified in the bad epidemiologist. Nevertheless, the text by the name of the first author and page in approach seem to be sufficient to number. view that attempts to bridge the gap; `t| mm eesros Whr W '* w 5.000 2.000 o 1,000 ASBESTOS-RELATED LUNG DISEASES 1920 1980 3,000 ^2.000 i 1,000 189 iher (4); reprinted by permission'll cs -here it is mined and where'S ;ui .s based on world consump-? imated at 3,000,000 tons. The fig-1 estimated at 5,100,000 tons, with; in now surpassing the production* -Id. *K "!^U .lie practicing physician is often; >f medical help for the exposed salth is affected, parcieularlyjf related to the use, rather'than sbestos products, or if exposure >nal, i.e., by neighborhoods* id. by Weiss (17) that "the^clti? ck patient against his tnempng ith a similar constellation of If-buried in his appercepQjR 1 in relation to what he'reSug --s jre, usually written by peew ; field of vision'' erroneous conclusions because ; people directly in frontof epidemiologist sees .rsonal unit in relation to a se" and "misses a trtith^ a mass of data." Perhap* on the bad clinician gis. zvenheless, the di' em to be sufficient to rm^ opts to bridge the gap'Ltd - 1880 1900 *940 Fig. 2. Diagrammatic representation of the growth of the asbestos industry and the recognition of the associated biologic effects. The following symbols indicate the association with asbestos: ? = suspected;i~ ~ I = probable; = established. purpose of the present review is to evaluate cur rent information, particularly that obtained from epidemiologic studies, in light of the impli cations of this knowledge for clinical practice. The Asbestos Minerals Physical Characteristics and Fiber Types The physician may well question the relevance of the physics and chemistry of the asbestos min erals to the state o his art. The answer is con tained in Gilson's summary of the 1964 New York Conference on the "Biological Effects of Asbestos" (5), in which he identified one of the questions requiring further investigation; ``Is the type of asbestos an important factor in the risk of asbestosis, bronchial carcinoma, mesothe lioma, and other tumors?" Because subsequent observations have suggested that this is so (see later in this review), knowledge of the type of asbestos to which a person has been exposed should guide the practicing physician in estab lishing a diagnosis and estimating a prognosis. Asbestos is the general term given to a group of minerals that are fibrous in character and re sistant to high temperatures, the two qualities on which their industrial use depends. The most important commercial fibers (shown in table TABLE 1 PATHOLOGIC EFFECTS OF ASBESTOS EXPOSURE IN MAN Organ Effect Asbestos corns Carcinoma "Asbestos" bodies and/or fibers Diffuse interstitial fibrosis (asbestosis) Carcinoma (bronchial) Hyaline plaques and calcification Hum intestinal tract Malignant mesothelioma Pleural effusion Malignant mesothelioma Neoplasia Carcinoma Carcinoma ear thought to be causal, except where indicated not cause, established. Association with Asbestos Exposure' Established Possible Established Established Cofector with cigarettes Established Establishedf Possible Estabiishedt Established Remotely possible Remotely possible Reference - 5-9 11-14 5-9 . 5-9 5-9 5-9 5-9 10 5-9 5-9 15 16 1 tt 190 MARGARET R. EECKLAKE 2) are chrysotile (a white, usually long, silky fi ber), crocidolite (a harsher blue fiber), amosite (brown and harsh), and anthophyilite, chiefly mined and used in Finland. In addition, some of these fibrous minerals also occur in the bearer rock of mines developed primarily for the exploi tation of other minerals, such as talc, mica (18), and iron, as, for example, in the iron mines at the head of Lake Superior and in Labrador. Differences in- the physical properties of the various fibers determine their particular com mercial usefulness. Thus, for example, chrysotile, which consists of long, mainly pliable fibers that split progressively into finer fibrils, lends it self to incorporation into textiles, whereas croci dolite and amosite, which are more acid resis tant, are of particular value for marine insula tion. Certain asbestos cement products may be made from blends of chrysotile and amosite and/or crocidolite. These differences in the physical properties of the fibers (and in conse quence, in their aerodynamic behavior) may ac count for differences in the health effects of ex posure; indeed, it has been argued that "only by relating experimental biologic evidence with the variations in physical size and form ... can we ultimately arrive at valid medical conclusions" (18). This question is discussed in a later sec tion of the present review. Uses of Asbestos: Occupations at Risk World production and use of asbestos have grown greatly since the late nineteenth century; between 1877 and 1967, asbestos production and use increased from 50 tons to 4,000,000 tons per year, an 80,000-fold increase. For industrial ized countries, such as Britain and the United States, the increase in asbestos use between 1910 and 1970 was 7-foid (18, 19). This reflects in creases in volume of manufactured goods as well as in the variety of uses developed for the ma terial. These are outlined broadly in table 2. Appreciation of the wide variety of uses of asbestos is important to the physician and serves as an indicator of the many occupations poten tially at risk from exposure (table 3). These occupations include asbestos mining, milling, and handling in preparation for its use, either directly (as, for instance, in spraying when mixed with oil) or for its incorporation into the manufacture of a great variety of asbestos-con taining products. The latter may be classified broadly into textiles, asbestos cement and other construction products, paper products, friction materials, and insulation products. It is also used #' in the chemical and plastics industries, where ' "l its binding properties (in particular, the posi- '* tive charge of chrysotile) enhances its union'-.;, with filler and pigment (Lindell, 7, p. 323). ; Once incorporated into manufactured items, ; the fiber is relatively well bound and is there- / fore less likely to pose a health hazard to the many workers who userthe newly manufactured 'v'y products (see Secondary Uses, table 2), so long ~-r. as the product is not sawn, disrupted, or cut any way; however, asbestos fibers are virtually'^1' . indestructible. Thompson, 5, p. 196) aptly de-Jjp'< 1 scribes this as a "half-life of an infinity of 1 years." The fibers may be released into the mosphere again when the original product isre-^0^ * moved, replaced, or destroyed, as may occur the construction and shipbuilding industries, * in connection with demolition, repair, and/ or refitting. Exposures of this sort, particularly'^;.; if they occur in a contained environment, such'-;"' as the hold of a ship undergoing refitting, may v-. involve workers whose primary job has noth-- ing to do with asbestos, e.g., welders or masons.;^. Indeed, failure to appreciate these sources of ex- ) posure in both construction and shipbuilding industries (19, 20) probably accounts for re-emergence of asbestos-related disease in the 1960s. There appears to be no direct infoima-/i%y tion on the numbers of workers at risk in ;5'' different countries, other than an estimate of i-y 250,000 persons for the United States in 1972* (21)- - '" The reason for including the information on'JL the occupations at risk (table 3) in a clinical .V review is to offer the physician an overview of % _ the uses of the mineral, so that when faced^-; with an individual with an illness that asbestos related, he can formulate a systeiriajac enquiry into the person's occupational bbtojTt^v; The physician should thus cover possible sures in mining, milling, and manufactunng^W^j. well as in the application of manufattW^: products containing asbestos, directly, or time of demolition or replacement (19, 26). The physician must not only seek tails of the patient's own jobs, past and but must also ascertain whether this carried out at the side of other jobs involved the handling of asbestos pn or materials, particularly if in a closed 0 ventilated environment. ` r''x :Ss* R^ - i I TABLE! i 2 l s_ 0F_ AS EST0S: p r o p e r t ie s , s o u r c e s , os cement and other er products, friction C?;. oducts. It is also used V'V ics industries, where , particular, the posi- . , enhances its union adell,7, p-S23). manufactured items, bound and is there- p;?L health hazard to the : newly manufactured Jses, table 2), so lngj|||l .1, disrupted, or cut inl||p ,tos fibers are virtually; n, 5, p. 196) aptly de-^ lite of an infinity ofX oe released into the at^g e original product is re-J royed, as may occur inf lipbuilding industries,^ nolition, repair, ^/JjW this sort, particularly^^ j ned environment, such^^^. dergoing refitting, primary job has noth^^.e.g., welders or masonij^ :i- -hese sources of ex-' a and shipbuilding^ bably accounts for( thej s-related disease in the^ o be no direct infornia^ of workers at risk-.in. er than an estimate _ United States in l97^j '. , ding the information^ ; (table 3) in a clinical; Physician an overview^ ral, so that when :h an illness that ma;m n formulate a systemat^ Dn's occupational thus cover possible^Cggj ng, and manufacturing^ ication of manufacw sbestos, directly, or** replacement (l9'Jffcf mst not only seekjngj jwn jobs, past an<^ P^si! lin whether this ^ ie of other workers^" adling of asbestos K arly if in a closed^ > E En In fo rm a tio n co lle cte d b y D r. G raham G ibbs fro m the fo llo w in g reference sources: Zussm an (3 ), Speif and Leinew eber (1 8 ), N. W . H e n d ry , in (5 ), p. 12; R. Gaze, in (5 ), .. 2 3 ; K . V . L in d e ll, in (7 ), p . 3 2 3 . ' ' tN o longer in o p e ra tio n . * * Being phased o u t. !; t .i ! wm. OCCUPATIONS AT RISK FOR ASBESTOS EXPOSURE IN MINING, MILLING, MANUFACTURING, AND SECONDARY USES* Process Products Made or Used Jobs Potentially at Risk Production Mining Milling Handling Rock mining, loading, trucking Crushing, milling Transport workers, dockers, loaders. those who unpack jute sacks (recently replaced with sacks that do not permit fibers to escape) Primary uses in Spray insulation Filler and grouting Manufacturing of Textiles Cement products "Paper" products Friction materials Insulation products Spray of fiber mixed with oil Cloth, curtains, lagging, protective clothing, mailbags, padding. conveyor belts Sheets, pipes, roofing shingles. gutters, ventilation shafts, flower pots Millboard, roofing felt, fine quality electrical papers, flooring felt, fillers Automotive products: gaskets, clutch plates, brake linings Pipe and boiler insulation, bulkhead linings for ships Spray Insulators (construction, shipbuilding) Blending, carding, spinning, twist- .. Ing, winding, braiding, weaving, ' slurry mixing, laminating, mould ing, drying . Blending, slurry preparation, rolling, pressing, pipe cutting ' Application Construction New construction Repair, demolition Shipbuilding Construction Repair, refits -- Boards and tiles; putties, caulk. paints, joint fillers; cement products {tiles, pipes, siding, shingles) Insulation materials Insulation materials {boards. mattresses, cloth) for engines, hull. decks, lagging of ventilation and water pipes, cables Insulation materials, as described for "construction" ... Directly, carpenters, laggers/painters, , tile layers, insulation workers, . sheet metal and heating equipment workers, masons; indirectly all other workers on construction sites, such as plumbers, welders, electricians Demolition workers for all of these .- Laggers, refitters, strippers, steam fitters, tailmakers. joiners, shipwrights, engine fitters, masons, painters, welders, caulkers J. .z Directly, all above jobs on refits, dryv. dock, and other repairs operation* Indirectly, maintenance fitters and repair men, electricians, plumbers, *- welders, carpenters -5^ Automotive industry Manufacture Gaskets, brake linings, ' Installation of brake linings, undercoating gaskets, and so on Repair Gaskets, brake linings, undercoating Service men, brake repairmen, repairmen. auto mechanics * Information collated by Dr. Graham Gibbs from references 2, 3, 18-20, and 22-26. sKjWL^ Indirect Exposure (Domestic, Neighborhood, Enviro nmental) Exposure to asbestos fiber is not confined to the place of work (27); the search for exposure in the background of patients with mesothelioma (10, 28-31) has brought to light several fora* of indirect nonoccupational exposure. Thef currence of mesothelioma in the family bers of asbestos workers led to the recognition^ of indirect domestic exposure; the source JS wti' fa b: e: a] Tc. tl P; P' h: C( 3- jbs Potentially at Risk jading, trucking g ers. dockers, loaders, pack jute sacks aced with sacks that t fibers to escape) prs (construction, ship- 19, spinning, twist3, ^raiding, weaving, -ig, laminating, mould- 'X ry preparation, rolling, . ,:-y >e cutting i,j: - iters, laggers, painters, xpf; sulation workers, nd heating equipment ,ns; indirectly all on*,sstt'ru--c--ti-o--n sites. *uch.-jrsg^; ,elders, electricians kers for all of these s, strippers, steam . ^ kers, joiners, ship- .i-, le fitters, masons, jers, caulkers v-_igj ove jobs on refits, drYJ -ier repairs operations^ ntenance fitters and* metricians, plumbery ienters u brake linings, so on ulXfi ,rake repairmen- to mechanics^ .** light several^ exposure. 1 i the family to the recogoit .e; the soureej is presumed to be the dust brought home in the worker's overalls (10, 31). Likewise, the associa tion between residence near a mine, mill, or factor)- and the occurrence of mesothelioma brought to light the importance of neighborhood exposures (27). Such neighborhood exposure is also presumed to account for occurrence of pleu ral plaques and/or calcification in residents of the mining area of Finland (32). Pleural plaques have also been described in agricultural populations (33-35); in some instances, they have been attributed to the working of soil that contains asbestos fibers, e.g., in Bulgaria (33, 34). The surprisingly high prevalence of asbestos bodies (as evidence of exposure) in routine au topsies indicates an environmental exposure for the residents of most of the larger cities of the world; however, the amounts in the general atmosphere are small (36), and these autopsy find ings should probably be regarded more as an index of exposure rather than of disease poten tial. The Advisory Committee report that fol lowed the Lyon Conference (7) concluded that "there is at present no evidence of lung damage by asbestos to the general public," and "the amount of asbestos in the lungs of members of the general public is very small compared to those occupationally exposed." Finally, attention has recently been directed toward the widespread occurrence of asbestos fibers in certain natural water sources (37-40). An eyent that brought this to the notice of the general public was the discharge of mine tail ings containing fiber into Lake Superior, a source of drinking water to many cities in the center of die North American continent (38). It is now also recognized that fibers also occur in many natural waters, particularly in mining re pons; however, the Advisory Committee report emanating from the Lyon Conference (7) judged there to be no evidence at present of an increased cancer risk resulting from asbestos fibers present in water, beverages or food or in fluids used for the administration of drugs." The question must, however, remain under close Krutiny. Biologic Effects of Inhaled Particles ; . Deposition in the Lung ^cr or nt inhaled asbestos fibers will be ^posited n the lung depends on the aerodybehav>or of the particles, the dimensions of the respiratory tract they enter, and the pat tern of breathing that carries the particles. The aerodynamic behavior of particles is a function mainly of diameter, but also of size, shape, and density. The varying characteristics of commer cially used asbestos fibers make it obvious that the environment to which asbestos workers are exposed will contain particles having great variation in size and composition. These include fibers (so-called if their length is at least 3 times their diameter), which may be long (as long as 200 jim) or short. In addition, a working en vironment is likely to include a range of smaller particles and/or fibers released from the break down and disruption of the primary fiber, as well as those due to any other nonasbestos par ticles added by the mining or industrial pro cess. Inhaled asbestos particles follow the moving airstreams with each inspiration, and, once they make contact with any part of the surface of the airways or airspaces, are not resuspended in the expiratory airstreams (41, 42). Deposition of the larger inhaled particles (more than 5 /xm in di ameter) occurs mainly in the nose (assuming nose breathing) and major airways, owing to inertial impaction and sedimentation. Because of Brownian movement, deposition of the small er particles (less than 1 nm in diameter) occurs mainly in the more peripheral airways and air spaces. This deposition profile is summarized in figure 3. Deposition patterns can be profoundly modi fied by breathing patterns; nose breathing causes a high retention rate, even of small fibers, within the nose (41, 42). However, under work ing conditions, including heat and exertional stress, most workers resort to mouth breathing. Deeper, slower respirations favor a more even distribution of inspired air, and, thus, a more even distribution of inhaled particles. Lung volume also influences distribution and, possi bly, retention patterns, particularly if