American Journal of Industrial Medicine 22905-923 (1992)

HISTORICAL PERSPECTIVES IN OCCUPATIONAL MEDICINE

Coal Workers’ Pneumoconiosis: A Historical Perspective on Its Pathogenesis A.G. Heppleston, DSC, MD, FRCP, FRCPath

The earliest observations on coal workers’ pneumoconiosis identified fundamental factors and posed particular problems in its genesis. Among the former, intensity of exposure and particle size were recognized, while argument commenced on the roles of stone dust, thus anticipating the quartz question, and of complicating pulmonary states, which introduced the idea of infection. Major studies of the disease were precipitated by its greatly increased prevalence, which became evident among South Wales coal workers from the 1930s. The principal directions of enquiry remained the same as in Scotland a century before, namely the components of coal mine dust responsible for fibrosis and the additional factor required for the development of massive fibrosis. The combined human and experimental evidence now makes possible conclusions in which confidence may be placed. 0 1992 Wiley-Liss. Inc. Key words: fibrosis, quartz exposure, massive lesions, tuberculosis, lipidosis, lung function, coal workers, macrophages, molecular biology, cytokines

INTRODUCTION Exploration of disease processes increasingly proceeds at the molecular level and, to this pattern, investigation of the pneumoconioses is no exception. The characteristic response to inhalation of mineral particles (whether compact or fibrous) is, under natural conditions, dominated by alveolar macrophages, and cells lavaged from exposed individuals release (in culture) mediators of the inflammatory reaction such as oxidants, chemoattractants, and growth factors, though the rather nebulous element of individual susceptibility may also play a part [Rom, 19911. In respect to coal workers, the presence of simple pneumoconiosis correlated with an increased release of the cytokine tumor necrosis factor (TNF) from blood monocytes, particularly when stimulated in vitro by coal mine dust [Bonn et al., 19881. Alveolar macrophages too secrete cytokines including TNF and interleukin-1, but these effects do not distinguish simple pneumoconiosis from massive fibrosis [Lassalle et al., 19901. Arachidonic acid (AA) metabolites are also inflammatory mediators likewise released by

Institute of Occupational Medicine, Edinburgh, United Kingdom. Address correspondence to Professor A.G. Heppleston, Bridgeford Gate, Bellingham, Hexham, Northumberland, NE48 2HU, United Kingdom. Accepted for publication March 2, 1992.

0 1992 Wiley-Liss, Inc.

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alveolar macrophages and, after inhaling coal dust, those from rats reveal increased production of thromboxane A, and leukotriene B, but diminished secretion of prostaglandin E, [Kuhn et al., 19901. Whether these mechanisms are, on balance, beneficial remains uncertain, since AA metabolites may enhance both the defensive and fibrogenic responses. The protease-antiprotease hypothesis may even be invoked to account for emphysema in coal workers [Rom, 19901. These avenues indeed lead to better understanding of basic processes, but they are not restricted to the domain of dust disorders, for elucidation of which other lines of enquiry may be equally or even more appropriate. Consideration of the pathogenesis of coal workers’ pneumoconiosis (CWP) from the earliest reports bears out this contention and discloses persistent themes. PIONEERS

Almost two decades before the morphological appearance of dust disease as seen in coal workers was first recorded, the fundamental features of particle disposition in the lung formed the topic of a remarkable account dealing with nonminers who were presumably town dwellers. Pearson [1813], in a paper presented to the Royal Society, described black or dark blue bronchial glands together with maculae, lines, and points of similar color beneath the pleura and throughout the whole interior substance of the lungs, features generally more evident in older individuals. By extraction with strong acid or alkali he obtained a black sediment, which could be ignited with the emission of “charcoal acid” and which was considered to be “animal charcoal in the uncombined state. ” From the physiological aspect, Pearson believed the charcoal to be inspired with the air as invisibly small particles, derived from burning of coal, wood, or other inflammable materials and then retained in the minutest ramifications of the air tubes or even in the air vesicles. This coaly matter was absorbed by the lymphatics of the lung and conveyed to the bronchial glands and possibly to the thoracic duct. Larger particles remained unabsorbed, never penetrating further than the air tubes from which they were expectorated. George Pearson thus recognized, on chemical grounds, that fine coal particles reach the alveoli suspended in the inspired air. The case of John Hogg, a coal miner from Dalkeith, constitutes the first record of the macroscopic appearance of CWP [Gregory, 18311. The uniform black color of both lungs was, in the upper and middle lobes of the right lung, associated with massive lesions exhibiting irregular and intercommunicating cavities which were traversed by bands and contained much black fluid but did not suggest tuberculosis. Pigmentation was also noted in the bronchial glands, while digestion of lung tissue left a black powder which, on heating, emitted gas resembling that from coal and burned readily to leave a fluid similar to impure coal tar naphtha. Accordingly, the black matter was considered to be coal dust inhaled occupationally. Perhaps John Hogg deserves to be set beside Nellie Kershaw who, almost a century later, provided the first pathological evidence of asbestosis [Selikoff and Greenberg, 19911. The histological deficiency was soon remedied by T.W. Jones [ 18341, apparently in a Glasgow collier, in whom dust was located interstitially and “wherever the black matter existed in greater quantity, there the air-cells were dilated,” as Craig [1834] also noted in an aged town dweller. This observation most likely constitutes the first recognition of focal emphysema attributable to dust accumulation, while Craig also anticipated modern fixation technique by recommending inflation of the

