Document jBmzrjgXLg7D65a1pB361jOEy

FILE NAME Talc TALC DATE 1955 DOC TALC497 DOCUMENT DESCRIPTION Saranac Studies of NY State Tremolite Talc Arch Indust Health - An Experimental Study of the Effects of Talc Dust on Animal Tissue An Experimental Study of the Effects of Talc Dust on Animal Tissue G. W. H. SCHEPERS M.D. D.Sc. and T. M. DURKAN M.E. Saranac Lake N. Y. The occurrence of a series of deaths from pulmonary disease following exposure to take mining in upper New York State caused The Saranac Laboratory to inquire experimentally into the precise causative agent of this form of pneumoconiosis This series of experiments in which one of us T. M. D. participated was conducted at The Saranac Laboratory under the supervision of the late Leroy U. Gardner M.D. during the period 1937-1941 and the results are now reported for the first time They have lost neither their relevance nor importance as instances of tale pneumoconiosis recur sporadically and a recently resected lung apical lobe from a paper worker suspected to be suffering from tuberculosis revealed on study by one us G. W. H. S. that tale dust may cause lung disease in the most unexpected of occupations study of the dust to which eight fatal cases were exposed and of the minerals recovered from their lungs showed that the mineral tale is but one of the components of commercial tale to which they were exposed Along with the tale there occur in variable proportions tremolite anthophyllite quartz serpentine and dolomite The animal experiments were therefore designed to probe the specific effects of each of these compo- _ Recorded for publication July 11 1955 Director Dr. Schepers and Associate Director Mr. Durkan The Saranac Laboratory nent substances In these experiments the mineral or mixture of minerals in the form of a dust suspension was introduced into animals by the intravenous and by the intratracheal technique Rabbits guinea pigs and rats were used but not both techniques were employed for each species Minerals selected for their purity were used and in some instances contaminating substances were re moved or reduced in amount by sedimentation in heavy liquids The progressive and essential steps followed in conducting these experiments are summarized in the accompanying Tables ^ separate control study with quartz was not performed as the effects of this substance had already been established by previous experiments at The Saranac Laboratory and those experiments serve as a control standard The intravenous method of introducing dust into animals was used in an investigation which the mineral dust ground until the particles were 3 and smaller in size was injected into the vein of rabbits and of rats Table ) Both species were used in the studies with tale soda tremolite and serpen- tine and rabbits only in experiments with soda tremolite anthophyllite and dolo- mite The intratracheal technique was employed in three sets of experiments In one set Table 2 the four minerals studied were injected in the form of particles 3 and less in size and in addition two of the minerals tremolite and anthophyllite were used as a dust composed of particles 20...and smaller in diameter In the second set Table 3 which was conducted with fibrous minerals the material was crushed and then separated 317 A. M. A. ARCHIVES OF INDUSTRIAL HEALTH Table Intravenous Injection Experiments with Tale and Associated Minerals Minerals Particle Size 3 and less - Dosage For rabbits the total amount of dust injected was 1.0 gm divided into 20 equal doses each dose was 5 ml of a % suspension injected twice a werk for 10 weeks into the ear vein For rats the total amount of dust of a 0.25 suspension and increasing weeks into the tail vein injected was to 0.5 ml of 100 mg divided into 18 doses beginning at 0.5 ml a % suspension injected twice a week for nine Periods at Which Animals Were Killed Usually at intervals of 3 to 6 months up to one year after injection and at intervals of 6 to 12 months thereafter . Mineral Tale Georgia Time Ball- ` milled Hr 1,900 Tale Georgia Tremolite soda Tremolite soda Tremolite soda Anthophyllite Serpentine Serpentine Dolomite . 72 140 48 310 1,400 72 72 144 Animals 4 rabbits S rats 4 rabbits + rabbits 4 rats 4 rabbits 4 rabbits 6 rats 3 rabbits Maximal Survival After Last Injection Mo. 24 15 19 24 10 24 12 12 24 Results Bronchitis bronchiolectasia endarteritis proliferans macrophage catarrh pleural thickening Inert Inert Inert Minute cellular infiltrates Minute cellular infiltrates Persistent paravascular granulomata Persistent paravascular granulomata Transient phagocytosis and toxemia 4 4 4 q q * "4 q A 4 q 4 TABLE Intratracheal Injection Experiments with Tale and Associated Minerals 3 Dust Composed of Small Particles or Short Fibers 4 Dosage The total amount of dust injected was 150 mg of a 10 suspension injected a week apart divided into three equal doses each dose was 0.5 ml Animals Used Guinea pigs Periods at Which Animals Were Killed Usually at intervals of 3 to 6 months up to one year after