breathing occurs at less than the normal functional resid ual capacity (FRC) in the range of airway clo sure (43, p. 98). Likewise, there is some evidence that the state of the airways in smokers is such that inhaled particles will penetrate less deeply into the bronchial tree and thus tend to be de posited more centrally than in nonsmokers (44). Pulmonary Clearance Clearance of particles deposited on the mu cous blanket is brisk, with half-times of minutes 194 MARGARET R. BECKLAKE that a system of macrophage recruitment meets onslaughts of free fibers and/or particles. Short fibers (< 5 jim) appear to be readily and com pletely phagocytosed, but long fibers are not, even when attacked by more than one macro phage, which may lead to cell fusion (Allison, 7, p. 89). Clearance of inhaled particles by these mechanisms is believed to be more than 98 per cent effective for most deposited particles (48). % Deposited 0.01 0.05 0.1 0 5 1.0 Um Median OtaneMr. p 5 10 50 Fig. 3. [From Brain and Valberg (42); reprinted by permission of publisher; copyright 1974, American Medical Association.] Aerosol deposition in res piratory tract. The percentage aerosol deposited was calculated from the assumptions in the model re ferred to above for a tidal volume of 1,450 ml and a frequency of 15 breaths per min. The profile of depo sition of an aerosol is influenced by its effective aerodynamic behavior that (since the distribution of mass for many aerosols is log-normal) may be de scribed by the mass median diameter of the aerosol and its geometric standard deviation. In this figure, per cent aerosol deposited is related directly to the mass median diameter, whereas the 2 lines referring to each lung 2one (i.e., N-P, T-B, and P, respectively) indicate the differences in per cent deposition that would result if the geometric standard deviation of the mass median diameter varied from 1.2 to 4.5 ft. N-P = nasopharyngeal surface; T-B = ciliated tra cheobronchial surface; P = nonciliated pulmonary surface. to hours. Mucus and cells from nonciliated air ways bearing ingested particles from the major airways are cleared to the pharynx; the material trapped in the nose is also cleared to the pharynx. Here, pulmonary and nasal debris mix with saliva and are swallowed or expectorated (42). This phase of clearance does not appear to be affected by the presence of asbestos lung disease (45) and, under certain circumstances, the ef fects of smoking in producing bronchitis may even speed this phase of clearance (46,47). Particles deposited in the nonciliated regions may be cleared relatively rapidly if they remain on the surface (with a half-time of 24 hours), but once they penetrate fixed tissues, clearance is slowed, with half-times ranging from days to thousands of days (42). It has also been sug gested that macrophages decrease the likelihood of fibers penetrating the alveolar walls (42), and Penetration, Retention, Distribution, and . Mobilization of Uncoated Asbestos Particles ' within the Lung . The use of electron microscopy has revealed the presence of many, many submicroscopic, un coated asbestos fibers and fibrils in the lung substance of the exposed worker, far more than was ever imagined when the lung fiber popula tion was evaluated by light microscopy alone (49-51). It is also now evident that the pro portion of uncoated to coated fibers (i.e., those that form the core of an asbestos body) is very large, of the order of 75 per cent (49), an obser vation that suggests a very high penetration and retention rate for the submicroscopic particles released into the working environment. Alter natively, these small fibers and/or particles might represent the breakdown products of what were initially larger fibers that had pene trated the alveolar parts of the lung. A second reason for underestimation of the amount of as bestos fiber retained in the lung is the difficulty encountered in its recovery from lungs at au topsy, compared to that of other pneumoconio sis-producing dusts (Nagelschmidt, 5, p. 64). The difficulty in recovery applies more to chrysotile than to other fibers, presumably be cause of its greater solubility (magnesium, in particular, tends to be leached out) and, hence, its tendency to break down chemically and physically after prolonged residence (51). Within the lung, there appears to be a ten* . dency for fibers to accumulate in the peripfi;. eral regions of the lower zones as indicated by ., the early appearance of fibrotic reactions -J these areas. This distribution has been attributed to posture and gravity effects (Thomson, 9, p-_ 138). 7 Most uncoated particles that have penetiateO v the lung tissue appear likely to remain whete^ they are, particularly if they are intracellular;- Some clearance does occur via lymph chann?** r to hilar and mediastinal nodes, where coat . and uncoated particles are seen (Hourihane, 5, p. 647), although this appears to be less tb* ,-ecruitmem meets ad/or panicles- Short be readily and com- long fibers are not, lore than one macrocell fusion (Allison, 7, led panicles by these to be more than 98 >sc deposited particles I J| j , Distribution, and led Asbestos Particles Lung . i microscopy has revealed ( nany submicroscopic, un- ' ' ->nd fibrils in the lung V worker, far more than the King fiber popula- -.rcj light microscopy alone 'V- evident that the procoated fibers (i.e., those n asbestos body) is very per cent (49), an obserry high penetration and '' ' .v"v ubmicroscopic particles n? environment. Alterfi and/or particles jrecisdown products of :?'<> er fibers that had pene s of the lung. A second :yjjr. ion of tile amount of a the lung is the difficulty >very from lungs at au : of other pneumoconioiogelschmidt, 5, p- 64)- > >very applies more r fibers, presumably be-}W:l lubiiity (magnesium, leaclied out) and, hen/||i|y: down chemically ed residence (51). ire appears to be a cumulate in the er zones as indicated pjM of fibrotic reactioiw^p ution has been a{tribute^ effects (Thomson, 9% **3,-54^ cles that have penetra^^ likely to remain if they are inmcdfgyjl ccur via lymph chanpp* nal nodes, wherej*'* rs seen (HoiinJ is , . ,ears to be less.* ASBESTOS-RELATED LUNG DISEASES in the case of other fibrogenic dusts, such as sil ica. This difference in clearance attributed to the greater cytotoxic effect of silica, which tends, therefore, to maintain an extracellular position (50), may explain why hilar node enlargement is a more consistent finding in association with silica exposure than in association with asbestos exposure (52). Less is known about the penetration of in gested fibers through the wall of the gastro intestinal tract, although animal studies suggest that this does not occur (53), except in the face of a heavy load delivered directly into the stomach (40). What relevance this has to human, disease, such as peritoneal mesothelioma, re mains to be determined. Once it has penetrated the 'lung, the dust appears to remain fixed, but may be remobilized, apparently even from dust macules or scars, the operative mechanism perhaps being episodes of pulmonary edema and/or infection (48). It is believed that such remobilization of dust may result in its excretion, a phenomenon that might explain the rare event of apparent re gression of radiologic changes in the worker removed from exposure (Manfreda, Y.: Unpub lished data). Alternatively, it may become re sequestered and contribute to the extension of disease in the face of no further exposure. Despite the fact that pleural reactions (effu sion, fibrosis, and/or calcification and neo plasm) are common manifestations of asbestos exposure, there is little direct evidence as to how the asbestos gains access to the pleura, which presumably must happen to explain the pleural reactions. Asbestos bodies are rarely seen in the visceral pleura and have never been reported in plaques located in the parietal pleura of ex posed persons, even though they may be readily found in the interstitial tissue of the same lung (54). By contrast, asbestos fragments have been found in mesotheliomas even without evi dence of asbestosis or coated fibers in the lung (Hourihane, 5, p. 647). This has led to the suggestion that fibers that become coated in the lung are less mobile and less susceptible to lymphatic clearance than uncoated fibers. Thus, *ltron microscopic studies may reveal many re uncoated fibers in the pleura than antici pated from the scarcity of coated fibers. Alter***d'ely, any fibers that are cleared to subpleural y^tphatics may undergo dissolution more *1) here than elsewhere in the lung. In any information that would shed light on this 0x wight well lead to improved under standing of the factors underlying the pathogen esis of mesothelioma. Coated Asbestos Fibers (Asbestos Bodies) The coated asbestos fiber was recognized early in the 1900s, because of its characteristic ap pearance under light microscopy (55). It is usu ally a rod-shaped structure with clubbed ends, often beaded along its length, is yellow to brown in color, ranges in length from 10 to 30 ^m and in thickness from 1 to 6 /*m, and has a central, paler core. The coating, consisting of ferritin granules and an amorphous ma terial, probably protein, varies in thickness from very thin to 5 nm (55-57). On the basis of animal studies, coating is now believed to be an intracellular process and fol lows the engulfing of particles by macrophages to which they adhere (56). Several macrophages may fuse to engulf large fibers. It is while the fibers are surrounded by partially fused ma crophages that coating begins (58). The fiber then becomes incorporated into intracytoplasmic vacuoles, and the first coating material appears to be some form of acid mucopolysac charide (56). Iron in the form of hemosiderin then accumulates in the cytoplasm of the ma crophage. Iron micelles, possibly derived from breakdown of hemoglobin, become subsequent ly incorporated into the phagosomes, and tend to concentrate around the fiber; eventually, there is clearing of ground substance (57). It is of interest that the process appears to be a pro gressive one, with the coating increasing with time and uncoated fibers becoming coated months or years after instillation (56); how ever, because the proportion of uncoated to coated fibers in human lungs appears to remain constant with time (49, 59), there must also be a parallel process of aging and dissolution of the coated fiber. There is some evidence that the coating of a fiber renders it nonftbrogenic. Why some particles become coated and others do not is not understood; however, size may be important, with the typical asbestos body devel oping only on large particles (greater than 5 ura) that cannot be completely engulfed by one macrophage (58). It must also be emphasized that noc all coated fibers seen in the lung have an asbestos core, and the process of coating is apparently used by the lung in response to a variety of other fibers encountered in the environment. These include glass and cotton fibers, diatomaceous earth, talc, graphite, and carborundum particles (10, 55). m `wt. !* .i-jl f & 196 MARGARET R. BECKLAKE For this reason, the noncommittal term, "fer ruginous" body (60), has been suggested as a more exact description in the absence of posi tive identification of the fiber core. Although accurate identification is now possible using techniques like the electron beam, laser mi croprobes, ultrasonic disintegration, and mass spectroscopy (55), these techniques are expen sive in time and money and will remain re search tools for a while (Langer, 7, p. 119). As such, however, they have brought to light cer tain interesting facts. For instance, it has been shown that although all fiber types may become coated in the laboratory animal (56), in man it is the amphibole fiber that is found more fre quently as the core of a ferruginous body than the chrysotile fiber (49, 59), even when both types of uncoated fiber are seen in the lung (Pooley 1, p. 222). The significance of this ob servation remains to be determined; it may sim ply represent the relatively high solubility of chrysotile in relation to the other asbestos fibers. Cellular Effects Neither the original theory that the fibrogenic effect of asbestos fibers and particles was due to physical irritation nor the solubility theory, attributing their action to leached-out metal ions and/or silicic acid, can satisfactorily explain all of the experimental and clinical observations (Wagner, 5, p. 691). This leads to the hypothe sis that host factors, in particular the immune system, might be important, either because of the production or localization of abnormal globulins in alveolar phagocytes or fibroblasts, or because of autoantibodies developing in re sponse to lysis of phagocytes. The use of tissue and cell culture techniques has further increased understanding of the bio logic effects of asbestos at the cellular level (Al lison, 7, p. 89). Potential target cells in man are the macrophages (which are responsible for phagocytosis), mesothelial cells, alveolar epithelial cells (which may undergo malignant transformation), and fibroblasts (which partici pate in the fibrogenic reaction). Two types of cytogenic effects have been detected, an early one attributed to the interaction of asbestos with the cellular membrane, increasing perme ability (a reaction that is inhibited by serum and other biologic macromolecules), and a late reaction attributed to inter-reaction of the al ready ingested particles with the membranes around the secondary lysosomes. Because of the findings of similar direct cytotoxic effects on macrophages and mesothelial cells, but much . less often on the fibroblast, it is believed that fibrogenesis may therefore be evoked through the macrophage response. In addition, there . are differences between the various asbestos types in their cytotoxic effects, chrysotile show- . .. ing more potent cytoxicity and capacity for he- , molysis than amosite and crocidolite. Effects at the organ level are presumed to re suit from the numbers of cells involved, the sites ... of their accumulation (e.g., the tendency for ' macrophages to aggregate in peribronchiolar . ... locations), and the cumulative effects of con tinued assault from inhaled fibers and parti- * cles. It is not known whether the development of such changes is determined primarily by the amount of dust accumulated in the lung (to be " ' discussed in detail under Dose Relationship) / or whether it depends to an important extent on a person's biologic susceptibility. Expert- ments in animals and epidemiologic data in man suggest that both are important. The rele vant evidence will be considered separately un- - der the various asbestos-related lung diseases. . .-- Dose Relationship of Biological Responses to ; .. Asbestos Exposure .\ . The concept of a dose relationship of response . to stimulus, already familiar in pharmacology, ; was introduced by Hatch (61) in an effort to , . throw light on the nature of the apparent varia- ;; tion in the biologic response to inhaled dust, y.-- (Why is one person affected and not the man who works beside him?) Its importance is obvi-. ous, not only as a tool for explaining variations in biologic response, but for the very practical `;r ^ reason that inherent in a dose relationship lies the information for a logical and scien-.^'^ tific basis on which to establish the criteria for ^4- environmental control. Moreover, without such^.J.-, a relationship, the association between dose and^V^;; response is probably not causal. - Hatch's concept (61), illustrated in figure 4,^ ^ - takes into account the possibility of differences^^ in responsiveness between persons (or. be^*, /' tween populations) by introducing the third diy tmension. The implication is that a given dose-^, response curve can be developed for a g*vCIV|^ person (or population), but that it will be.aptgg*.