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lung and drying before section so as to ascertain the exact location of the black matter. In conformity with pathological opinion of the day, Craig distinguished “true melanosis’ ’ (secondary melanoma) from “spurious melanosis” (pneumoconiosis), and further implied that accumulation of extraneous black matter in the lungs of healthy town dwellers, particularly older persons, differed merely in degree from spurious melanosis. Only when large amounts of black matter were inhaled, as by colliers, did the lungs become solid, and retention might be favored by tuberculosis or an “excavated state of the lung.” Supporting evidence was provided by an iron molder long exposed to high atmospheric concentration of wood charcoal [Hamilton, 18341, as well as by a chimney sweep, whose lungs had a “plum-pudding” structure and on chemical extraction contained carbon [Makellar, 18461. Comparative analysis with soft coal and lamp black suggested to Graham [ 18341 that carbonaceous matter in the lungs of miners conformed with the latter and was derived from ill-trimmed oil lamps, as used in Scotland where there was no risk of explosion. Using material from three cases of “spurious melanosis” in long-term colliers, Marshall [ 1833-1 834a, 1833-1834bl essayed the original attempt to trace consecutive stages in the disorder. Deep pigmentation throughout a crepitant and buoyant lung was followed by the formation of solid massive lesions in which softening later occurred to form an inky fluid and, if bronchial communication had existed, to black spit. Regarding the origin of the disease, he excluded blasting with gunpowder or lamp soot, and adhered to the role of fine coal dust, noting black staining of spit after each shift-and during strikes. Along with Craig, Marshall believed that pulmonary disease, arising from natural and recognizable causes, preceded in every instance the accession of the peculiar affection and related its irregular occurrence to the greater production of dust where hard coal was wrought long and under dry conditions. Gibson [ 183318341 went further in contending that Marshall’s cases represented ordinary phthisis in lung pigmented by harmless coal dust. Another view, contrary to Marshall’s, attributed pulmonary disease in coal miners to working in stone combined with bad ventilation, while dismissing coal dust and lamp black inhalation as harmless (Dewar, Philp, Steele and Stevenson, cited by Thompson [ 18371). Declining to go so far but conceding that disease was more severe and rapid in stone workers. Makellar [ 18451 maintained that miners of pure coal succumbed to “black phthisis.” He contended that this form of disease, whose features conformed with earlier descriptions, might be favored by hereditary predisposition, although tubercular phthisis was not prevalent in the colliery community, and such as occurred was mostly in females. To describe the black lung of coal workers, Stratton [1838] introduced the term “anthracosis” (Greek, charcoal). The extent to which interpretations of the nature and genesis of CWP depend on the observations of a small group of physicians, working in the Scottish lowlands during the fourth and fifth decades of the nineteenth century, can only be described as outstanding. The magnitude of their contributions is emphasized by the restricted amount of material then available, and the technical limitations of the period. Of the questions raised by the early investigators, two in particular begged for resolution but for long proved to be contentious issues, namely, the component(s) in coal mine dust responsible for the generation of connective tissue, and the nature of massive lesions. THE FALLOW PHASE Interest in CWP spread to the continent of Europe and, although the main contributions were hardly notable for the introduction of fresh concepts, detail was

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expanded. Giving the best histological account and chemical analysis (to that date) of pulmonary pigmentation, whether occupational or not, Robin and Verdeil [ 18531 recognized interstitial accumulation of carbon often in small packets (suggesting laden phagocytes) located subpleurally, in septa, and in the substance of lobules, as well as around bronchi and blood vessels, with lymphatic transport to hilar glands. Palpable islets of pigmentation could be detected in the parenchyma, and massive type lesions might be found, in approaching which air passages and vessels abruptly terminated and in which cavities with tuberculous features or without (i.e., probably ischemic) could occur. Crocq [1862a] likewise recorded the case of a collier with massive pulmonary lesions, in which the cavities could represent tuberculous or nontuberculous varieties. In addition, the lungs showed black spots (suggesting focal dust lesions), and nodules similar in texture to the massive lesions. Despite reports claiming that tuberculosis was rare among colliers, Crocq nevertheless considered that they ought to be more than usually liable to this disease, and concluded that a relative antagonism existed between the presence of coal and the formation of tubercles. In consequence, he was led to propose carbon inhalation as a treatment for pulmonary phthisis [Crocq, 1862b]. In essence, these findings were confirmed in copper and bronze molders exposed to a confined atmosphere charged with charcoal dust plus some coal and calcined sand, the extracted minerals reflecting this composition; the presence of silica did not apparently affect the pathological features [Tardieu, 18541. Based on the examination of four specimens of miners’ lungs sent to him from outside Germany, three coming from Scotland, Virchow [ 18591 contended that the pigmentation was hematogenous rather than the result of deposition from the inspired air, and he regarded the lesions as an organizing pneumonia. Although the account provides the first histological illustrations from diseased miners’ lungs, it is surprising that the great man was evidently unaware of previous studies convincingly showing the pigment to be both mineral and inhaled. Only after Traube [ 18601 published his account of the lung changes in a charcoal worker was Virchow [ 18661 finally convinced of the extraneous origin of the pigment in coal workers, and came to accept anthracosis as an entity distinct from other pigmented states of the lung. The means by which inhaled dusts exerted their deleterious effects began to receive attention. According to one view, interstitial penetration of particles was achieved by virtue of their hard, sharp edges, although the alleged paucity of connective tissue proliferation in coal workers militated against such a simple stimulus, based on the pronounced induration sometimes seen in these men and for which another component was apparently needed [Traube, 18601. Whilst endorsing this mechanical explanation, the nature of the material inhaled, whether carbonaceous or siliceous, assumed secondary importance according to Greenhow [ 1865a,b; 1866a,b,c; 18691. The observations of Greenhow, an Englishman, are exceptional for first employing polarized light in the study of lung dust. By demonstrating that rounded particles of inhaled iron oxide readily gained access to the pulmonary interstitium, Zenker [ 18671 not only decided the issue but introduced from the Greek the term ‘‘pneumonoconiosis,” and emphasized the essential resemblance in etiology between pulmonary anthracosis and siderosis, for whose anatomical changes dust itself was responsible. Confirmation that fibrosis was not dependent on imtation by hard and abrasive particles was later afforded by the failure of inhaled silicon carbide with its sharp edges to elicit fibrosis in guinea pigs’ lungs [Gardner, 19231. Intensity of exposure and particle size as pathogenetic factors may be deduced from Crocq’s

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[ 1862al reference to inequalities in incidence of disease, for which were implicated greater pulmonary retention in more dusty atmospheres or where the particles were finer. Inhalation of coal dust, he maintained, did not lead to irritation or inflammation but, by a process of accumulation, acted in a purely mechanical manner, the presence of symptoms denoting the repletion of the lungs by foreign material. With the study of more material came the realization that the pulmonary responses to stone and coal dusts were not identical and, moreover, that simple and indurated forms of what was called chalicosis (i.e., silicosis) and anthracosis could be differentiated [Seltmann, 1867; Arnold, 18851. Both these contributors reaffirmed the belief that pulmonary tuberculosis commonly complicated silicosis, whereas an antagonism appeared to exist between the infection and anthracosis, while connective tissue proliferation became much more prominent after sandstone inhalation. Conveyance of pigment to the lungs in atmospheric suspension received experimental confirmation and suggested the requirement of an additional inflammatory element in causing pulmonary induration [Knauff, 1867; Claisse and Josue, 18971. Arnold [ 18851 was equally concerned about dust collection and transport within the lung, for the study of which he embarked on a remarkable series of experiments in several species exposed to inhalation of soot, emery, and sandstone which, in that order, revealed increasing proliferation of connective tissue.

DECADESOFDOUBT Interest in lung disease of coal workers waned until World War I, after which it waxed, since greater mechanization in coal-getting increased production of atmospheric dust, and suppression measures did not keep pace. The effects on miners took time to become apparent, notably in the coal field of South Wales, which from west to east contained deposits of anthracite, steam, and bituminous types. Prior to that time, statistics from different countries led to the widespread belief, on which Arlidge [ 18921 commented, that serious lung disease associated with coal getting belonged to past history. The improvement was widely attributed to shorter working hours and especially to better ventilation, which was dictated in the first place by the necessity to prevent explosions. The views of J.S. Haldane [1918, 1923, 1930-1931, 1938-19391 exerted great though not unchallenged influence in discussions of dust disease among coal miners; these views were based, in large measure, on occupational and mortality statistics together with certification rates. He contended that, whereas silicosis was brought about by inhalation of siliceous dust and led to tubercular infection of the lungs with fibrosis exceeding that of ordinary phthisis (as in Cornwall, on the Rand, or after driving headings through sandstone or highly siliceous rock), coal miners’ phthisis (or “silicosis” as at that time it was alternatively called) showed no statistical evidence of silicosis and the risk of tuberculosis was much less. This relative immunity to phthisis was also evident in coal-boat loaders or coal trimmers as they became known. Claiming that coal mining was a healthy occupation and that the diminished liability to phthisis had existed for generations, Haldane believed that coal dust with its low free silica content tended to prevent this complication in anthracite and other districts. On the contrary, dangerous dusts containing a high proportion of free silica increased susceptibility to invasion by tubercle bacilli. An equally dogmatic stance was adopted by Cooke [1938], who was averse to using the term “anthracosis” to describe a

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definite pathological state, preferring the designation of “silico-anthracosis” to encompass the typical black masses with cavitation and inky fluid coexisting with discrete black nodules throughout the rest of the lung fields. Haldane saw no justification for the diagnosis of silicosis solely from x-ray appearances or the corresponding postmortem findings in the absence of a history of prolonged exposure to highly siliceous dust, and he asserted that silicosis did not arise from inhalation of dust containing only a small proportion of free silica. It had, nevertheless, to be conceded that after about 30 years of work at the coal face some healthy hewers, especially from the anthracite mines, showed x-ray mottling of the lungs such as occurred in silicosis and that excessive exposure to so-called harmless dusts may be deleterious, though in ways not specified. These miners had never worked in stone drifts where exposure to dust from highly siliceous rock might have occurred. The difficulty was to account for the numerous cases of “silicosis” certified from the anthracite area of South Wales, despite the lack of working histories showing exposure to highly siliceous dust and the absence of an increased occupational mortality from phthisis. To account for the contrasting findings between disease in coal workers and genuine silicosis, Haldane adduced experimental evidence showing inhaled coal and shale dusts to be cleared from the lungs but quartz to be retained, from which it seemed that the former dusts might assist elimination of harmful particles such as quartz or tubercle bacilli. So long as dust in coal mines was not explosive, nor inhaled in excessive quantities, no harm and possibly some good might accrue. Coal or other carbonaceous dusts were deemed to possess a high degree of adsorption for unspecified soluble substances, with shale being less active, and quartz minimally so. According to the amount of these substances they had adsorbed, dust particles were attracted to and stimulated collecting cells. Quartz particles presumably remained intracellularly and, being inert, were dangerous, whereas coal dust, being a reservoir of stimulatory substances, encouraged particle excretion. Sustained by the experiments of Mavrogordato [ 19221 and Carleton [ 19241, Haldane persisted with the view that colliers at that time did not develop miners’ phthisis, despite exposure to some free silica, which was thought to be eliminated in the drift from the lungs set up by coal dust stimulation of phagocytosis. Had Gardner’s [ 19291 inhalation experiments been known to Haldane, he would have derived further encouragement from the aggravation or reactivation of pulmonary tuberculosis by silica. Another of Haldane’s contentions concerned the impact of hard physical exertion, entailed in winning coal, on the genesis of emphysema and bronchitis. The latter was also blamed on chilling as miners rapidly descended long slopes (in “spake trains”) to reach anthracite workings [Jones, 19351. It should not be forgotten that Haldane was a renowned physiologist and Jones a mining engineer, both of whom depended for their opinions on mortality statistics and neither of whom cited pathological findings; they thus remained in ignorance of the precise characteristics displayed by the underlying disease. In the light of statistical and morphological evidence emerging during this period, Haldane’s interpretations required reassessment. The account by Cummins and Sladden [1930] of the histological changes in the lungs of workers from the anthracite area of South Wales merits particular attention. They recognized hard, black, or dark grey massive lesions and nodules in the apex of upper or lower lobes, coupled with small black maculae which had well-defined, polygonal outlines and were scattered throughout the lungs; tissue between masses and nodules might be

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emphysematous or normal in appearance. Tuberculous changes, of a relatively acellular type, sometimes coexisted with the massive lesions, but in advanced cases cavitation and liquefaction could occur independently of infection. Cummins and Sladden considered anthracotic fibrosis to be a special disease of coal workers for which inhalation of silica was a preceding and essential requirement, the latter determining the seventy of fibrosis which might lead to disability and death. As H.M. Medical Inspector of Mines, Fisher [ 1934-19351 now drew attention to several peculiarities of the disease: a) the increasing diagnosis of silicosis in coal workers; b) the greater number of cases in South Wales, especially the western anthracite area; c) the fact that in many cases it was not possible to trace a history of working in siliceous rock nor of exposure to stone dusting (used to minimize explosions); and d) in many cases, death was due to heart failure and not to tuberculosis. Fisher was evidently coming to believe that pneumoconiosis could follow inhalation of poorly siliceous dust, but, in discussing his paper, Collis [ 1934-19351 reverted to the distinction between “true silicosis” from inhalation of free silica with its predisposition to tuberculosis and “anthracosis” of coal workers which did not do so. For the latter, Owens [ 1934-19351 proposed to substitute the distinctive term “koniosis” apparently unaware that he had been anticipated by Zenker [ 18671. During this period, the King Edward VII Welsh National Memorial Association for the Prevention and Treatment of Tuberculosis (1930, cited by Fisher [ 1934-19351) noted that apparently healthy South Wales coal miners showed x-ray evidence of fibrosis which increased with length of exposure and was most evident in men from the anthracite field. Moreover, the Report of the Medical Research Council (1937-1938, cited by Haldane et al. [1938-19391) concluded that in recent years, it had become apparent that coal miners were subject to chronic pulmonary disease of a disabling nature, which did not come within the accepted definition of silicosis. RESURGENCE