- plicable only to another person (or populationjj^/. of the same "susceptibility." In this context, ceptibility might be related to any of biologic characteristics, for instance, the cy of clearance mechanisms in the lung.j^^ anatomic characteristics of the lung/airway.sygj ` Fig. 4. tnissio Medic lation trays i of susdose ; sothelial cells, but much oblast, it is believed that efore be evoked through ionse. In addition, there een the various asbestos tic effects, chrysotile showxicity and capacity for he- md crocidolite. i level are presumed to re 's of cells involved, the sites on (e.g., the tendency for tgregate in peribronchiolar : cumulative effects of con n inhaled fibers and parti n whether the development determined primarily by the iL, jjnulated in tire lung (to be ;J| under Dose Relationship) VvJPf nds to an important extent logic susceptibility. Expertand epidemiologic data in oth are important. The rele- ":'^^%v be considered separately unstos-related lung diseases, i | < ^logical Responses to ; dose relationship of response ^ ly familiar in pharmacology,1? Hatch (61) in an effort to', nature of the apparent varia ble response to inhaled dust on affected and not the man him?) Its importance is obyi- tool for explaining variations!; lse, but for the very practical; .rent in a dose relationship ion for a logical and stiem ch to establish the criteria!for mtrol. Moreover, without such e association between dose and biy not causal. sisiSgj ot (61), illustrated in figure,^, nt the possibility of difference| ss between persons (orib^s ns) by introducing the thirddi- nplication is that a given can be developed for a olation), but that it will be^apj another person (or popula^^ ceptibility." In this context,;*! it * related to any ex , for instance, the e5g< mechanisms in the lung^! cteristics of the lung/airvvaV Fig. 4. (Modified from Hatch (61); reprinted by per mission of publisher; copyright 1968, American Medical Association.) Dose response for a popu lation. The curve on the horizontal plane por trays the dose-response relationship for a population of susceptibility such that 50 per cent respond to the dose indicated by the dotted line. If only 25 per cent xvere responsive to that dose, the curve would be proportionately displaced downward toward the dose axis; if 75 per-cent were responsive, it would be appropriately displaced upward. tem, or the physical fitness of the person (less fit persons ventilate more for a given work load). Alternatively, susceptibility might be con sidered in the immunologic sense. A major problem, however, in applying the dose-response concept to the study of asbestosrelated disease in animals and man lies in the measurement of dose. Presumably, the relevant dose (in Hatch's terms, the dose delivered at the critical site in the body) is the amount of asbes tos dust and fiber retained in the lung, i.e., the amount inhaled less the amount exhaled and/ or cleared from the lung. Although estimates of the amount inhaled can be derived from direct . measurements of dust and fiber in the working Environment and from ventilation volume, there is no practical way to measure the amount of dust exhaled and/or cleared from the lung, either in the laboratory animal or in . #Un. Thus, at best, it is possible to measure (or I estimate) only the first one half of tire dose equa- t*e., the concentration and amount of dust (in Hatch's terms, the magnitude iJj exposure to external conditions that give rise =o stress). . "This shortcoming is perhaps less crucial under experimental conditions in which animals can be raised throughout life in environments with different, but known and constant, dust con centrations. Such studies have, in general, shown dose relationships for amount of fibrosis and can cer risk (62). In addition, it seems possible that mathematical computation, taking into account intermittency and pulse exposures (42), may enable future studies to make even better esti mates of dose. In epidemiologic studies, estimates of dose have had to be much more crude, being based on the number of years of service in an industry (63-68); the number of years since first expo sure (63, 69, 70); or the total years of exposure, together with an estimate of the dustiness of a worker's job (71-79); or cumulative dust ex posure calculated from dust concentrations for given jobs. Doses may be calculated for each individual worker on the basis of his or her work history (80-95), or for groups of workers in given jobs in a given industry (96-98). In all of these studies, there has been the problem of calculating the dose for workers whose expo sure usually extended into the remote past, with information about dust concentrations being at best scanty and incomplete and in most in stances nonexistent. Despite the shortcomings of the methods for estimating dose, a relationship of estimated dose to response has, nevertheless, been a consistent finding (table 4). This consistency has been true with exposures encountered in mining, manufacturing, and secondary usage, including removal of old asbestos insulation. Furthermore it applied to all of the responses examined, i.e. lung fibrosis, as reflected by symptoms (64, 77 92), lung function (64, 78, 84, 87) and radio graphic changes (65, 69, 88, 95), and lung can cer, as reflected in mortality statistics (63, 66 68, 71, 74, 77, 79-83, 85, 93). For mesothelioma, in which much less exposure seems to be capable of producing a response in certain circumstances (see neighborhood and domestic exposure), there is also some evidence for a dose effect us ing fiber counts in the lungs at autopsy as a measure of exposure. A more complete discus sion of dose-response relationships follows in the sections devoted to various asbestos-related lung diseases. It must be pointed out that although doseresponse relationships are evident to a greater or lesser extent for all responses, the degree of cor relation is surprisingly low, perhaps because one seldom, if ever, finds more than a 50 per cent 198 MARGARET R. BECKLAKF response rate, even in those exposed to the heavi est doses. In addition, the response is usually the result of past, rather than current, expo sures. This poor correlation has led to the current interest in "susceptibility," i.e., factors account ing for between-subject differences in response. The concept of the dose-response relation ship, insofar as it applies to exposed workers, can be explored only by studies that use epi demiologic techniques and consider all of those at risk. Of what relevance is the concept of doseresponse to a physician dealing with the health problems of an individual patient? In the first place, knowledge of dose-response relationships may provide the answer to why a particular pa tient was at risk; second, this information may alert the physician to the potential risk to other workers; third, it may have importance in establishing prognosis and determining man agement. Thus, in the detailed descriptions of the various asbestos-related lung diseases that fol low, their relationship to exposure dose, and possible differences in the dose-response rela tionships of the various fiber types will be dis cussed and summarized in the final section in terms of the implications to the physician. Significance of Coated and Uncoated Fibers in Clinical Material The presence of ferruginous bodies (so called in this section because positive identification of the fiber core has been undertaken in only a few of the more recent studies) or coated fibers in biologic material derived from persons who are occupationally exposed to asbestos has long been recognized as a hallmark of exposure (55). Their presence in routine autopsy material, first reported from Cape Town, South Africa (99), has subsequently been confirmed in many countries, in urban and rural communities, in all parts of the world, in fact, whenever sought (table 5). Prevalence tends to increase with the vigor of the search and depends on the amount TABLE 4 LISTING OF STUDIES* THAT SHOW A DOSE RELATIONSHIP . BETWEEN ESTIMATED EXPOSURE* TO ASBESTOS AND BIOLOGIC RESPONSE he dose-response relariber types will be dis.n die final section in o the physician. md Uncoated Fibers in nous bodies (so called ositive identification of ndertaken in only a few ies) or coated fibers in d from persons who are to asbestos has long been nark of exposure (55)., utine autopsy material, ;pe Town, South Africa been confirmed in many 1 rural communities, in n fact, whenever sought ids to increase with the depends on the amount V*.. SHIP C RESPONSE <N r> 10 <0 C> CO <0 - -j - oooooo>-3Oot-f-O3 c a. q n n n n O C) ^ r- r- - ffifflffiffloiQffloioioiffifflfliaoia n<0 ^<0 1in0 <D G> Cl 0) O o <0 a ^ <9 <0 <0 W' WE W OTW WWWWW aw 5E m to f? c c C c S .2 .$ .2 .2 cC 0O O0*0 <n in io in tn W-1 VUJ) CO r <I- m2O iDn O 2 (3 D cc CL " 2 W * " 2 * * * I * I ^ ^ " ci n os -t r-' O' qoqqT<vcootno(\woo'o oor255 o 2 CO > Ec o nN oi- o- _iO"-O0O00O0^)O0O00O1O0O0 O OO IfD. *- 01 CO UJ .2 1<0 3 XZ0 < c cra UceJo *~> 1 VcCO V0 B5) % E 3 < c h50 <<0 E Vc BHcI c > 5 "5 0 B Vc 2 < W - I < uS3 c. iS Cl < w g uj c'* 5? Ou * i * 2 <j5-JwCD(CDS 5 si I I f 055 3=2 XI !f Ii ! l: 14C 200 MARGARET R. BECKLAKE of u'ssue examined (99), or if lung juice is ex amined, the vigor with which it is extracted. When digested lung tissue is examined, preva lence approaches 100 per cent (113, 114). It is not likely that these figures have been much in fluenced by the presence of overt asbestos-related lung disease, which was usually specifically ex cluded from the autopsy series examined (16) or was found to be minimal, perhaps a small single area of basal fibrosis (98,99). Despite the fact that ferruginous bodies may not contain an asbestos core, it is probable that most of those found in the lungs of many city dwellers do (Planteydt, 7, p. 80). Thus, preva lence of ferruginous bodies may reasonably be regarded as a reflection of community ex posure. In keeping with this is the rural-urban gradient, evident in table 5, which lists the data by increasing prevalence. Thus, rural areas and small cities fall at the beginning of the table; large industrialized urban centers, at the end. A similar rural-urban gradient was seen in an other series in which counting methods were standardized (Oldham, 7, p. 231). Prevalence was also consistently higher among men than women. In addition, it increased with age (16, 111), and when within-city distribution was examined, as in the study of London, England, higher prevalences were found among those who lived closest to the docks and/or the industrial heart of east London, among those engaged in heavy manual work, and among those whose occupations were in shipping, transport, and en gineering (16). In addition, there is the inter esting observation that prevalence increased with time (1936 to 1966) in London, England, but not in New York (see table 5). Ferruginous bodies have been found on rare occasions in the hilar nodes in persons believed to have been heavily exposed (120), and more rarely, beyond the limits of the thoracic cavity, e.g., in spleen, sinuses; tonsils (54), and hy aline liver plaques (59). Further, in autopsy material obtained from cases with asbestos-re lated lung disease, fiber count appeared to be some reflection of dose (54, 59,120). As already mentioned, the ratio of coated to uncoated fibers within the lung appears to be fairly constant at 10 to 30 per cent (49, 59). Thus, although a count of coated fibers under represents the total fiber content of the lung, it should, nevertheless, reflect reasonably accu rately trends with respect to age, sex, residence, and occupation. From the clinician's point of view/this infor ' t mation, based on epidemiologic studies, carries the clear message that the presence of asbestos fibers, coated or uncoated, in biopsy material, autopsy material, or, for that matter, sputum (117-119), which after all, only reflects the lungs' effluent, is an indication of past or cur rent exposure to asbestos (provided the fiber is positively identified). If the fiber is not posiMM tively identified, exposure to asbestos remains the likely, but not the only, explanation. Giv-5*N; en a history of occupational exposure to asbes rJ|| tos, the physician is unlikely to require positive -J|| fiber identification for any clinical purposes In the absence of history of asbestos exposure, such identification might be useful, but of more importance would be an exhaustive review of all of the patient's previous occupations for how- ~ ever brief a period of time, as well as investiga- ?-r tion of the possibility of nonoccupational ex- ^ posure. . Pleural Plaques, Hyaline or Calcified (Fibrotic Thickening of the Parietal Pleura) -^ Two types of pleural reaction are seen in asso*j|Sv. ciation with asbestos exposure; (I) an exuda-^^. tive reaction, usually widespread, involving\ ' A; both parietal and visceral pleura and usually,/ the lung parenchyma, with obliteration of the HJ; pleural space; and (2) a discrete reaction, volving the parietal pleura, usually in more than one location, and referred to as a pleural plaque (120). The first is associated with toms and affects function (121) and will be con-,,;sidered later in this review together with pul-J^|/' monary fibrosis. The second, usually a radio graphic diagnosis in an otherwise healthy per^ son, wiil be considered in the present section-. Both reactions may, of course, occur together in the same person; however, the clinical pre^ sentation is likely to be dominated by the extent of the exudative reaction. Pathology Macroscopic appearances. Pleural plaques cur as discrete, raised, grey-white lesions on the inner surface of the rib cage and on the phragm. In a series of patients who had pie plaques described at thoracoscopy, Mattson Ringqvist (121) commented that "despite confusion of different sizes and shapes, times suggesting an archipelago, the p*11??*? the plaques is nevertheless monotonous: a flat^S, slightly uneven surface, white and shiny A; synovia or mother-of-pearl, steep edges abrupi here a ing ed; The di they t< ribs, ncentral surface The di in the not oci apices, served cardiuj larly in Plaq free of have u: hemith with ui ly, plat thorax; plaque; thickncbe mor, to the 2. does nthickne Mien sist of . with fe\ ing fasl and cor (54, 12) beneath roundin tissue, s and dev layer oi flepositi plaques, f the ( the com **1 tissu occur at ^Uy witl tion wii Sttently. Altho; been re: n`en in ` Stained ex ** pres point of view, this informiologic studies, carries the presence of asbestos ! v ted, in biopsy material, or that matter, sputum : all, only reflects the idication of past or cur- os (provided the fiber is If the fiber is not posi- sure to asbestos remains i only, explanation. Giv- ttional exposure to asbes- |! nlikely to require positive or any clinical purposes, -tory of asbestos exposure, ght be useful, but of more ; an exhaustive review of i- I vious occupations for how- time, as well as investiga- y of nonoccupational ex- ine or Calcified (Fibrotic -retal Pleura) reaction are seen in asso-} exnosure: (I) an exuda- : J) iespread, involving : pleura and usually, with obliteration of the : 2) a discrete reaction, in-"j pleura, usually in 'more id referred to as a pleural st is associated with symp-' tion (121) and will be con-t' review together with pul*. ? second, usually a radiom an otherwise healthy per-' red in the present section^ of course, occur together^ however, the clinical pnejl be dominated by the extentJ tion. 'aihology arances. Pleural plaques 0^ d, grey-white lesions on the, e rib cage and on the of patients who had pI^Trj t thoracoscopy, Mattson Mgjj mmented that "despite ent sizes and shapes, archipelago, the psttenL thelessmonotonous: aft rf- white and shiny^ -c *rl, steep edges tf* -'3c m abruptly from the surrounding normal pleura, here and there rounded mounds with overhang ing edges. The consistency was that of cartilage." The distribution of pleural plaques is irregular; they tend to be more marked over the lower ribs, may follow or cross rib lines, may be con centrated in the posterior, lateral, or anterior surfaces, but not the cartilaginous portions (54). The diaphragm is usually involved, frequently in the area of the central tendon (54). They do not occur in the costophrenic angles or over the apices. Mediastinal plaques have not been ob served (120), but the pleural surface of the peri cardium is not infrequently involved, particu larly in the advanced case (54). Plaque formation appears to occur in areas free of adhesions, and the same person might have unilateral obliteration of the pleura in one hemithorax and abundant plaques in the other, with unfused pleural surfaces (54). Alternative ly, plaques might involve one part of the hemi thorax; adhesions, another part. Occasionally, plaques are found under adhesions (54). Their thickness varies greatly. Calcification appears to be more common in plaques situated in relation to the anterolateral portion of the upper ribs; it does not appear to relate in any way to the thickness of a plaque (54). Microscopic appearances. The plaques con sist of collagenous connective tissue, cell-poor, with few fibrocytic nuclei, arranged in undulat ing fashion in a coarse, basket-weave pattern, and containing only few thin-walled capillaries (54, 121). Elastic staining shows intact lamellae beneath the plaque in continuity with the sur rounding normal parietal pleural connective tissue, suggesting that plaques are extrapleural and develop between the latter and its covering layer of mesothelial cells (54). Some calcium deposition is present in a high proportion of plaques, and occurs as granules along the course of the collagen fibers, ceasing abruptly where the connective tissue changes into normal pleu- - Tal tissue (54). Cuboidal mesothelial cells may ccur at the edge of the plaque (54), occasion*lly with metaplastic changes (121, 122). Associa tion with bronchial cancer is discussed subse quently. . ^Although coated asbestos fibers have not reported in relation to pleural plaques, *vtn *n the extensive series of 172 sections ex- l^ne^ ^ Meurman (54) under polarized _ examination of ashed tissue has revealed Presence of uncoated fibers in many cases (123, 124). With electron microscopy, it is ap parent that most plaques contain many small, submicroscopic fibers. It is of interest that these are more concentrated in the calcified zones than in the fibrous zones (Le Bouffant, 7, p. 249). Epidemiology and Pathogenesis The association between pleural plaques and asbestos exposure, originally suspected on clinical and epidemiologic grounds, has been amply confirmed by population studies, wheth er exposure was occupational or nonoccupa tional. In occupationally exposed groups, such as miners (88) and shipyard workers (75, 76), the prevalence of pleural changes on the chest radiograph has been shown to increase in rela tion to estimated dose of asbestos, although it is difficult to disentangle age and exposure effects. All varieties of fiber have been implicated, the highest rates occurring with anthophyllite (Jones, 7, p. 243). In addition, factors associat ed with the site and nature of the deposit ap pear to be important; for instance, in Quebec, prevalences of calcification differed by as much as 13-fold in 2 adjacent mining areas, working the same fiber in the same geologic deposit (88). In those not occupationally