In the 1830s, the Scottish coal fields had attracted attention but a century later the self-same questions on a larger scale begged for investigation in South Wales. As a consequence, the Medical Research Council embarked on a multidisciplinary enquiry, the results appearing in three special reports, though the present purpose focuses on the pathological and experimental findings obtained at the Postgraduate Medical School of London, the Pneumoconiosis Research Unit set up in Penarth (South Wales), and the Welsh National School of Medicine in Cardiff. Fibrogenesis by Coal Mine Dust

According to Belt and Feris [ 19421, much of whose material was provided by pathologists working in Cardiff and Swansea, the pulmonary changes observed in 42 Welsh coal miners fell into five pathological categories, the first four of which represented progressive stages. Reticulation referred to proliferation of reticulin fibers among dust-laden phagocytes distributed as streaks in the parenchyma; reticular nodulation included, in addition, focal indurations of irregular outline; in mixed nodulation, collagen fibers were also present; confluent fibrosis followed fusion of dust reticulation with added collagenous fibrosis; silicotic nodulation, on the other hand, took the usual form of concentrically arranged collagen with an outer capsule of densely-woven and sharply defined collagen, together with an ash pattern distinct

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from the diffuse one of dust reticulation. They also recognized a peculiar form of tuberculosis in combination with pneumoconiosis, the infection being so modified as to be scarcely identified except by detection of the bacillus. Emphysema, though a common finding, apparently exhibited no particular features and dust was considered not to be responsible. Thus portrayed, the primary lesion appeared to be a diffuse and symmetrical state of both lungs, thought to correspond with the early x-ray condition of so-called reticulation, but which later exhibited nodulations of variable shape though similar structure. The tissue response was proportional to the amount of dust and was regarded as a storage phenomenon or foreign body reaction of the simplest type, for which silica (i.e., mostly combined and not free) rather than coal was blamed. Analysis of mineral residues from the lungs of South Wales coal workers again concentrated on quartz content in relation to pathological category, but no statistical differences transpired between the earliest and the most severe grades [King and Nagelschmidt, 19451. Coal itself (i.e., independently of siliceous minerals) and the silicates kaolin and mica were considered, but eliminated in favor of quartz as the major etiological agent despite inability to account for confluent fibrosis. A larger series of 86 coal workers and tin miners had the advantage of whole lungs for analysis [King et al., 19561. No significant differences in the percentage contents of quartz and silicates existed between colliers and tin miners, but increasing content of total dust, quartz, and silicates in parallel with pathological grade led to the belief that total dust and quartz contributed to the genesis of CWP. When the pulmonary reactions to a range of selected dusts were tested in rats after intratracheal injection [Belt and King, 19451, pure coal elicited a minor degree of fibrosis similar to dust reticulation in miners. With dusts of mixed composition, no uniformity in pathogenicity was detected and among silicates as a whole, there was very considerable spread. Some silicates were considered to be fibrogenic even though the amount of quartz was very small or negligible. Stone dusts led to widely different reactions and unexplained discrepancies appeared when isolated fractions of mine dusts were examined. Pursuing the quartz theme in CWP, 2% mixed with anthracite failed to induce fibrosis by inhalation exposure of rats and the same concentration of quartz alone was also without effect [King et al., 19581. Although coal dusts from the lungs of two miners elicited collagenous fibrosis, the response could not be attributed to the small proportion of quartz (0.7% and 1.6%)and blame was attached to all the insoluble dusts [King et al., 19621; after inhalation, definite fibrosis occurred only when 20% quartz had been added to coal dust [Ross et al., 19621. On experimental grounds, convincing evidence of a particular role for the small quartz component of coal mine dust remains elusive [Heppleston, 19881. Surface impurities, probably derived from clays or their ions (notably aluminum), have been blamed for the lack of a clear relationship between toxicity and quartz content of coal mine dusts [Le Bouffant et al., 19821; evidence of surface contamination was indeed detected by physical methods [Kriegseis and Scharmann, 19821. Such contamination, especially by illite, was, however, inadequate to explain the different reactions to coal mine dusts with similar quartz contents [Davis et al., 19911, and dusts possessing widely different concentrations of quartz failed to induce equally distinct changes in pulmonary collagen levels [Robertson et al., 19881. It must be pointed out that neither of these latter studies paid attention to an important determinant of fibrogenesis, namely particle-induced generation of lung surfactant by type I1 cells, despite several illustrations disclosing its

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presence together with the foreign-body reaction which may ensue. Earlier experiments had actually shown illite and muscovite to evoke lipo-proteinosis in rats [Martin et al., 19771. Misinterpretations may be expected from conclusions which omit to take account of the nonfibrotic component of the pulmonary reaction to mineral particles [Heppleston, 19911. Furthermore, no correlation emerged between in vitro cytotoxicity , dust composition, or epidemiology, and in vivo procedures fared little better [Le Bouffant et al., 19881; for this disparity, interference by surfactant may again be responsible, as some experiments already suggest [Wallace et al., 19881. The material available to Belt and Ferris [1942], based in London, consisted of samples from relatively advanced cases, and their view was at variance with the earlier account by Cummins and Sladden [ 19301, who, working locally in South Wales, had identified the early changes as being focal in character. It tends to be overlooked that Badham and Taylor [ 19361, in describing the pathology of pneumoconiosis in coal workers from New South Wales, Australia reached two important conclusions. In their experience, dust fibrosis took the form of nodular (i.e., focal) lesions and led to the development of a circumscribed type of emphysema which could be disabling. Moreover, coal dust, apart from the minimal content of free or combined silica, was responsible for the fibrotic changes in the lungs of these men. Observations from the Welsh National School of Medicine, where for many years numerous autopsies were performed on coal workers referred by coroners, substantiated the focal distribution of simple dust lesions. Part, at least, of this divergence may be attributed to fixation technique, Belt and Ferris [ 19421 depending on undistended specimens, whereas Cardiff investigators routinely distended lungs intrabronchially to natural size with formalin as fixative before sectioning days later. In a series of steam-coal trimmers, whose work in the holds of cargo ships exposed them to intense concentrations of coal dust with little or no contaminating rock dust, Gough [ 19401 reported black nodular lesions, composed of dust and a small amount of connective tissue and surrounded by localized emphysematous spaces. In Welsh coal workers as a whole, emphysema was a common finding in and around focal collections of dust [Gough, 19441. The typical lesion of simple CWP exhibited several distinctive features from an early stage: a localized distribution with several such lesions in a lobule; a large amount of dust mostly in packets representing laden macrophages; a comparatively small amount of fibrous tissue, mostly in the form of reticulin fibers irregularly disposed among phagocytes; and in many, especially later, cases, emphysematous spaces limited to the substance or periphery of focal dust lesions [ Heppleston, 19471. Three-dimensional microanatomy revealed the simple dust lesion of coal workers to be a sleeve of laden macrophages with intermingled reticulin and perhaps collagen fibers occupying alveoli around the usual three orders of respiratory bronchiole, which were often dilated but never constricted as they were traced back to the parent terminal bronchiole [Heppleston, 19531, changes more accurately described as proximal acinar emphysema due to dust. At planes of section other than longitudinal, the enlargement presents as air spaces in and around stellate foci of dust. In being focal, the essential lesion of CWP corresponded with that of silicosis, but differed in other respects, namely, the amount and nature of dust, the quantity and disposition of fibrous tissue, and the presence of focal emphysema. These structural features were thus sufficiently dissimilar as to suggest a different causation. The harmlessness of coal mine dust could no longer be sustained, but again the minor

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quartz component has been invoked as the active agent. Exceptionally, coal workers are exposed to airborne dusts containing appreciably higher proportions of quartz than the usual level of 1 5 % and, under such circumstances, silicotic lesions may develop. However, evidence collated from diverse sources, including the Institute of Occupational Medicine in Edinburgh from where the pathological aspect of British Coal’s Pneumoconiosis Field Research (PFR) program was conducted [Ruckley et al., 19811, combines to indicate that in pathological terms the fibrogenic response to the usual mine and similar mixed dusts does not exhibit specific features and in humans may sometimes occur independently of the quartz content [Heppleston, 19881. The mode by which coal mine dust operates evidently involves the macrophage fibrogenic factor, the first dust-provoked cytokine to be recognized [Heppleston and Styles, 19671. Release of this factor appears to depend on concentration rather than coal composition [Heppleston et al., 19841. Furthermore, the amino acid constituents of the factor are now known and it has been shown to be active in vivo [Aalto et al., 19891. Whatever the mineral component of coal mine dust contributes to fibrogenesis, the response does not dominate in the customary manner of quartz. After immobilization by newly formed connective tissue, mine dust acts in an essentially mechanical fashion. Dust cells incarcerated at the typical location lead to imbalance between the forces of inspiration and expiration, mainly by loss of the geodesicallydisposed smooth muscle on which expiratory shortening and narrowing depend; the resultant dilatation of respiratory bronchioles then produces the characteristic emphysematous appearance in section. This feature cannot be blamed on loss of elastic tissue, since it is disrupted and fragmented in dust foci irrespective of the presence or absence of emphysema; the protease-antiprotease hypothesis thus appears to be irrelevant to this situation. The enzyme hypothesis would, in any case, need to account for restriction of emphysema to sites of focal dust aggregates, in contrast to the diffuse change encountered in cases of genetically-determined protease deficiency.

Massive Fibrosis Several morphological features emphasize that, in order to account for massive lesions in coal workers, a factor(s) additional to dust is required: a) the symmetry with which simple dust lesions are distributed throughout the lungs and the asymmetrical disposition of massive fibrosis which may affect only one lung; b) the occurrence, in some cases, of intense pigmentation without massive disease; c) the not infrequent development of progressive massive fibrosis in the presence of very little dust; d) the different histological pattern of dust and connective tissue between simple and massive lesions; and e) the prominence of hyaline change in the connective tissue of progressive massive fibrosis as compared with simple lesions. The earliest observations implicated inhaled dust combined with independent pulmonary disease in the genesis of what became known as progressive massive fibrosis and, in recent decades, the question of an immunological contribution has arisen. The dust factor. Its importance was established by the rising attack rate of progressive massive fibrosis with increasing background of simple pneumoconiosis [Hurley et al., 1987; Maclaren et al., 19891. However, many cases of progressive massive fibrosis occurred in men with radiological categories 0 or 1 of simple disease, so that prevention of higher x-ray categories would not solve the whole problem [Shennan et al., 19811. Moreover, divergent pathological features occurred for similar dust burdens and, although the concentration in progressive massive fibrosis was