exposed, particu larly in Finland, there is some evidence to sug gest that prevalence relates to the proximity of place of residence to mining areas (33, 54). Similarly, there is an increase in the prevalence of pleural changes on the radiograph in some agricultural populations in which the soil con tains asbestiform mineral (33,34). Given this association between exposure and pleural plaques, however, no satisfactory theory has been developed to explain how parietal pleu ral reactions develop in response to the inhala tion of fibers and particles and their deposi tion in the lung, which may itself show no re action to the dust. Furthermore, until recently, the presumed causative agent, namely, the as bestos fiber or particle, had only rarely been de tected at the site of the reaction, that is, in the pleural plaque using electron microscopy as in dicated above. One hypothesis is that pleural plaques result from traumatization of the parietal pleura dur ing breathing by sharp asbestos spicules pene trating the pleura. This trauma is believed to produce hemorrhage and subsequent organiz ation of the blood clot in a manner comparable to the process seen in large hemothoraces (33, 123). Against this theory is the failure to dem- swi ftUV4 w mu o i-.'l onstrate inflammatory exudates, and the con spicuous absence of adhesions in association with pleural plaques. Also, intracellular trans portation via pulmonary lymphatics and then retrograde spread via the chest wall lymphatics due to the massaging action of the respiratory muscles does not seem likely in the absence of hilar and/or mediastinal lymph node enlarge ment, neither of which has been found in asso ciation with pleural plaques (124, 125). The disproportion between the marked parietal pleural response and the small amount of etiologic agent led to speculation about individual sensitivity as a factor, a hypothesis for which there is support in some studies, but not in oth ers. Asbestos-exposed workers with plaques have higher concentrations of gammaglobin (126), but similar concentrations of circulating rheu matoid factor and antinuclear antibodies (127), compared to persons not exposed to asbestos. Thomson (9, p. 138) suggests the following sequence of events: Fibers, particularly long ones, tend to move toward the lung periphery; some leave the lung and reach the parietal pleu ra and/or the diaphragm, and those that are held up by the ribs or tendinous part of the dia phragm elicit a reaction in the submesothelial tissues that eventually leads to the formation of a pleural plaque. Calcification, when it occurs, is essentially of a dystrophic type in acellular and degenerated collagen. It is probably more realistic, however, to ac cept the conclusion of Jones and Sheers (7, p. 243) that the pathogenesis of pleural plaques that occur in association with asbestos exposure is unknown. For this reason, and because the dose relationship only partly explains the ob servations, any further light that could be thrown on the pathogenesis of pleural plaques might make an important contribution to the under standing of how asbestos produces its biologic effects, and eventually, how they might be con trolled. Clinical and Radiologic Manifestations Pleural plaques, hyaline or calcified, in the absence of obliterative pleural lesions and pul monary fibrosis, are rarely associated with res piratory symptoms, including dyspnea (128). This is in keeping with the fact that their effect on function, although detectable in popula tion studies (128), is modest and is mainly seen as small reductions in lung volumes (129). By contrast, radiologic changes may be very striking, particularly in the presence of calcifi cation. Hyaline plaques, however, may be diffi cult to see without special oblique views, and will be detected best by high kV techniques, i.e., 110 to 140 kV, whereas calcified plaques are bet ter demonstrated by lower kV techniques (60 to 80 kV) (Bohlig and Gilson, 7, p. 25). Calcified plaques are usually seen on the posteroanterior film as irregular outlines of un even density; they can easily be missed in over penetrated films, particularly if they overlie the coastal cartilages (10). Noncalcified plaques, usually only seen on the posteroanterior film if they lie in the lateral costal regions, i.e., at right angles to the X-ray beam, appear as ill-defined I opacities along the costal margins. Oblique films "! * will be necessary to visualize plaques that are. '/v located anteriorly or posteriorly. Routine ra-. :| diography, however, can apparently detect only a small proportion of plaques identified at au topsy; in one series, only 15 per cent were de tected, and detection was confined to the most heavily calcified plaques (124). The most usual clinical presentation is as an incidental radiologic finding in an asymptomat ic patient. This should alert the physician to the possibility of exposure if this is not already known; in the absence of occupational expo sure, neighborhood or domestic exposure should be sought. Although the presence of hyaline pleural plaques alone does not appear to cause symp- toms of disability, there is some evidence that they affect prognosis. Thus, in some series (130), they were associated with a higher-than-expected incidence of bronchial carcinoma (Smith, 8, p. J 277), whereas in Quebec chrysotife miners and millers, this was not so (92). Malignant meso- ' thelioma has also been reported as developing in the mesothelial cells at the edge of the plaque (122). V- V Pleural Effusion (Benign) X ?.- Exudative pleural reactions, which may occur.^v; : in association with all of the asbestos-related { lung diseases, may also occur as the primary, or,:>;, . * at least the most prominent, clinical mamfes-^ .! tation (131-135), presenting as an "idiopathic^.,. f pleural effusion" (131); hence, the justification ^ for considering this diagnosis separately clinical review of the asbestos-related lung dis*, . eases. The present description is based on 30 cases so far published (134); however, pleu^g ral effusion may well be a more frequent i __ festation of asbestos exposure than this modest number suggests, particularly if it were th< ex cu'. ph. see en? du.er am the urn inti infi in bur ana ed tha C one cau fus: ma; tatj and wit. flu\ COU: mm clin self- me) quit dat. ofte past \i> nig) side? alu. the) expt afte: that non S jn M r*? * I ASBESTOS-RELATED LUNG DISEASES 203 be diffi- _ie views, and ichniques, i.e., iaques are bet* echniques (60 25). seen on the .;r, | outlines of unrnissed in over* hey overlie the cified plaques, anterior film if ns, i.e., at right ar as ill-defined is. Oblique films plaques that are ; rly. Routine ra-, ently detect only ; identified at au- r cent were de led to the most ntation is as an an asymptomat- physician to the v|| is not already upational expo-./3j e> ure should hyaline pleural r to cause symp-_ ne evidence that* ,ome series (130), ier-than-expected^ ma (Smith, 8, p. otile miners and. Malignant meso-'J 1 as developing in. .ge of the plaqu^ - wf which may 0<x&4 ie asbestos-related; as the primary, og/ , clinical manif^ as an e, the justification^ is separately js-related lunS ,n is based on_tf*g 14); however,; p]g ore frequent e than this v ' v/ere quently shown to be a phase in the develop ment of other pleural changes. Pathology. On macroscopic examination at thoracotomy, the pleural surfaces show an active exudative process, characterized by increased vas cularity and symphysis. Associated pleural plaques do not appear to be a feature. Micro scopic examination shows variable pleural thick ening, with "pleural drift of carbon and other dusts and iron-positive granules" (131). Oth er features include regenerating mesothelium and extensive collateral circulation (131), and there is one report of a granuloma (134). The underlying lung tissue shows varying degrees of interstitial pneumonitis, from mild, low grade inflammation to organized interstitial fibrosis, in which asbestos bodies and fibers are usually, but not invariably, found. Election microscopic analysis for uncoated fibers has not been report ed in this type of case, but it can be assumed that these would be found. Clinical features. The usual presentation is one of recurring pleural effusion of unknown cause, associated with chest pain (131). The ef fusion may be unilateral, bilateral, or one side may follow the other in sequence. The presen tation may be acute, with fever, leukocytosis, and an increased sedimentation rate, or chronic, with minimal systemic reaction.--The pleural fluid is frequently blood stained (red blood cell counts ranging from 5,000 to 50,000 cells per mm3) and, in most cases, is an exudate. The clinical course varies from that of a benign and self-limiting illness (132, 133) to the develop ment of chronic pleural thickening that re quires decortication (131). The patient's asso ciation with asbestos may be current, or more often may have been brief and in the remote past (131). Differential diagnosis. The diagnosis of a be nign asbestos pleural effusion should be con sidered a diagnosis only by exclusion. The chief alternative to be excluded is malignant meso thelioma, one of the manifestations of asbestos Exposure that may not develop until many years - after the first exposure. The pleural effusions *hat commonly complicate the latter tumor may precede by months or years the definitive diag nosis of the tumor. Indeed, one could argue ' ' 'H^nst accepting the diagnosis of benign asbes- Plural effusion until all of the present re- are followed to death, and death l?ttn l attrifiutable neither to carcinoma nr t0 mesothelima- However, as ^^'up becomes longer (134), the justifica tion for this diagnosis increases, and asbestos exposure can reasonably be added to the long list of causes of benign, recurrent pleural effu sion. Diffuse Interstitial Pulmonary Fibrosis (Asbestosis) Definition Diffuse interstitial fibrosis of the lung associated with asbestos exposure was recognized in the early years of the twentieth century, the first asbestos-related disease to be so recognized (1); however, the term "asbestosis" to describe this pneumoconiosis was not suggested until 1927, when Cooke (136) used it to describe the case of a female asbestos textile worker. It is usual to include fibrosis of the associated visceral pleu ra under this term, but not that of the parietal pleura (10). There is merit in maintaining this specific usage in line witli the widely accepted use of the term pneumoconiosis (137), rather than to use the term "asbestosis" in a generic sense to describe all asbestos-related diseases of the lung and pleura, even neoplasms (10). Pathology Macroscopic appearances. The main patho logic features that had been described with care by the 1930s in individual case reports (138, 159) were reviewed by Hourihane and McCaughey (116) in the light of their own patho logic material, based on 69 cases of clinical as bestosis examined at the London Hospital. Ma croscopic changes ranged from small areas of basal fibrosis (if sufficiently localized, these may escape recognition by the naked eye) to the fully developed case of a diffuse, fine fibrosis affecting both lungs. Lung size tends to reflect the extent of the fibrosis; when this is diffuse, the lungs tend to be small. Cut surface shows the fine, grey-colored fibrosis that generally ap pears to affect subpleural areas first, often quite extensively, before advancing into other lobes with the extension of the disease process. Lower lobes tend to be affected first, then middle lobes, and eventually, upper lobes (10, 116, 140). Small honeycomb cysts may be seen, in the lower lobes particularly, and fibrosis and honeycomb ing also tend to be concentrated subpleurally (140). Emphysema, centrilobular or bullous, is frequently found, with characteristics essential ly the same as in emphysema not associated with asbestosis (140, 141). The pleural surface in re lation to the fibrosis is invariably involved in rs ;'! 204 MARGARET R. BECRLAKE the fibrotic process, either mildly, giving the ap pearance of a milky covering to the fibrosis, or with widespread fibrosis and symphysis (116, 140). The hilar lymph nodes are not usually enlarged or otherwise affected (10,142). Conglomerate lesions of massive fibrosis, com parable to the progressive massive fibrosis of coal workers, occur in the absence of tuberculosis (Gough, 5, p. 368), but are rare, unless the ex posure has been to mixed dust including talc (10, 143) or silica (142, 144). In addition, these lesions appear to have a predilection for the lower lobes (142, 144), unlike other forms of progressive massive fibrosis. The occasional soli tary fibrotic lesion is seen, for which the term asbestoma has been used (145). Necrobiotic nodules associated with rheumatoid disease (sim ilar to those seen with Caplans' disease in coal workers) are seen (146-149), but only rarely (10). Microscopic appearances. In animal studies, early dust reactions include a desquamative al veolar response (Webster, 9, p. 117), a reaction that may have its counterpart in man (144,150). In addition, there is one case report of desquam ative interstitial pneumonia' with asbestos bod ies in the lung (150), and the view has been ex pressed that this is one end of a spectrum that ends with fibrosing alveolitis (151). An idea of the abnormalities in the early stages of fibrosis comes from examination of biopsy material, usu ally sought to establish a diagnosis of asbestosis (131, 145). The early reaction in the interstitial tissue resembles that of other forms of intersti tial pneumonia, with mixed leukocyte infiltra tion of the alveolar walls, moderate numbers of phagocytes in the alveoli, and varying degrees of organization with fibrosis (131, 145). In some cases, the early changes are concentrated at the level of the respiratory bronchiole, where reticulin fibers, macrophages, and dust particles col lect (10, 116), leading subsequently to what has been termed the basic lesion of asbestosis, name ly, a peribronchiolar fibrosis (116). From here, the process extends outward to involve the sur rounding alveoli, leading to diffuse alveolar wall thickening, with peribronchiolar and perivascu lar fibrosis (116). In an occasional case, the fibro sis remains almost exclusively peribronchiolar (144, figure 5), but the more usual picture is that of a diffuse fibrosis, involving the interstitium, frequently associated with areas of solid fibrosis, where laminated collagen may replace the entire parenchyma. Such areas may also show alveolar cell hyperplasia and sclerosis of vessel walls (116). The presence of ferruginous bodies is to be expected, and electron microscopy is likely to reveal very large numbers of uncoated and very fine particles and fibers (152). The pathologic findings in workers exposed to amosite and crocidolite have been shown to be es sentially similar to those associated with chrysotile exposure (Wagner, 8, p. 373). Pathogenesis Reactions at the cell level have already been discussed, and at the organ level are presumed to relate to the number of cells reacting, which in turn is believed to relate to the retained "dose" of asbestos dust and/or fiber. This ap pears to be true for mild and moderate fibrosis, respectively, in animals (62) as well as in man, in whom the response has been related to "dose" retained, as reflected by concentration of coated and uncoated particles in the lung tissue at au topsy (49); however, there does not appear to be further progression from moderate to severe fibrosis associated with an increase in dose (49, 62). It is, therefore, postulated that the progres sion from moderate to severe fibrosis is due to other factors, e.g., nonspecific inflammation, as suggested by Ashcroft and Heppleston (49) or possibly to self-perpetuating host responses, as suggested by Turner-Warwick (144). Thus, based on her observations that non-organic-specific autoantibodies, especially antinuclear antibod ies (ANA), occur with only slightly greater fre quency in exposed, compared to nonexposed, persons in the general population, and with in exposed populations, with greater frequency in those with clinical disease than those with out (153-155), Turner-Warwick proposes that ANA acts as an accelerator once the fibrosis has been initiated by a separate agent (Turner-War wick, 7, p. 258). Such an explanation would fit the clinical observation that asbestosis may ap pear for the first time and progress long after exposure to dust has ceased. The possibility that genetic factors influence the response to expo-, sure is suggested in one study in which the HL-A B27 occurred with greater frequency in asbestosis cases compared to the general population (356). There is also a progressive decrease in the total lymphocyte count with advancing fibrosis, and the suggestion has been made that the cellular immune mechanism is disturbed in asbestosis 057). The progression from diffuse interstitial sis to conglomerate fibrosis may, in the have been associated with tuberculosis t 21. Oinous bodies on microscopy is ibers of uncoated fibers (152). The ; exposed to amoi shown to be esiciated with chry- 373). have already been ?vel are presumed 11s reacting, which ie to the retained for fiber. This ap- 1 moderate fibrosis, as well as in man, I en related to "dose" entration of coated - lung tissue at auloes not appear to moderate to severe crease in dose (49, d that the progres- I i i \ i e fibrosis is due to : ic inflammation, as .-.'.v- dcpoleston (49) or .: - : ' responses, as V k. (.*). Thus, based .'v lon-organic-specific Szh ntinuckar antibod- -'?i- slightiy greater fre- ed to nonexposed, luiation, and with- J hse gtrheaanterthforesqeuwenhchy-jr&.