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approximately double that elsewhere in the lung affected by simple pneumoconiosis, the quartz percentage in massive lesions was no higher, and ranged between 1 and 10% [King et al., 1956; Nagelschmidt et al., 19631. Quartz was not, therefore, considered to be an important factor in the genesis of progressive massive fibrosis; instead a second factor, probably tuberculous, was held to be required. The bearing of dust content and composition on pathological changes proved problematical in the PFR program. Least dust occurred in macules and most in progressive massive fibrosis, but between other groups, clear quantitative differences failed to emerge [Ruckley et al., 19811, and great variation in dust content was found for particular forms of lesions whether simple or complicated in type [Chapman and Ruckley, 19851. More ash and quartz were retained by miners of low rank coal, yet percentage composition of the dust between pathological grades from the same rank corresponded [Douglas et al., 19861. However, carbon pneumoconiosis occurred when the lung dust was virtually free of crystalline silica [Watson et al., 1959; Miller and Ramsden, 19611 and Nagelschmidt [1968] encountered cases of massive CWP in whose lung dust no quartz was detected. Similarly, hematite pneumoconiosis, whose morphology closely resembles that of CWP, occasionally occurs without detectable quartz in the lung dust of simple or complicated disease [Faulds and Nagelschmidt, 19621. Theoretically, selective transport to the hilar glands might clear the lung of quartz while leaving its pathological effects, but this argument fails in the face of complicated pneumoconiosis developing after exposure to dusts containing no quartz [Ruttner et al., 1952; Barrie and Gosselin, 19601. The infective factor. The pioneer studies introduced the idea of an infective origin for massive lesions in both coal and stone workers, and had since been applied to other occupations such as hematite mining. From their vast experience of silicosis in South African gold miners, Simson and Strachan [ 19351 distinguished morphologically and by guinea pig inoculation tuberculous and nontuberculous nodules and massive lesions, a conclusion with which Gardner [ 19401 concurred. The situation remains unchanged, since, among silicotic individuals from Hong Kong, the main risk factors were dust exposure level, background profusion of small radiological opacities, and a history of tuberculosis [Ng and Chen, 19911. The origin of progressive massive fibrosis in coal workers merits brief recapitulation in view of persistent resistance to the tuberculous concept. Objections stemmed largely from the low recovery rate of tubercle bacilli during life, 1.1% by laryngeal swab [Cochrane et al., 19521 and 7.7% from sputum [Kilpatrick et al., 19541, but bacilli appear in sputum only when lesions communicate with a bronchus, many of which are obliterated in massive lesions. However, culture from the bronchus prior to autopsy yielded a 28% positivity, and bacilli were recovered from 35% of 118 massive lesions [Rivers et al., 19571. Particularly impressive was James’ [ 19541 meticulous analysis of massive lesions from 254 Welsh coal workers. Combining bacteriological procedures (culture and guinea pig inoculation) with histology, tuberculosis was identified in 40% of all cases, but breakdown by age gave the strongest indication of an infective origin; from men younger than 40, 88% were positive but only 29% from subjects of 60 or over. The inescapable conclusion was that infection occurred as an early event and that as age advanced it tended to die out. Diminution in progression of progressive massive fibrosis with increasing age [Cochrane et al., 19561 may be seen as a reflection of the underlying pathology. More-

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over, the decrease in prevalence of progressive massive fibrosis over recent decades coincides with the decline of respiratory tuberculosis in the general population. Pursuing the origin of progressive massive fibrosis from environmental and radiological standpoints still emphasizes the dust factor [Hurley et al., 1987; Maclaren et al., 19891, though not unequivocally the quartz element [Cowie et al., 19901, but the PFR program did not seek an infectious agent in human tissue. Because all PFR autopsy material was provided by outside pathologists, it was received in a fixed state and was therefore unsuitable for bacteriological study. Had this been possible, division of the radiological appearances of PMF into several types would have been superfluous, since the pathological character of a tuberculous infection would suffice to explain the alleged distinctions. Decades previously, Cardiff pathologists had recognized the common features of massive lesions and large fibrous nodules which they described as “infective.” No other organism has been incriminated in man and evidence for a tuberculous component in the formation of PMF is too strong to be ignored or discounted. How dust and infection might interact has yet to be unravelled. The monocytic response to tubercle bacilli may, however, facilitate generation of the macrophage fibrogenic factor in the presence of mineral dust and, thereby, promote the development of massive lesions at sites favored by tuberculosis. A role for infection gained credence from experimental observations in which guinea pigs received coal mine or hematite dust combined with mycobacteria of low virulence either by injection or inhalation [Zaidi et al., 1955; King et al., 1957; Byers and King, 1959, 19611. Massive fibrosis, dissimilar to the separate effects of either dust or bacteria, resulted and, of particular significance, the infection ultimately died out [Zaidi et al., 19551. Recovery of mycobacteria from human and experimental massive fibrosis thus corresponds, with older men showing the lowest positivity and late animal lesions being negative. The immunological factor. With the exception of rheumatoid pneumoconiosis (Caplan’s syndrome), an initiating role for the immune system in generation of progressive massive fibrosis is difficult to sustain. The reactions, whether humoral or cellular, exhibit no consistent relationship with the presence of progressive massive fibrosis, nor can a predictive value be attached to antibody levels or to histocompatibility antigens. The immune system may, however, be involved secondarily to preexisting fibrotic lesions, although in a variable manner [Heppleston, 1988, 19911.

Functional Correlation “Simple pneumoconiosis causes only slight increase in breathlessness over that which develops even in normal men as they grow older; in complicated pneumoconiosis, on the other hand, the breathlessness is often severe, and its severity can be related to the radiographic change, provided that, as the authors emphasize, the age of the subject is taken into account.” So stated the preface to the monograph on lung function in CWP by Gilson and Hugh-Jones [ 19551, a view which persists in many quarters, and lung function studies are often considered to bear out the clinical conclusion. Gilson and Hugh-Jones demonstrated that, when average findings for dyspneic index and maximum voluntary ventilation (MVV) were compared with radiological category, simple pneumoconiosis showed little deficiency, but their scatter diagram of MVV revealed a wide range of values with considerable overlap between age groups and between x-ray categories. Some cases of simple disease, including younger subjects, were as severely affected as certain individuals with

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category B pneumoconiosis, while other instances of complicated CWP exhibited values above the average. In general, mixing efficiency became impaired with advance of pneumoconiosis and emphasis was laid on the 30% decrease in gas transfer for the severest cases of CWP. However, when the overall index of ventilatory inequality (mixing efficiency) and the removal of CO from the inspirate were analyzed, a wide scatter of values and little relation to age emerged within each radiological category, while overlap between categories was again evident; yet in average terms these divergencies, including abnormal ones in simple disease, were submerged. Although deficits in lung function may not equate with clinical disability,the authors nevertheless acknowledged that the 30% variation, which occurred around the mean dyspneic index, indicated that some cases of simple pneumoconiosis exhibited disability and this could be severe in the 55 age group. Gilson and Hugh-Jones doubted the suggestion based on microanatomy [Heppleston, 19531 that focal emphysema, as seen in simple disease, might lead to disability by an increase of the distal dead space on the grounds that inequality of ventilation shows no age relationship whereas they claimed focal emphysema to be more common and severe in elderly (age 55) subjects. Instead, they invoked increasing impairment of lung elasticity with age and believed that focal emphysema would thereby be rendered more prominent. However, pathological evidence was not adduced in support and two considerations make this proposal implausible. Reduced retractility of the lung as a whole is likely to result in panacinar not focal emphysema, while the rigid sleeve of dust and connective tissue would protect the adjacent dilated respiratory bronchioles from the general effects of impaired elasticity. On histological grounds, dust-related consolidation of alveoli and atrophy of bronchiolar smooth muscle suffice to account for the degree of focal emphysema in mechanical terms at specific local sites [Heppleston, 19541. Other evidence suggests that simple pneumoconiosis in coal workers is not the innocuous entity commonly supposed. An early study correlated the mottled radiological features of simple disease with the presence of characteristic focal lesions and their localized emphysema as seen in whole lung sections [Gough et al, 19491. This type of emphysema was much commoner among coal miners with both simple and complicated disease when compared with nonminers, especially in the presence of punctiform opacities, and its extent was closely related to ventilatory impairment as indicated by the FEV, [Ryder et al., 19701. Criticized for selectivity, the stance was maintained, since emphysema can be assessed only on morphological grounds, and they went on to claim that impairment of ventilation reflected the degree of emphysema rather than the radiological category of simple pneumoconiosis [Lyons et al., 19721. Their conclusions were vindicated when, in a study controlled differently, localized but not panacinar emphysema was shown to be more frequent in coal workers than noncoal workers, and its severity to be related to the amount of dust in simple foci [Cockcroft et al., 19821. Compared with micronodular opacities, those of the pinhead variety were also associated with a significantly lower transfer coefficient and a more compliant lung correlated to smoking history, consistent with the occurrence of focal emphysema in relation to dust lesions producing the finer opacities [Cotes et al., 1971; Musk et al., 19811. Moreover, the grade of focal but not general emphysema was a factor in predicting radiological score, while the presence of the focal form apparently leads to marked overreading of the radiograph [Rossiter et al., 19671. With benefit of serial observations on coal workers over a long period, ven-