*| wick proposes thatjj|g;; ' once the fibrosis has 2?;^ > agent (Turner-War-JpgJ- ;planation would t asbestos/s may ap-^=^' progress long after^^^.. The possibility tbat^^s^ ie response to expo-e^f y in which the HLrA^ equency in asbestod* ral population (156)-, decrease in the total vancing fibrosis. *^ ade that the S3sturbed in as! A ;e interstitial ', may, in -culoaS'P* ASBESTOS-RELATED LUNG DISEASES but this is rare today in the United States (Enterline, 5, p. 156) and in Britain (Smither, 5, p. 166). Nor does such progression appear to relate to a "rheumatoid" diathesis (90). On the other hand, rheumatoid disease developing in the asbestos worker is liable to be associated with the appearance of lung changes of unusual and rather marked character. The relationship of emphysema to asbestos dust exposure remains to be elucidated. Physio logic studies suggest that airway obstruction is common; in the presence of fibrosis, particularly if this is peribronchiolar in location, it would seem reasonable to ascribe it to the dust load. In the absence of dust fibrosis, and given the im portance of the smoking habit, it is more difficult to determine the role of a dust load in the de velopment of emphysema. To date, there has been no systematic autopsy study in which the prevalence of emphysema and/or chronic bron chitis in workers exposed to asbestos was com pared with the prevalence in nonexposed per sons, such as that of Ryder and associates (158) in coal workers, a study that dearly showed the excess of emphysema in coal miners. An open mind should be kept on the subject until fur ther evidence is available. gresses, they become more widespread and oc cupy a greater part of inspiration. They are attributed to the "sudden opening of airways in deflated territories of the lung" (159), an ex planation supported by the fact that they shift to the gravitationally lower lobes with changes in posture (128) and have been shown to be consistently detectable at a given transpulmonary pressure (160). Other adventitious sounds, such as wheezes and rhonchi, are less common. Air entry and chest expansion are likely to be affect ed in proportion to associated pleural changes. Clubbing of the fingers and toes is said to be present in most cases (10), although by no means is this always true (161). This sign does not necessarily indicate advanced disease, be cause it is also reported in men who are still able to work (96, 119). The lack of correlation with severity of fibrosis is seen particularly when the clubbing is evaluated systematically from casts of digits to allow measurement of the hyponychial angle (118, 119) by the method of Regan and associates (162). It is of interest that smok ing also appears to play a part in the develop ment of this sign (Harries, 7, p. 19), an associa tion detected in epidemiologic studies, the sig nificance of which is unknown. Clinical Features The symptoms and signs of diffuse interstitial fibrosis due to asbestos exposure are no different from those of all other forms of diffuse inter stitial fibrosis. Thus, the most prominent symp tom is breathlessness, first noted under the stress of effort, then at rest, as the large working re serve of die lung becomes progressively re duced. Cough, either dry or with sputum, not as consistently present as dypsnea, may be se vere, with distressing paroxysms (10). Although generally attributed to airway, rather than to interstitial, lung disease, this symptom occurs with greater frequency in the asbestos-exposed worker than in his nonexposed counterpart (96, 97. 118) and often cannot be attributed to dif ferences in smoking habits, suggesting that this *ympiom also relates to asbestos exposure. Chest P^n, not a frequent complaint, has been attri buted to muscle aches, because it appears to be present only when dyspnea is severe (10). The most characteristic physical sign is the P^sence of crepitations, which are described as 'ing a "crisp, clean, quality" and occurring in inspiration, usually over the lower or _ ^ung zones (JO). A deep inspiration . T he necessary to elicit them. As fibrosis pro Radiographic Changes In considering the chest radiograph of the in dividual case for diagnostic purposes (10, 163), evaluation of the pulmonary parenchyma should be based on the following features: small, irreg ular, and/or round opacities, scored for size or length, profusion, and number of zones af fected; hairline ring (honeycomb) shadows; a diffuse haze or ground-glass appearance not ob viously due to pleural shadows; short horizon tal septal lines or Kerley B-lines, believed to represent lymphatic obstruction (144), and occasional longer hairline shadows. Pleural changes are likely to be present as well (in more than one half of the cases in one series of compensation board material), whereas in 20 per cent of cases, they were present without par enchymal changes (163). Rounded opacities are more evident when the occupational exposure has included silica (95). These findings are in general agreement with previous reports (163 166). Thus, it can be seen that the radiologic features of asbestosis are no different from those of all other forms of interstitial fibrosis, except for the prominence of associated pleural chang es, in particular, calcification, which should a 206 MARGARET R. BECKLAKE always call attention to the possible association with asbestos exposure. A systematic classification of the radiologic changes associated with asbestos exposure em bodying most of the features described, together with the pleural changes, was developed for epi demiologic purposes, first as the UICC/Cincinnati classification (167), later adopted as the ILO U/C classification (168). Its features in clude a reading sheet, an extended 12-point scale to grade parenchymal changes, and stan dard films to assist in the evaluation of pleural and parenchyma! changes .(obtainable from the International Labour Office, Occupational Safe ty and Health Branch, CH 1211 Geneva 22, Switzerland. Price: Sw Francs 250.-) The use of this classification, by improving precision and probably also comparability between studies, has enhanced the value of the X-ray as an epi demiologic tool (169). Thus, it enables a better placement of the film in the multidimensional "continuum which extends from complete 'nor mality' at one end to the most severe degree of abnormality at the higher" (Bohlig 7, p. 25). In particular, it has permitted the exploration of the exposure-dose relationships (using the chest radiograph to measure response) in working populations. In addition, this classification has been adopted by compensation boards in several countries to improve consistency in the reading of the chest radiograph and should be used whenever the evaluation of a person's films must be considered relative to those of others. It must be emphasized, however, that this classifi cation is descriptive and not diagnostic; further more, although radiologic changes so described relate reasonably well to lung function changes in population studies (87, 95), their relation ship to disability, which is likely to vary con siderably from subject to subject, has not been widely studied. Lung Function Lung function tests have been applied to the study of asbestosis since their general introduc tion to clinical medicine in the 1940s. In gen eral, there are 4 clinical areas of application (10): first, for diagnosis and assessment of dis ability; second, for following the evolution of disease with time; third, for the surveillance of healthy workers, with a view to detecting early changes; and fourth, for preemployment exam ination to screen the "susceptible" person. In addition, information gained from epidemi ologic studies using pulmonary function test ing to determine exposure-response relation ships has permitted inferences to be drawn about early effects of asbestos on the lung, in formation that may ultimately have considerable practical value in terms of the worker's health. Diagnosis. Interstitial fibrosis associated with exposure to asbestos is generally believed to be associated with the restrictive and "alveolar capillary" block patterns of pulmonary func tion, similar to that seen with the interstitial fibrosis from other causes (Becklake, 7, p. 3). Characteristic features of the established case (with clinical and/or radiographic evidence of disease) are: general restriction of lung vol umes, particularly vital capacity (VC), with less effect on residual volume; decrease in flows, such as 1-sec forced expiratory volume (FEVj), in proportion to the decrease in VC, so that the ratio of FEVj to forced vital capacity (FVC) is relatively well preserved; decrease in diffusing capacity, attributable in part to the decreased lung volume (170), although decreased mem brane transfer and inhomogeneity of regional ventilation-perfusion relationships within the lung undoubtedly contribute to the impaired gas transfer (43, p. 879). Impairment of gas ex change capability, reflected by arterial desatura tion, increased alveolar-arterial Po2 gradient, and hyperventilation, may at first be evident only under the stress of exercise, but later occurs at rest. The C02 exchange is not usually affected, and arterial C02 retention is not usually a fea ture of the established case. Although there is no evidence to suggest that asbestosis due to chrysotile is any different from that due to other fibers, one epidemiologic study suggests that there may be greater decrease in function for equivalent estimated exposure to crocidolite compared to chrysotile (94), a dif ference that could be explained by greater re tention of crocidolite compared to chrysotile for equivalent estimated exposure; however, in the light of the potential and, indeed, inevitable inaccuracies that beset all efforts to evaluate remote past dust exposure, in amount and/or nature of the fiber, this interesting observation requires further confirmation before it is as* sumed that different fibers have different fibro- genic potential in man. . It is usually claimed that airway obstruction is not a feature of asbestosis (10, 170--172)? however, a review of 375 published cases (17$)^ most with unequivocal parenchymal radiologic * changes, indicated that a considerable number of... patients had airway obstruction (11 per cent e-response relation:nces to be drawn :os on the lung, in ly have considerable the worker's health, rosis associated with erally believed to be ctive and "alveolar of pulmonary funcwith the interstitial (Becklake, 7, p. S). the established case .iographic evidence of striction of lung volapacity (VC), with less ue; decrease in flows, ratory volume (FEV1), ease in VC, so that the ital capacity (FVC) is decrease in diffusing part to the decreased ough decreased memmogeneity of regional uionships within the ute to the impaired gas mpairment of gas ex- arterial desaturaai. .al Po2 gradient, iay at first be evident xercise, but later occurs e is not usually affected, on is not usually a fea- vidence to suggest that le is any different from me epidemiologic study be greater decrease in estimated exposure to chrysocile (94), a dif- xplained by greater rempared to chrysotile for posure; however, in the and, indeed, inevitable all efforts to evaluate ure, in amount and/or^^^`|T interesting observationj tnation before it is I >ers have different J that airway obstrucnoo,sbestosis (10, 170-372)^ 75 published cases (37w ! parenchymal radiologicj r siderable nuroberpC .1 .ction (11 per ceng ASBESTOS-RELATED LUNG DISEASES 207 compared to 39 per cent with a restrictive pat tern), whereas in 18 per cent, the function im pairment suggested a mixed picture of obstruc tion and restriction. In addition, scrutiny of epidemiologic studies in working populations (i.e., studies that, by their nature, exclude the disabled and all but a few of those with radio logic disease) invariably shows a sizeable num ber of persons with evidence of airway obstruc tion (64, 72, 170, 174-176). However, there is no clear evidence showing an excess of airway obstruction in asbestos-exposed populations compared to those not so exposed (96, 172), and there is no clear evidence that within ex posed populations, the prevalence of obstruc tion increases with increasing exposure (172). The restrictive patterns of lung function also does not show an increased prevalence in rela tion to exposure (172). To this time, therefore, epidemiologic studies of lung function have not been able to eluci date the relationship between airway obstruc tion and asbestos exposure, or the part played by the cigarette habit (additive or synergistic). In consequence, even in the presence of radio logic changes, there is usually hesitation in at tributing the obstructive component of a work er's disease to asbestosis, despite the fact that de creased conductance has been shown in other forms of interstitial lung disease (177). With out radiologic changes, there is even greater reluctance to attribute the obstruction to asbes tos exposure. Nevertheless, there is enough in direct evidence to suggest that in response to as bestos exposure, the character of the function impairment may be obstructive in a certain number of cases (173); until further evidence is available, an open mind should be kept in this regard. Assessment of disability. The relationships between organ malfunction (as reflected in what may be called descriptive measurements of the lung, i.e., its size or lung volumes, and in the measurements related to its mechanical proper ties), organ failure, generally considered to be present only when gas exchange function is impaired (43, p. 442), and disability (diminu tion of performance as perceived by the subject himself) are not straightforward. Thus, consid erable amounts of organ malfunction (i.e., ab normalities of lung function tests) can be present without organ failure (i.e., abnormal U?0^ .ases)* even under the stress of effort, ewise, disability in the form of unusual reathlessness may be perceived by the subject early or late in the development of his disease. This discrepancy between function and symp toms is also found in some epidemiologic stud ies (172, 178, 179), but not others (96, 97). The important conclusion for clinical practice is that in the individual case, disability cannot be predicted witli reliability from symptoms, function, or radiographic changes. It should therefore be evaluated by appropriate exercise tests, if necessary at more than one load, for each case individually (Becklake, 7, p. 3). Evaluation of changes with time. Serial mea surements of lung function in individual cases of asbestosis with time suggest that deterioration is most closely reflected in VC (64, 78, 180) and, possibly, maximal voluntary ventilation. The diffusing capacity of the lung for CO (Dlqo). originally proposed on theoretic grounds as well as on the basis of some limited observations (176), may not be as useful (128). Support for these conclusions also comes from epidemiologic studies of exposed working popu lations in which decrease in VC, in particular the 1C component of VC, showed a closer rela tionship to estimated dust exposure than did Dlco. measured either by the single-breath or the steady-state technique (87, 94). Other tests that showed a relationship to exposure were FEVj (87) and maximal mid-expiratory flow (94); however, serial studies of an epidemio logic nature (i.e., following changes in a whole working population, rather than in a few se lected subjects) would provide more precise in formation on this point. Early detection. This implies detection of dust effects in a person before he or she perceives them as symptoms. Persons showing these early changes are more likely to be found in a work ing population than in a clinic population, be cause clinic attendance presupposes symptoms. Furthermore, within a working population, it is reasonable to suppose that symptoms will oc cur more frequently in those with heavier ex posures. In one epidemiologic study confined to exposed persons without clinical or radiologic evidence of disease, and with normal routine lung function, it was possible to detect changes in the lungs' mechanical properties (specifical ly, a decrease in compliance and an increase in calculated upstream resistance) in those with heavier dust exposure (84). These changes sug gesting a dust effect at the small airway level would be compatible with peribronchiolar fibro sis (116). Similar results were obtained in a sub sequent study of a larger number of subjects, 208 MARGARET R. BECKLAKE reported in preliminary form (Z81), using the closing volume test. At present, these observa tions have no practical significance, because it remains to be shown (1) that what is detected is, in fact, the beginning of a process that will ultimately lead to asbestosis, and (2) that any intervention, such as removal from exposure, would prevent the ultimate development of dis ease. From what has been said about pathogen esis, however, it appears that in its earlier stages of development, the fibrosis of asbestosis ap pears to be related to dust accumulated, and therefore, by implication, removal from expo sure by preventing further accumulation might slow the process. These findings, therefore, have potential application in the future. Function versus radiographic methods in the early detection of asbestosis. Several early clini cal studies, some based on small numbers of sub jects, suggested that in asbestosis changes in func tion preceded radiographic changes (64, 128, 176). The changes in function identified were in VC (64, 128) and Dt-co (176)- Subsequent epidemiologic studies suggest that at least as far as these two tests of function were concerned, they were no more sensitive than radiologic changes (87, 94, 95). It must be emphasized that the latter conclusions were based on betweengroup comparisons of subjects classified by dust exposure, for which identification of appropri ate "normal" standards is unnecessary. Detect ing abnormality in the individual case with cer tainty is another matter, because this requires reference to standards of normality, which for both radiographic studies and tests of function have fairly wide ranges. Periodic comparative chest radiographs or function tests, are likely to improve the chance of detecting early abnormali ties in a given person. It must be borne in mind, however, that the radiologic changes are invari ably of a nonspecific nature, similar to those occurring with aging or the cigarette habit (182); hence, the opinion that in an individual case they reflect early fibrosis should be guarded. Diagnosis The criteria for diagnosis of asbestosis depend on the purpose for which diagnosis will be used, and the degree of certainty required. A work ing clinical diagnosis can be reached on the ba sis of an exposure history (present, past, or remote past) and the presence of one or more of the following: effort dyspnea, basal crepita tions, radiographic changes of parenchymal and/or pleural disease, and lung function im pairment of any sort (10, 96, 97, 172). If all 5 criteria are present, the diagnosis would gener ally be considered established for most compen sation boards. With fewer criteria, there is less certainty. In the absence of an exposure history, or if the exposure history is considered too short to account for the amount of disease present, a tis sue diagnosis may be called for, particularly in compensation cases for which attributabilicy is in doubt. In such situations, an open lung biop sy (145) is preferable to a needle biopsy (183), particularly if radiographic changes are mini mal. Biopsy material should be critically exam ined by light microscopy for pathologic features, including presence of coated fibers, and by electron microscopy for the presence of uncoat ed fibers, using appropriate extraction proce dures (Pooley, 7, p. 50). Also, occasionally, the presence of asbestos bodies in the sputum (117 119) may alert the physician to the possibility of exposure and result in an appropriately ex haustive enquiry to reveal the source of ex posure. Coated fibers are, of course, commonly found under conditions of heavy and current exposure. Prognosis, Complications, and Medical Management . The outlook for the person with asbestosis has undoubtedly improved considerably during the past 20 years, both in Europe (67) and in Nordi America (63), with age at death, years of exposure until diagnosis, and years of survival after diagnosis increasing conspicuously in roost countries. Also, risk of premature death due to other respiratory diseases seems to be confined :' . : .. to those with high dust exposures (McDonald, 7, pp. 155-179). Perhaps because of the longer survival period, * `" workers with asbestosis are now surviving into the lung cancer age (63), and deaths from this ' cause are assuming a much greater importance ,, (McDonald, 7, pp. 189-217). In addition, it_ *. should be noted that lung cancer is becoming a-S-'- more common cause of death in the general population. ... Medical management of asbestosis is restrict-*-.^:, ed to the symptomatic care given to subjects^^g-' with interstitial fibrosis, whatever the cause. Tbe,^ 'V1 use of corticosteroids is not advocated, because.* the agent, asbestos, is, as far as is known, fixed injj the lung tissue. Appropriate treatment of inter-?! -4 ( < t ! 1 h 1 a fi d f; w ol tr to th te. is of ha de; or SOI. (Hthe doe ing sis i gest evid A nne: ten's to a and sion ly, it nual larly in th. this, . that j livene Malign Paritor Primai plurfpc P^ritor. function im'V If all 5 aid gener- most compen, there is less history, or if i too short to present, a tisparticularly in tributability is pen lung biope biopsy (183), nges are minicritically examologic features, fibers, and by sence of uncoatxtraction proceoccasionally, the e sputum (117-- the possibility opropriateiy ex .* source of exurse, commonly vy and current n *dical J ith asbestosis has 'ably during the >7) and in North i'-,- th, years ' of ex rr -R s of survival aft- cuously in most -sat ire death due to s to be confined -9|g' ires (McDonald, ||||| survival period, w surviving into deaths from this^ ?ater importance x* In addition, it"| :er is becoming a'"3 ; in the general 2| - *'4P estosis is restnet-^ jiven to subjects^ er the cause- The3 ivocated, because*! s known, fixed in, eatment of interij i\ current infections may be particularly impor tant in view of the suggestion that nonspecific inflammation may contribute to progression of fibrosis (Ashcroft, 7, p. 236). There is no real evidence to suggest that the only possible effec tive therapeutic intervention, namely, to re move the person from exposure, has any real in fluence on the outcome of the case. One assumes that removal might halt further progression, a hypothesis for which there is some evidence (62). It is also known, however, that disease can both appear and progress many years after removal from exposure (63); thus, research should be directed at possible ways of determining what factors determine this future progression and whether it is possible to define the stage or level of exposure at which removal might be an effec tive preventive measure. Pre-employment evaluation of lung function to screen out high-risk persons is, in theory, the most important area of future health pro tection; yet, this is also the area in which there is no systematic evidence to indicate what type of person to screen in or screen out. Attention has been directed toward die pre-employment detection of obstructive lung disease, acute or chronic, on the assumption that such per sons are at high-risk of developing asbestosis (Hunt, 5, p. 406). The smoking habit, certainly the greatest risk factor for bronchogenic cancer, does not usually constitute grounds for refus ing a recruit. Its role in the development of fibro sis is less clear, there being some evidence to sug gest a synergistic effect with dust (185), and some evidence to the contrary. An interesting possibility, as yet completely unexplored, is that certain physiologic charac teristics, for instance, the relative size of airways to air spaces (184), may constitute risk factors and might, for example, be the basis for exclu sion of certain types from dust hazard. Final ly, it is possible' that pre-employment and an nual measurements of lung function, particu larly FVC, might also prove to be a useful tool in the health care of the worker (87); however, this, too, should be introduced only in a way that permits a critical evaluation of the effec tiveness of such a procedure. Malignant Mesothelioma of the Pleura and Peritoneum Primary malignant mesotheliomas arise from the pluripotential mesothelial cells (of the pleura, peritoneum, and pericardium) and in conse quence, may present with widely varying histo logic features. Nevertheless, they have been con sidered a pathologic entity (10,185), albeit rare, for some time; their association with asbestos exposure was mentioned as early as 1946 in an individual case report (10). This association was dramatically brought to the attention of the medical public by Wagner and colleagues (27) in a report of 33 cases with occupational and/or environmental and/or domestic exposure in the crocidolite mining area of the Northwest Cape, South Africa. The association with asbes tos exposure has now been confirmed from many parts of the world (table 6). Pathology A characteristic feature of the macroscopic appearance of the malignant variety is the ten dency to spread along serosal membranes (186), encasing the lung by a bulky, lobulated mass that usually invades the fissures. Areas of necro sis within the tumor may give rise to cystic spaces filled with glutinous fluid, a distinctive feature of this tumor, although not necessarily a specific one, because it is also seen in adenocarcinoma (10). Local metastases to chest wall, mediasti num, and pericardium, rather than remote me tastases, declare malignancy of the tumor; how ever, metastases to hilar and abdominal lymph nodes are not uncommon, and, occasionally, more distant sites, such as liver, thyroid, adre nals, bone, and brain are involved (10, 186). It has been emphasized, however, that the diag nosis is one of exclusion, and that all potential sites for primary growth (particularly lung, pan creas, intestine, and ovary) must be exam-, ined; consideration must also be given to the possibility that the primary tumor has already been removed (McCaughey, 5, p. 603). The peritoneal tumors present a similar appearance, but do not tend to engulf the abdominal organs to the same extent as the pleural tumors. Gluti nous ascitic fluid, however, is a common feature (10). Primary pericardial tumors do not ap pear to be associated with asbestos exposure. Microscopically, 4 varieties are recognized ac cording to the dominant cell types (186, 187). Epithelial, or tubulopapillary, tumors are char acterized by branching acini, lined by colum nar or cuboidal cells, often containing mucin and having a tendency to spread. Mesenchymal, or sarcomatous, tumors range in appearance from cellular fasciculated fibrosarcoma to myx oma, with the amount of associated collagen in the tumor varying considerably. The undifferen- w O Q5 $ ASBESTOS-RELATED LUNG DISEASES 211 tiated, or polygonal, type is usually composed of (Newhouse, M. L.: Personal communication). Un solid sheets of cells with abundant eosinophilic like bronchial cancer, smoking does not play cytoplasm, which may look remarkably benign. a synergistic role in the development of meso The mixed type comprises all of the character theliomas. istics previously described. Some believe that all The most disconcerting aspect of the relation tumors would turn out to be of the mixed var ship between malignant mesothelioma and as iety if a sufficient number of sections were tak bestos exposure is its documented association en (Planteydt, 5, p. 80). A surprising and not uncommon finding is the presence of only one tumor element in the metastases (10). with apparently low levels of exposure, for rela tively brief periods in the remote past from neighborhood or domestic sources described (27, Although ferruginous bodies are usually 30, 31). The commonest documented neighbor found in the lungs in cases of asbestos-associated hood exposure is that of children playing in the mesothelioma (Hourihane, 5, p. 647), it is streets within one-lialf mile of a factory or unusual to find parenchymal fibrosis (i.e., as- mine, usually for several years in early child bestosis) of any degree when the tumor arises hood, although one cannot usually be certain in the pleura; on the other hand, in peritoneal that they did not also play in the waste and/or tumors, pulmonary fibrosis may be a prominent the tailings. However, neighborhood exposures feature, giving rise to the hypothesis of obstruc seem certain to have been less than those to tion to the thoracic lymphatic drainage and which workers themselves were exposed, imply retrograde lymphatic spread of the asbestos fiber ing lack of a dose relationship to exposure. On to the abdominal lymphatic system. Peritoneal the other hand, in certain other occupational tumors, representing perhaps 10 per cent of ca groups, such as the workers in the London as ses, appear to occur more frequently in some bestos textile factory studied by Newhouse and series (30) than in others (201), and one study associates (30), a dose effect on risk can be dis shows a sex difference in the preponderant tu cerned. Furthermore, when dose is measured by mor site, peritoneal tumors being more fre number of asbestos bodies and/or fibers in path quent in women (30); however, peritoneal tu ologic material (187, 188, 197), this is found to mors predominate in some all-male series (Seli- be higher than in the general population, al 1 koff, 7, p. 209). though lower titan usually seen in relation to Epidemiology: Association with Asbestos pulmonary fibrosis. Exposure Pathogenesis Despite their being rare tumors, estimated to have an incidence of the order of 1 per 1,000,000 per annum in the general population, the as sociation of mesothelioma with asbestos expo sure has been consistent in all parts of the world (table 6). Although all commercial fibers except anthophyllite (77), but including talc, have been implicated, there are important between-fiber differences in mesothelioma risk, be ing greatest with crocidolite, less with amosite, and apparently even less with chrysotile. With amosite and chrysotile, there appears to be a higher risk in manufacturing than in mining and milling. These were the conclusions reached by the Advisory Committee on Asbestos Cancers at the Lyon meeting (7, p. 341) and are based on published epidemiologic studies, including prospective and retrospective mortality studies. In addition, mesothelioma rates seem, in gen- to be increased in cities that have ship wilding or ship repair industries (202), and in *me working populations may approach 10 cent, particularly if exposed to crocidolite Animal experiments indicate that, when given intrapleurally, all types of asbestos fiber, as well as certain types of glass fiber, are capable of producing malignant mesothelial tumors, and risk appears to increase with dose (Wagner, 7, p. 285). Inhalation experiments, on the other hand, tend to produce cancers. This has led to the hypothesis that all types of fiber, once they reach the pleura, exercise "biologic activity." There is some evidence, however, that this ac tivity is size dependent, fibers less than 2.5 ^m in diameter or between 10 and 80 /*m in length being particularly effective at inciting mesothe lial growths (Stanton, 7, p. 289). For these rea sons, opinion is moving away from the view that the gradient of biologic activity shown in man, at least with regard to risk of developing mesothelial tumors, is due to chemical differ ences between fibers, and toward the view that it is due to physical differences between fibers. Thus, it is believed that the determinants of pathogenicity of a fiber are the degree to which it penetrates and settles in deep lung spaces, and  I 1: i;. fl; 212 MARGARET R. BECKLARE this, in turn, is controlled by its aerodynamic properties (Timbrell, 7, p. 295). In addition, it must be pointed out that ma lignant mesothelioma is not uniquely associated with asbestos exposure, and a small number of cases without such a history are seen in all series; this proportion is usually small, but has reached over 80 per cent (197). Mesothelial tumors aris ing in the pericardium have not been linked to asbestos. Despite the now accepted association of ma lignant mesothelioma with asbestos exposure in man, the pathogenesis of this tumor is far from dear. Presumably, it is only by sustained re search, using animal models, and looking for risk factors in exposed populations, that an un derstanding will eventually be reached of the mechanisms underlying its development. In deed, some believe elucidation of the relation ship of this tumor to exposure to be the most important area for future research, and the key to understanding the mechanism by which ex posure to asbestos produces its effects in man (202). Clinical Features Pleural tumors invariably present with dull chest or shoulder pain, of insidious onset, but slowly becoming persistent enough to interfere with sleep (Ehnes, 7, p. 267). In some cases, however, die pain may be severe and pleuritic. Breathlessness, usually related to accumulation of pleural fluid, weight loss, tiredness, and cough follow. As mentioned previously, there may also be a history of previous pleural effu sions (203). The presumed sequence of events is as follows: serous effusion, perhaps developing in association with plaques, possibly clearing later, to recur with blood staining, increasing in amount as die tumor develops; invasion and thickening of parietal and viscera) pleura, eventually leading to the lung's becoming im prisoned, with retraction and immobilization of the chest cage on the affected side (117). The presenting symptom of a peritoneal tumor is also usually dull pain, later followed by swelling and weight loss. The physical signs will depend on the stage at which the patient first presents; usually, pain precedes systemic symptoms and the presence of dear physical signs by weeks or months. Apart from the dinical signs of the effusion and/or pleural invasion, dubbing of the fingers is com mon; acute arthropathy which may also be a feature of associated asbestosis (204) has been reported, with regression and reappearance, aft er surgical removal and recurrence of the tumor, respectively (Elmes, 7, p. 267). There is only one report of hypoglycemia in association with pleu ral mesothelioma (204); the association may therefore be taken as incidental. The present ing signs of abdominal tumors are invariably fluid and swelling; complications include par tial or complete intestinal obstruction. The clinical course is usually one of rapid progression; for pleural tumors, the average sur vival time from onset of symptoms is approxi mately 6 months; for peritoneal tumors, 13 to 14 months. This varies, however, and in one se ries, 17 per cent were alive after 3 years (187). Nevertheless, the more benign the course, the more