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tilation (FEV,)was most impaired in cases of category B complicated pneumoconiosis, but a substantial proportion of their eventual impairment had been acquired while still classified as category A complicated disease or simple pneumoconiosis; hence, cases destined to reach serious disablement showed evidence of progressive impairment at very much earlier radiological stages [Lyons and Campbell, 19761. Complicated pneumoconiosis typically, though not universally [Shennan et al., 19811, develops in lungs affected by the more severe grades of simple disease, which by virtue of localized emphysema, could be responsible for some of the disability generally attributed to massive fibrosis. As seen in whole lung sections, progressive massive fibrosis and emphysema both contributed to impairment of ventilation, the emphysema being localized and dust-related [Lyons and Campbell, 19811. Even in the absence of progressive massive fibrosis, moderately high exposure to dust may cause severe impairment of lung function [Hurley and Soutar, 19861 and of exercise capacity [Cooper and Johnson, 19901. The increasing effectiveness of dust suppression measures combined with periodic medical examination of employees may eventually so reduce the prevalence of CWP, both simple and complicated, that correlation of lesions with function and disability no longer retains the importance it had when the disease achieved its maximum impact. CULMINATION

Although the two main questions raised by the pioneers did not prove easy to answer, and changing conditions underground long clouded the issues, they have gradually been reduced to the point where a definitive assessment may be attempted, even if mechanisms at the molecular level still require clarification. Quartz? Whether the quartz surface is contaminated or its particles simply diluted by the majority components of coal mine dust is in practice immaterial, since quartz is thereby prevented from exerting its characteristic pathological effect. Instead, it is reduced to behaving in a nonspecific manner along with the other constituents. Cytokines may indeed be involved in the mild fibrogenesis which ensues in vivo, but operation of these mediators is not confined to mineral particles, rather representing a general response to diverse irritants. It would, nevertheless, be of value to enquire whether the cytokine response differs between feeble and powerful stimulants of fibrosis; if the interconnections appear similar, the possibility of alternative fibroblast receptors may warrant exploration. The complexity of cytokine responses was lately exemplified in vitro by induction of their secretion through the agency of compounds from coal mine dust other than silica, a situation suggesting their direct relevance or an interaction between components in the genesis of CWP [Gosset et al., 19911. It is, however, essential that such investigationsproceed to enquire whether and, if so, how these short-term in vitro findings apply to long-term in vivo fibrogenesis in the manner already shown for the macrophage fibrogenic factor, whose detection ultimately relies on the fibroblast. Coupled with such information is the necessity to explore the interplay of the fibrogenic and the surfactant generating effects of mineral particles. Failure to take into account the role of surfactant vitiates conclusions drawn from animal experi-

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ments intended to test the quartz hypothesis in relation to CWP. It is similarly remiss to ignore analyses which detected little or no quartz in lung residues from pneumoconiotic coal or other workers. Infection? Argument about the origin of progressive massive fibrosis will no doubt continue, but, because such lesions are now much less frequently encountered, it may never again be possible to repeat the bacteriological observations of James [1954], whose work deserves a more conclusive emphasis than his own modesty permitted. It might appear anomalous that, coronary and unrelated disorders apart, the usual mode of death in coal workers with progressive massive fibrosis should be heart failure rather than tuberculosis, a phenomenon to which Fisher [ 1934-19351 had alluded and which, as cor pulmonale, was later established pathologically in the large series of James and Thomas [ 19561. Along with -Wells [ 19541, they demonstrated severe restriction of the major vasculature in massive fibrosis, which, combined with emphysema and possibly chronic bronchiolitis, accounted for the cardiac change, a situation later confirmed on a smaller scale by Fernie et al. [1983]. The development of cor pulmonale does not, however, detract from the tuberculous origin of progressive massive fibrosis, since the lesion usually becomes sterile with increasing age of subject. It is, therefore, justifiable to conclude that, whatever the mode of death, tuberculosis plays a determinant role. REFERENCES Aalto M, Kulonen E, Pikkarainen J (1989): Isolation of silica-dependent protein from rat lung with special reference to development of fibrosis. Br J Exp Pathol 70:167-178. Arlidge JT ( I 892): “The Hygiene, Diseases and Mortality of Occupations.” London: Percival. Arnold J ( 1885): “Untersuchungen uber Staubinhalation und Staubmetastase.” Leipzig: Vogel. Badham C, Taylor HB (1936): The lungs of coal, metalliferous and sandstone miners and other workers in New South Wales, chemical analysis and pathology. Studies in Industrial Hygiene No. 19. New South Wales: Annual Report of the Department of Public Health, pp 100-143. Barrie HJ, Gosselin L (1960): Massive pneumoconiosis from a rock dust containing no free silica. Nepheline lung. Arch Environ Health 1:109-117. Belt TH, Ferris AA (1942): Histology of coalminers’ pneumokoniosis. “Chronic Pulmonary Disease in South Wales Coalminers.4. Medical Studies.” Medical Research Council, Special Report Series NO. 243. London: HMSO, pp 203-222. Belt TH, King EJ (1945): Tissue reactions produced experimentally by selected dusts from South Wales coalmines. “Chronic Pulmonary Disease in South Wales Coa1miners.-111. Experimental Studies.” Medical Research Council, Special Report Series No. 250. London: HMSO, pp 29-68. Borm PJA, Palmen N, Engelen JJM, Buurman WA (1988): Spontaneous and stimulated release of tumor necrosis factor a (TNF) from blood monocytes of miners with coal workers’ pneumoconiosis. Am Rev Respir Dis 138:1589-1594. Byers PD, King EJ ( 1959): Experimental infective pneumoconiosis with coal, kaolin and mycobacteria. Lab Invest 8:647-664. Byers PD, King EJ ( 196I ): Experimental infective pneumoconiosis with Mycobacrerium tuberculosis (var. muris) and haematite by inhalation and by injection. J Pathol Bacteriol 81:123-134. Carleton HM (1924): The pulmonary lesions produced by the inhalation of dust in the guinea pig. J Hyg 221438-472. Chapman JS, Ruckley VA (1985): Microanalysis of lesions and lymph nodes from coalminers’ lungs. Br J Ind Med 42551-555. Claisse P, Josue 0 ( 1897): Recherches exphimentales sur les pneumoconioses. Arch Med Exp Anat Pathol 9~205 -234.