likely that the pathologic classification should be revised to benign mesothelioma (205). Diagnosis and Treatment The diagnosis can be definitely made only by tissue examination. There are a number of rea sons why it is difficult to make a positive diagno sis of this tumor during life, even when ade quate biopsy material is available. These in clude the wide variety of cell types within a single tumor, especially those of the mixed type, and the need to exdude primary tumors else where, Nevertheless, it is claimed that diagno sis on biopsy material can be accurate in most cases (Hourihane, 5, p. 647). In addition, there is the difficulty of obtaining agreement be tween pathologists on histologic characteristics (McCaughey, 7, p. 58), a difficulty reflected by the relatively modest number of cases, less than 50 per cent in some series (206), subsequently confirmed by mesothelioma review panels. This difficulty may be less important in clinical medi cine, in which the important distinction is be tween a benign and a malignant tumor, than in epidemiologic studies that seek to investigate the association with a history of asbestos exposure, in which consistency of diagnostic criteria in ex- _ posed and unexposed groups is all important. . . Because of the between-tumor and witbin-tumor histologic variation mentioned previous ly, and the not infrequent development of the ; growth in the track of the biopsy needle, other methods of examination have been used to in crease the certainty of diagnosis. Thus, the pres ence of hyaluronic acid in the pleural fluid (207) or its demonstration in tumor tissue hy^* histochemical techniques (208) may be of some ^ value in distinguishing between mesothelioma jjg and secondary carcinoma, but is not the definnjjj| SBB& tive test it was originally believed to be Cytologic examination of pleural fluids, by lig the Co eff vis chc ca^ 1 po. ere an th. se'. tri in $h: fir ca se* in di in su re. a)! in th< of ti\ m R* an in th g* m u<. recurrence of the tumor, o. 267). There is only one in association with pleu4); the association may incidental. The presental tumors are invariably -replications include par- ial obstruction, is usual))' one of rapid d tumors, the average surof symptoms is approxiperitoneai tumors, 13 to es, however, and in one se e alive after 3 years (187). ore benign the course, the >e pathologic classification benign mesothelioma (205). and Treatment be definitely made only by .'here are a number of rea- to make a positive diagno sing life, even when ade* al is available. These inety of cell types within a Uy 'J*ose of the mixed type, cl primary tumors else- it is claimed that diagno.al can be accurate in most , p. 647). In addition, there obtaining agreement beon histologic characteristics 58), a difficulty reflected by it number of cases, less than e series (206), subsequently belioma review panels. This s important in clinical mediimportant distinction is be1 a malignant tumor, than in es that seek to investigate the history of asbestos exposure, y of diagnostic criteria in ex* td groups is all important. etween-tumor and within-tu-^ riation mentioned previous-^ frequent development of k of the biopsy needle, other, nation have been used to in*., y of diagnosis. Thus, the pr** ic acid in the pleural fluid. nstration in tumor tissue.bf miques (208) may be of ishing between mesothelioma dcfinfl c a, but is not the igii.iily believed to be <m ttion of pleural fluids vbyhg^ ( | 1 ASBESTOS-RELATED LUNG DISEASES and electron microscopy, may offer useful con tributory evidence. A series of papers under the general title "Assessment of Methods Used in the Studies of the Biological Effect of Asbestos to Pathology" (7, pp. 58-81) provides a most convenient and up-to-date summary of these methods, their precision, and general applic ability. The radiologic appearances vary according to the stage to which the disease has progressed. Common features are the presence of a pleural effusion, lobulated tumor masses that may be visible only after removal of the pleural fluid, chest wall masses, satellite lung lesions, and, oc casionally, hydropneumothorax (209). In a review of treatments (13, p. 277) Elmes pointed out that there is no effective curative treatment, although surgical excision, local and/or systemic cytotoxic therapy, and radio therapy have all been- tried. He also pointed out several features that suggest a considerable con tribution of the body's defense mechanism, both in the formation of abnormal tissue and in the shaping of its clinical course. Relative to the first point is the apparently low dose of exposure capable of eliciting a response; relative to the second is the not infrequent occurrence of chest injuries and/or infections at the onset of the clinical course, and the sometimes rapid dissem ination, apparently provoked by treatments, such as radiation or cytotoxic drugs. For these reasons, he believes that this tumor may eventu ally turn out to be controllable through improv ing body defenses. Thus, it is not surprising that the use of BCG vaccine in treatment is a matter of great current interest, with, as yet, no defini tive evidence on which to base clinical action. Meanwhile, therapy is symptomatic, and diag nostic measures should be kept to a minimum. Removal of fluid for diagnostic examination and to relieve breathlessness should be done as infrequently as possible. Indeed, as Elmes notes, the establishment of a precise diagnosis in life, given die absence of a potentially curative treat ment, is an academic, rather than a clinically useful, exercise. Carcinoma of the Lung Associated with Asbestos Exposure An association between asbestosis and bron chial carcinoma, suspected in the 1930s on the basis of individual case reports (210), was sub* c^uently confirmed in two British reports, one by the Chief Inspector of Factories, issued in 1W7, and the second, an analysis of autopsy ma terial from more than 1,000 cases of pneumocon iosis published in 1951 (211). From these, it appeared that asbestosis was associated with a much higher lung cancer risk than other pneu moconiosis, with 15 to 20 per cent of men re corded as having asbestosis dying from this cause. This risk was reported to have further in creased considerably in Britain by 1963 (10), and a similar increase in lung cancer risk during the same decades has been reported from Ger many (Jacob, 5, p. 536). The emergence of lung cancer as an important threat to the health of asbestos workers is attributed to the improvement in dust conditions, with less mortality from asbes tosis occurring after longer periods of exposure and, therefore, survival of workers through the long latent period of lung cancer (63). Subsequent epidemiologic studies have amply confirmed the association between asbestos ex posure and lung cancer, mortality experience being the chief method of study (63, 67, 82); however, table 7 indicates that despite the con sistently increased relative risk in these reports, there are considerable between-study differences as to its degree. Some of these differences must certainly be ascribed to between-study differences in the methods used to calculate risk (217), particularly in such factors as composition of the risk group (in terms of age, years of exposure, and length of follow-up), and the nature of the control or reference group, which could be eith er a low-exposure group within the working population, or an appropriate reference popu lation derived from national statistics. In addi tion, most studies deal with relatively small numbers of deaths (less than 100 in all but 2 of the studies), so that calculation would inevi tably be influenced by the addition or loss of one case. Finally, differences in exposure dose and smoking habits are other relevant factors for which standardization is seldom possible. As Wagner and associates point out, however, "an additional lesson to be learnt from the appar ent conflict of evidence is the need to pay more attention to the type of asbestos and to the physical state of the respirable faction of the dust" (218), and the evidence that there are real differences in risk associated with the diff erent fiber types, as well as the different types of exposure to the same fiber, is becoming more convincing. Such differences, however, have a greater significance in the field of environmen tal control and safety standards than in the prac tice of clinical medicine. The interaction of cigarettes and asbestos ex posure as risk factors, clarified to some extent by 214 MARGARET R. BECKLAKE epidemiologic studies, is, however, o very real importance in clinical practice. Carcinoma of the lung appears to develop only very rarely in the nonsmoker exposed to asbestos (63, 73) whereas the risk associated with exposure to both is considerably more than additive, and proba bly multiplicative (63,73,219). It was originally believed that the tumor was a scar cancer, because of its common location in the lower lobes, where fibrosis tends to be most marked (220). Animal experiments support this hypothesis (62). However, although usually found in lungs, which are the seat of fibrosis (67, 221), this is not always so (220). Cases have also been reported in association with rela tively mild fibrosis, and occasionally in the ab sence of fibrosis (220). Similarly, although cases occur almost exclusively in smokers (63, 219), there is some evidence to suggest that the dis tribution of cell types is different from that seen in smokers without exposure, namely, a greater preponderance of adenocarcinoma (222). This has led to the hypothesis that the carcinogens in cigarette smoke may have been delivered to the more peripheral regions of the bronchial tree by the fibers and dust particles (222). Not all series show this_ greater preponderance of adenocarcinoma, however, and the question re mains open. In one series, the presence of pleu ral plaques appeared to be associated with a higher risk for developing cancer (130), but it also seems possible that the presence of plaques may also merely reflect a higher exposure dose. Multiple primary tumors, sometimes of different cell types, have also been described in relation to asbestos exposure (223). The clinical picture, prognosis, and treatment are no different from those seen in the person not exposed to asbestos, except that the asso ciated fibrosis may limit the treatment options. Advice to, and help in, quitting smoking are clearly even more important for the worker ex posed to asbestos than his or her unexposed com panion, and a concerted effort at worker educa tion might prove worthwhile. Another practical problem concerns compen sation, in particular, the question of attributability of lung cancer to exposure in the absence of significant fibrosis. Some compensation boards, acting on the dose-relationship informa tion, award the benefit of the doubt if ex posure has been considerable in a nonsmoker. Finally, as has been emphasized elsewhere (220, 223), the "occupational history may not seem important in patients with carcinoma and is often not diligently pursued." The epi demiologic evidence summarized here un derlines the importance of establishing this as sociation. Other Asbestos-Related Cancers In most mortality studies of asbestos workers, there is a greater-than-expected risk, for all can cers (table 7). Lung cancer shows the greatest relative risk, followed by cancers of the gastro intestinal tract. The excess of gastrointestinal cancers is evident in all series, whatever the ref erence population used to calculate expected number of deaths, with one exception, namely, workers exposed in anthophyllite mining (77). This presumably is further evidence of the dif ference in the biologic effects of the different fiber types. There is also some evidence to sug gest that environmental exposures may be of importance in gastrointestinal cancer (16). In addition to lung cancer, there is increasing evidence that asbestos exposure is associated with cancer of the larynx (11-14). Like lung cancer, this cancer also has a long latent period (13). and cigarette smoking is a well-recognized asso ciated risk factor. Indeed, it is surprising that its association with asbestos has only recently been recognized, but this is perhaps because it is less common than lung cancer. An association between asbestos exposure and ovarian cancer, suggested originally on the basis of both clinical (10) and animal studies (15), has not, in the view of the Advisory Commit tee on Asbestos Cancers (7, p. 342), been con firmed in the first large mortality survey of wom en asbestos workers (7, p. 203). It is believed that the clinical cases originally believed to be ovarian tumors were malignant mesothelioma of the peritoneum (10,186). An association of asbestos exposure (as re flected in the lung count of asbestos bodies) and carcinoma of the breast in women has been reported in one study from London, England (16), a study that, paradoxically, did not show the same thing for carcinoma of the bron chus. Other cancers with suspected, but unsub stantiated, associations with asbestos exposure are leukemia, multiple myeloma, and Walden strom's macroglobulinemia (10). They are mentioned here, not to alarm physicians or their patients, but to underline the strength of the association between asbestos and many human cancers. For certain cancers this associa tion calls for clinical action, even though it re mains to be proved whether asbestos itself is iy pursued." The epiimmarized here un->i establishing this as- Cancers s of asbestos workers, pected risk for all can cer shows the greatest cancers of the gastro:e$s of gastrointestinal eries, whatever the refto calculate expected one exception, namely, iiophyllite mining (77). her evidence of the difeffects of the different 0 some evidence to sug1 exposures may be of tinal cancer (16). icer, there is increasing oosure is associated with -14). Like lung cancer, >ng latent period (13), a well-recognized asso., it is surprising that its has only recently been ei because it is less r. n asbestos exposure and i originally on the basis id animal studies (15), the Advisory Commit > (7, p. 342), been connortality survey of worn . p. 203). It is believed riginaliy believed to be lignant mesothelioma of bestos exposure (as re-,1 t of asbestos bodies) and st in women has been from London, England doxically, did not show; arcinoma of the bron* :h suspected, but uhsuIk with asbestos exposurt myeloma, and Walden emia (30). They.&! to alarm physicians .nderline the strength^* en asbestos and -tain cancers this assoa*^ ction, even thoughitxg st sbestos itself.asjbe il c + - c- p* 0) . . p p* s aa -- f-C <e <9 o O 13 ggg coo 200 o O to 2 2 9) 9) CC a ra e 33 V 22 p (0 o *0 c oc p* -= co co 3 TJ co 01 Ss o X o c 0 i2 O sc ui 1 | ) 05 6o p1 1 u> n CO co d-* ^ d c-. o O 1 o' T" (V w 2^ ov < n -- -1 CO <0 Cl Cl - oo Cm CM CM - p- S 02 u C v. M- S * *" <M O CM w 1": O t n r o o *- rj-' co co in i i^ 1 CM 10 "J *- o o CM CO CO r_ no CO 216 MARGARET R. BECKLAKE human carcinogen, or a cocarcinogen, and/or potentiator of cigarette smoke and/or other factors. The Influence of Fiber Type and the Nature of Exposure on Biological Response After the 1964 New York Conference (5), the UICC working group on cancer urged study of "the relationship of dust dosage (including concentration and duration of exposure) and the composition and physical state of the dust to the incidence of asbestosis, carcinoma of the lung, mesothelioma and other cancers." In other words, 2 areas were identified for urgent future research: (!) to establish whether dose-response relationships exist between exposure and bio logic response, and (2) to establish whether the composition and physical state of the dust affects these dose-response relationships. In the ensuing 11 years, health scientists throughout the world have gathered data in sup port of the first hypothesis, namely, that a doseresponse relationship exists for all of the re sponses listed (asbestosis, carcinoma of the lung, other cancers, and, probably, mesothelioma). Furthermore, this holds for all types of fiber and for all types of exposure investigated. The evi dence has been already summarized-in table 4. It has proved more difficult to investigate the second hypothesis, that composition and physi cal state of the dust influence the responses, be cause this requires the comparison of dose-re sponse curves for different fibers, or for the same fiber under different exposure conditions, e.g., mining and milling compared to manufac turing. Even animal studies in which exposure can be relatively well controlled are inconclu sive about the relative fibrogenicity of different fiber types (62, 224) although differences in car cinogenic potential have been shown (224). Epidemiologic studies in man in different oc cupationally exposed groups suggest differences between fibers, and between exposures, in terms of their carcinogenic potential both for lung cancer (table 6) and for mesothelioma (224); however, it is usually impossible to es tablish to what extent these can be explained by differences in exposure levels and associated fac tors, such as cigarettes and other co-carcino gens. Furthermore, exposures to one fiber type only are rare (usually in mining), and most production workers have mixed exposures (224). For instance, table 8 summarizes data collected in Quebec asbestos workers, exposed only to chrysotile fibers. Even in these results, which show a dose effect for all responses, there are between-area differences, particularly for ra diologic changes, for men of the same stock and working the same geologic deposit, and with ex posure calculated using the same type of index. Given these between-area differences, to what ex tent, if any, are these dose-response curves ap plicable to other working populations? Criteria for comparability require that both the dose and the response be measured in a similar fashion and that the populations com pared have equivalent susceptibility. Enough has already been said to indicate that even if the first 2 criteria were met, virtually nothing is known about the factors accounting for suscep tibility, much less whether it is possible to mea sure them in practice. The only comparison at- ' tempted was inconclusive, because mortality was assessed by fundamentally different techniques (figure 5). Thus, it is not possible to deduce from this comparison whether, indeed, there is greater risk for production workers compared to miners (figure 5, upper panel) attributable to differences in the nature of the exposure, an interpretation for which there is little scientific justification, or whether the risk is comparable for both groups, but the scaling (figure 5, lower panel) requires appropriate adjustment. Despite the difficulties in making between- .. study comparisons, a consensus has emerged, out- ; lined in a carefully reasoned paper by Kleinfeld (224), and in the conclusion of the Advisory . Committee on Asbestos Cancers (7, p. 341). It is believed that there are gradients in the meso- _ thelioma-producing potential, related to fiber type (greatest with crocidolite, less with amo- site and with chrysotile, least with anthophyl- ; lite) and to occupation (e.g., for amosite, ; ;greatest in insulation workers compared to mi- . ners). Gradients in fibrogenic capability of the .V; different fibers, less dear, may also be present, with crocidolite leading chrysotile, whereas gra dients in lung cancer risk may be more dosely related to the nature of the exposure, with-c production leading mining, at least for chryso-^ . tile. '= " To date, the best explanation of these gradi;Jf ents in biologic potential is that developed Timbrell (7, p. 295), namely, that biologic ac*^]/ tivity relates to the degree of penetration and k;, deposition in the lung (see also figure 6). Thu^ the greater mesothelioma potential of crocido^i lite compared to amosite, anthophyllite, afid^^g chrysotile, could be due to its smaller fiber a_^|g. and its other aerodynamic properties, which per* ~ mit greater penetration and deposition. Similar^ ? all responses, there particularly for ra- ihe same stock and eposit, and with ex same type of index, ferences, to what ex response curves ap- cmlations? y require that both be measured in a ie populations com- ptibility. Enough has cate that even if the virtually nothing is .ccounting for suscepit is possible to mea- e only comparison at- because mortality was different techniques possible to deduce .her, indeed, there is workers compared to anel) attributable to of the exposure, an rere is little scientific is comparable ai. __ (figure 5, lower .`adjustment. ^_ in making betweennsus has emerged, outad paper by Kleinfeld 5ion of the Advisory; .ancers (7, p- 341). It, gradients in the mesov^ itial, related to fiberp iolite, less with amo-^ least with anthophyl*^ (e.g., for amosite,: kers compared to mi* enic capability of may also be present, hrysotile, whereas c may be more . foe exposure, with' ag, at least for anation of these 1 is that developed.. mely, that biologic,* ee of penetration" ee also figure 6)^TM a potential of k -thophylhte,_ to smaller c properties, vht^ and deposition. SuTM v ASBESTOS-RELATED lung diseases r-li ;> ;i \m-:\iii jS&iii:! : i i 218 MARGARET R. BECKLAKE ly, the greater mesothelioma and, possibly, cancer potential of amosite in manufacturing processes, compared to mining, could be attrib uted to the smaller particle size for the fiber re leased in a production plant compared to that at the mine head. At the practical level of environmental con trol, regulations proposed for chrysotile in 1968 (225) by the British Occupational Hygiene So ciety were at a level (2 fibers per cm3 aver aged over 3 months) that, it was hoped, would allow no more than 1 per cent risk of disease (specifically, asbestosis) in a 50-year working life. Evidence suggests that this would also re- duce risk of bronchogenic cancer. At the time, the British Occupational Hygiene Society was uncertain that standards for other fibers should follow ``by analogy." They subsequently pro posed the same standards for amosite (226), but a standard 10 times more stringent for croddo- lite (227) was promulgated by government reg ulation. Furthermore, because all standards should be regarded as no more than an expres sion of die "best available hypothesis" of lev els adequate to protect human health, they should always be reviewed in the light of sub- / sequent evidence. This was done in 1973 for chrysotile, and no change was recommended .. (228). In the United States, the Occupational ' . Health and Safety Administration (OSHA) pro mulgated a standard of 5 fibers per cm3 in 1972, . to be reduced to 2 fibers per cm3 in 1976 (229), and there was a recent proposal to lower further the standard to 0.5 fibers per cm3 (230). These standards apply to all fiber types. Research should continue in an attempt to identify more precisely the reasons for between- fiber differences in biologic effect, because a better understanding of what determines the biologic responses of this mineral can only re sult in its human use being conducted under' conditions that more effectively protect the health of the exposed worker. . Fig. 5. [From Schneiderman (93); reprinted by per mission of publisher.) Dose-response relationship for cancer of the bronchus and lung. The data shown are those of McDonald (7, p. 189), describing chry sotile asbestos miners (left scale), and those of En terline and associates (82, 83), describing produc tion workers (right scale). In McDonald's data, mor tality was expressed as equivalent average death rates (85, 92) to enable a within-population comparison between men with low and higher dust exposure. The data of Enterline and associates were re ported as standardized mortality ratios, which used for comparison the most appropriate gen eral population statistics. Dust exposure in both studies was calculated in similar fashion and ex pressed in million particles per foot3-years (82, 83, 91). The vertical scales are drawn so that an equiva lent average death rate of 20 is equated with a stan dardized mortality ratio of 200 in the top panel and 400 in the bottom panel, which results in both sets of data falling on the same curve. Clinicaf Implications of the Epidemiologic Findings Faced with a patient in whom the diagnosis of one of the described diseases has been made, i.e., fibrosis of the lungs and/or pleura, or can cer of the lungs and/or pleura, ft may be im- : portant to establish whether, in this particular case, the disease is asbestos related. If the pa tient is currently' known to be exposed, this ' rarely presents a problem. If not, a systematic history is called for, and should include all his or her previous occupations (including short- term jobs, summer jobs, and so on), as well those of his or her work colleagues and family g members. In addition, places of residence should be noted, particularly if the diagnosis is rneso-./' ' thelioma and/or pleural plaques. The discov* ^ ery of asbestos fibers, coated or uncoated, in a;-, biologic material (sputum or biopsy or surgical .im material) requires explanation, if not already ^ evident from the history. Establishment of association with asbestos has importance if tributability is questioned (in cases of compen^v^ sation), as well as for other workers if the had not previously been recognized. : The dose relationship, particularly of cer. At the time, iene Society was her fibers should ubsequemly promosite (226), but igent for crocido- government regse all standards e than an expresypothesis" of levnan health, they . the light of subdone in 1973 for was recommended . the Occupational anon (OSHA) proers per cm3 in 1972, cm3 in 1976 (229), al to lower further - cm3 (230). These >es. in an attempt to ;asons for between : effect, because a iat determines the ineral can only rel lucted under' ;ti> , protect the V t- ASBESTOS-RELATED LUNG DISEASES CROCIDOL1TE AMOSITE 219 ANTHOPHVLLITE \ 1 r-' CHRYSOTILE At i the diagnosis of has been made, :>r pleura, or can- jj* a, it may be jmin this particular "U elated. If the pa-'.|3 be exposed, this not, a systematic^ ild include all hisj|f (including short*! so on), as well asj eagues and family^" 3f residence should^ diagnosis is rneso-j iques. The discofZ d or uncoated/ inj * biopsy or surgical^ on, if not already^ stablishment ofijj s importance if*t in cases of comp*.. -kers if the ng _ ed. - . .->i rticularly of fibr 10/jm Eig. 6. [From Timbrel!, V.: Physical factors as. etiologic mechanisms, in Biological Effects of Asbestos, IARC Scientific Publication No. 8, Lyon, 1973, p. 295; reprinted by permission of publisher.] Electron micrographs of crocidolite (north-western Cape Province), amosite (Transvaal), anthophyllite (Finland), chrysotile (Canada) at the same magnification (X 1700). Features to note are (7) the rectilinear shape of the amphibole fibers compared with the curved and twisted mor phology of chrysotile fibers; (2) the order of the diameters of the amphibole fibers, suggested by numerous electron micrographic examinations of these fibers from the 3 geographical areas, crocidolite < amosite < anthophyllite; (7) the longitudinal fragmentation of the chrysotile fibers and the small diameter (about 0.03 pm) of the ultimate fibrils. u> exposure should always be borne in mind, *nd the patient in whom disease develops after " relatively short period (for example, less than -j 25 years) must be taken as an indicator of un Satisfactory past and/or present working condv *os, requiring forceful corrective action. The *uae attitude should be taken toward the perV- in whom fibrosis is believed to be present in ,rr?i it* early stages or development, either on clini- radiologic, or functional evidence. Any _-4,c that this is not so because the "'environ- levels" to which the person was exposed `safe" is incorrect; levels were clearly not "safe" for the particular person concerned, either because of greater-than-suspected dose, or greater-than-average susceptibility. It must be emphasized that the clinician's job is not only to recognize the case of asbestos^related disease, but also to see that it is brought to the attention of the appropriate executive authority (in many areas, the Workmen's Com pensation Committee, which informs the com pany concerned). This recognition and re ferral has social implications at 2 levels. For the person, the implication is appropriate compen sation, society's fumbling best to make up for his or her loss of health. At the second level the capacity. At what point in time changes in one occurrence of an asbestos-related illness is ap or more of these methods of examination call proached as a failure of control measures, and for action remains to be established. one seeks to identify the point of failure so that For the currently exposed worker, research appropriate action can be taken to protect the in this area certainly has the most relevance, in 4; health of the new generation of workers (the particular, methods of identifying the persons children and younger colleagues of today's vic in whom the disease will progress, whether or tims), who may be currently entering the in not exposure continues. Animal work suggests dustry. that withdrawal from exposure may slow pro Nowhere is this more evident than with the gression (62), and in the absence of definitive , finding of a patient with malignant mesothelio data, this must also be assumed to occur in man. ~ I1 ma whose only possible contact with asbestos is With regard to the future worker, it remains to indirect, through neighborhood and/or domes be determined whether the person at high risk ' tic exposure. Given a history of neighborhood can be identified before entry into the indus- : exposure, should one advise the family to move try. Meanwhile, there seems to be merit in de for the sake of its other members? Probably not, ploying energy into maintaining currently pro because the long time lag of this tumor makes posed standards. Three times in the twentieth it most likely that they have already received century, levels have been set, because the asbes any exposure relevant to the future develop tos worker's health became a matter of public ment of mesothelioma. Should new families mov concern. Had the standards been more system ing into the district be advised against this, un atically adhered to, it is likely that the asbestos- less there has been appropriate action for en related diseases would not have re-emerged vironmental control over the previous years? An unanswerable question. Given a history of do mestic exposure, the clinician should at least be able to assure the new families that work prac as the "occupational illness of the 60s," a testi mony to the working conditions of the previous decade. It is to be hoped that current concern is translated into effective action for the work l I tice codes now insist that dusty work clothes are force currently entering the industry. not taken home to be cleaned. Faced with a person with a known exposure Acknowledgment _ risk, what medical measures can be taken to pro The writer wishes to express her very sincere appre- . tect his or her health? Sadly, it must be ad ciation to Dr. S. Hurwitz of the University of the mitted that there are none, because effective Witwatersrand, Johannesburg, South Africa, for able . health protection lies in effective environmental control, and medical surveillance is, probably correctly, considered a form of biologic moni toring supplementary to environmental moni toring (231). Thus, good work practices and quitting or refraining from smoking are the best "medical measures" for the individual worker; however, the examination implied by medical surveillance can provide other services, includ help in the literature search behind this review; to Dr. J. C. McDonald, director, and all members of the McGill University group engaged in research into the .... health effects of asbestos exposure since 1964, in tecognition of their stimulating collaboration during r this period, experience that forms the basis of the present review; to Dr. R. Oseasohn, Chairman, and Prof. F. D. K. Liddell, Dr. G. Gibbs, and Dr. M.A Arhirii of the Department of Epidemiology and Health, McGill University, and Dr. M. Newhouse of -v ing case detection and other forms of health the London School of Tropical Medicine and Hy*. ^. care. As knowledge improves, it is possible that medical surveillance will be able to fulfill its hoped-for role, namely, the detection of health effects in a person at a stage when some action (for instance, removal from exposure) might prevent eventual disablement. Given the "imperfect" state of the art, it is, at present, believed that medical surveillance giene for valuable editorial comment; to Dr. M- Pelnar, of the Institute of Occupational and ronmental Health, Quebec Asbestos Mining Assoda- j tion, for access to the Institute's extensive library of ^ reprints and for his editorial comment; and to DUDe , L. Cloutier, Jane Ross, Arlette Maurus, and Th. Hopkinson for their willing help in preparation.^';' the manuscript. should include a clinical examination (empha sis on basal crepitations), an annual chest radio graph, and a measurement of lung function, References ). Hamilton, A., and Hardy, H.: Industrial.T* cology, ed. 3, Publishing Sciences Group probably the most useful being the forced ex Acton, Mass., 1974, p. 421. ' h\! piratory volume test, and possibly the diffusing 2. Gilson, J. C.: Asbestos cancer: Past andg ASBESTOS-RELATED LUNG DISEASES te changes in one examination call ;hed. worker, research nost relevance, in fying the persons -gress, whether or nal work suggests re may slow pro- .ence o definitive d to occur in man. rker, it remains to person at high risk try into the indus- to be merit in de- ning currently pro 's in the twentieth . because the asbes*' \ matter of public been more system- y that the asbestoshave re-emerged >f the 60s," a testi5ns of the previous 5S**&.,.*>v- at current concern iffy * for the work- K ' A# me tent \ ir very sincere apprehe University of the' South Africa, for able; ehind this review; to^ nd all members of tbe^ ed in research into thej* ure since 1964, in rec-jp collaboration during5 arms the basis of the* isohn. Chairman, and. V. Gibbs, and Dr. M.^ of Epidemiology i Pr. M. Newhe>usey al Medicine and Hja comment; to Pr.*>M xupational and Eaw bestos Mining Asmo*s e's extensive library**! omment; and to DitfS te Maurus, and Tb^ aelp in prepara..vOTg H.: indust^g anui: ^ hazards, ProcRSoc Med, 1973,66,395 3. Zussman, J.: Asbestos: Nature and history, Rev Ciba-Geigy, 1972,2,3. 4. Sraither, W. J.: Asbestos and asbestosis, Ann Occup Hyg, 1970,13,3. 5. Biological effects of asbestos, I. J. Selikoff, and J. Churg, co-chairmen. Proceedings of a con ference held at the New York Academy of Sciences, Oct. 19-21, 1964, Ann N Y Acad Sd, 1965,132, pp. 1-766. 6. Biological effects of asbestos, M. Anspach, Chairman, Deutsches Zemralinstitut fur Ar- beitsmedizin: Gesellschaft fur Aibeitshygiene und Arbeitsschutz in der DDR, Dresden, April 22-25,1968, pp. 1-312. 7. Biological effects of asbestos, P. Bogovski, J. G. Gilson, V. Timbrell, and J. C. Wagner, ed. 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