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Cochrane AL, Carpenter RG, Clarke WG, Jonathan G, Moore F (1956): Factors influencing the radiological progression rate of progressive massive fibrosis. Br J Ind Med 13:177-183. Cochrane AL, Cox JG, Jarman TF (1952): Pulmonary tuberculosis in the Rhondda Fach. A survey of a mining community. Br Med J ii:843-853. Cockcroft A, Seal RME, Wagner JC, Lyons JP. Ryder R. Anderson N (1982): Post-mortem study of emphysema in coalworkers and non-coalworkers. Lancet 2:600-603. Collis EL (19344935): Discussion of Fisher (1934-1935). Trans Inst Mining Engrs 88:398-399. Cooke WE (1938): Silicosis in the British coalfields. Tubercle 19:289-306. Cooper JK,Johnson TP (1990): Exercise capacity in coal workers’ pneumoconiosis: an analysis using causal modelling. Br J Ind Med 4752-57. Cotes JE, Deivanayagam CN, Field GB, Billiet L (1971): Relation between type of simple pneumoconiosis (P or M) and lung function. In Walton WH (ed): “Inhaled Particles 111.’’ Old Woking, Surrey, England: Unwin Bros, pp 633-643. Cowie HA, Hurley JF, Hutchison PA, Pern Po, Soutar CA (1990): Factors influencing the occurrence of progressive massive fibrosis of various types. Rep TM 90/13. Edinburgh: Institute of Occupational Medicine, pp 1-123. Craig W (1834): Cited in Graham [ 18341. Crocq J (1862a): De I’anthracose pulmonaire ou de la ptnktration des particules de charbon dans le poumon des houilleurs. Bull Acad R Mtd Belgique (2nd series), 5:389-427. Crocq J (1862b): Note sur les inhalations de poussikre de charbon appliquees au traitment de la phthisie pulmonaire. Bull Acad R Med Belgique (2nd series) 5:784-799. Cummins SL, Sladden AF (1930): Coal-miner’s lung. An investigation into the anthracotic lungs of coal miners in South Wales. J Pathol Bacteriol 33:1095-1132. Davis JMG, Addison J, Brown GM, Jones AD, McIntosh C , Miller BG, Whittington M (1991): Further studies on the importance of quartz in the development of coalworkers’ pneumoconiosis. Rep TM 91/05. Edinburgh: Institute of Occupational Medicine, pp 1-76. Douglas AN, Robertson A, Chapman JS, Ruckley VA (1986): Dust exposure, dust recovered from the lung, and associated pathology in a group of British coalminers. Br J Ind Med 43:795-801. Faulds JS, Nagelschmidt G (1962): The dust in the lungs of haematite miners from Cumberland. Ann OCCUPHyg 4:255-263. Fernie JM, Douglas AN, Lamb D, Ruckley VA (1983): Right ventricular hypertrophy in a group of coalworkers. Thorax 38:436-442. Fisher SW (1934-1935): Silicosis in British coal-mines. Trans Inst Mining Engrs 88:377-384. Gardner LU (1923): Studies on the relation of mineral dusts to tuberculosis 111. The relatively early lesions in experimental pneumokoniosis produced by carborundum inhalation and their influence on pulmonary tuberculosis. Am Rev Tuberc 7:344-357. Gardner LU (1929): Studies on experimental pneumokoniosis V. The reactivation of healing primary tubercles in the lung by the inhalation of quartz, granite and carborundum dusts. Am Rev Tuberc 20~833-875. Gardner LU (1940): The pathology and roentgenographic manifestations of pneumoconiosis. JAMA 114:535-545. Gibson M (1833-1834): On the “phthisis melanotica” (so-called) of coal-miners. Lancet ii:838-839. Gilson JC, Hugh-Jones P (1955): Lung function in coalworkers’ pneumoconiosis. Medical Research Council, Special Report Series No. 290. London: HMSO, pp 1-266. Gosset P, Lassalle P, VanhCe D, Wallaert B, Aerts C, Voisin C, Tonne1 A-B (1991): Production of tumor necrosis factor-a and interleukin-6 by human alveolar macrophages exposed in vitro to coal mine dust. Am J Respir Cell Mol Biol 5431-436. Gough J (1940): Pneumoconiosis in coal trimmers. J Pathol Bacteriol 51:277-285. Gough J (1944): “Rep Adv Comm on the Treatment and Rehabilitation of Miners in the Wales Region Suffering from Pneumokoniosis.” Ministry of Fuel and Power. London: HMSO, p 17. Gough J, James WRL, Wentworth JE (1949): A comparison of the radiological and pathological changes in coalworkers’ pneumoconiosis. J Faculty Radio1 1 :28-39. Graham T (1834): On the existence of charcoal in the lungs. Edin Med Surg J 42:323-324. Greenhow EH (1865a.b): Specimen of diseased lung from a case of grinder’s asthma. Specimen of coal-miner’s black lung. Trans Pathol Soc Lond 1659-60. 60-61. Greenhow EH (1866a,b,c): Stone worker’s pulmonary disease. Specimen of collier’s lung. Specimen of potter’s lung. Trans Pathol SOCLond 17:24-27, 34-36, 36-38.

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