injection and at intervals of 6 to 12 months thereafter Maximal Time Survival i Ball- After Last : milled Particle Ani- Injection Mineral Hr Size mals Mo. Results Tale Georgia 650 3 and less 13 28 Bronchiolectasia and bronchitis perivascular and peribronchial cellular proliferation andperivascular fibrosis fibrocellular pleural sclerosis Tremolite Alps 48 and less ti 38 Transient macrophage reaction and persistent eosinophilia perivascular and peribronchial lym phocytic infiltration Tremolite Alps wee 20 and less fi 12 Incipient bronchiolectasia and peribronchial fibro- sis ineipient periarteriolar cellular infiltrates Anthophyllite 1,700 3 and less 6 12 12 Catarrhal bronchitis peribronchial periarteriolar and cellular masses peribronchial fibrosis Anthophyllite wee 20 and less 6 19 Bronchiolectasia and catarrhal bronchiolitis peribronchial fibrosis Serpentine 1,500 3 and less ts 12 Chronic bronchitis and bronchiolectasia TABLE Intratracheal Injection Experiments with Tale and Associated Minerals Dusts Composed of Long Fibers . Dosage Animals The total amount of dust injected was 75 mg of tremolite and 50 equal doses each dose was 0.5 ml of a % suspension injected injections of tremolite and two of anthophyllite Used Guinea pigs mg of anthophyllite divided into a week apart There were three Periods at Which Animals Were Killed For tremolite 1 4 8 12 and is months and for anthophyllite 1 8 and 12 months after last injection Mineral Fiber Length Animals Maximal Survival After Last Injection Mo. Results Tremolite Alps 20-50 6 18 Bronchiolectasia and bronchiectasis with peribronchial pro- a liferative fibrosis cicatrization interstitial fibrosis : and macrophage proliferation tremolite bodies cellular a metaplasia E Anthophyllite 20-50 6 12 Bronchiolectasia and bronchostenosis focal peribronchial cellular reaction irregular Abrosis An experiment with fiber tale was not conducted because attempts to obtain mineral specimens containing long fibers of tale were unsuccessful 318 EFFECTS OF TALC DUST ON ANIMAL TISSUE Table Intratracheal Injection Experiments Mixtures of Tale Minerals and Quartz Dosage The total amount of dust injected was 75 mg divided into three equal doses each dose was 0.5 inl of a 5 suspension injected a week apart Animals Used Guinea pigs Periods at Which Animals Were Killed Usually 1 4 8 and 12 months after last injection Mineral Mixture Per Cent 1399 1399 69 35 Anthophyllite 55 Quartz .. 84 Tremolite . 30 Anthophyllite 201 Tale eee. ** Tremolite i. 18 Anthophyllite 17 Tale ** Quartz 14 Particle Size and less and less 20-50 and less 3 and less 20-30 3 and less and less 20230 and less 3 and less Ani mals cy Maximal Survival After Last Injection Mo. 12 6 12 th 12 6 12 Results Multiple fibrocellular gramulomata bronchiolitis and bronchiolectasia perivascular fibrocellular reaction periadenitis and lymphold hyperplasia Massed macrophages and some central necrosis and peripheral minor fibrosis transient bronchitis Mussed confluent subpleural alveolar mural and perivascular cellular proliferation minimal fibrosis bronchioletasia and bronchitis Subpleural peribronchiolar and perivascular maes rophage and fibrocytic proliferation 6 12 Massive exuberant macrophage and fibrocyte vellu- lar proliferation bronchiolectasia and bronchitis minimal Abrosis by sedimentation in alcohol to isolate fibers approximately 20...to 50...long It is reported that the mineral tale may exist in fibrous form but attempts to obtain tale samples suitable for preparing fibers 20...to 50... in length were unsuccessful The occurrence of tale as a fiber mineral would appear to he uncommon The third set of intratracheal experiments Table 4 was specifically designed to mimic the dust exposures of the upper New York State industries and particularly to probe the influence of quartz on the combined or sep- arate pathogenicity of the other components of commercial tale The effects of these substances may now be scrutinized EFFECTS OF TALC AND OF ASSOCIATED MINERALS ON TISSUE Serpentine introduced into rabbits by the intravenous route serpentine dust produced within three months a moderate degree of alveolar macrophage catarrh with septal cellular proliferation Dust particles could be seen particularly within perivascular macrocytic accumulations In the case of the rat there is no comparable alveolar catarrh at 12 days but there are some macrophage and multinucleated giant accumulations at the angles between alveolar septa In both the rabbit and the rat small isolated granulomata composed of multinucleated giant cells charged koniophores unpigmented macrophages plasma cells lymphocytes and fibrocytes with intermingled capil- laries may be found at 12 months These foci have a perivascular and peribronchiolar distribution Dolomite The intravenous introduction of dolomite proved toxic to the rabbits some dying while the injections were being made and others within a few days Such animals showed a macrophage reaction in the alveoli by the third day with perivascular and peri- bronchiolar cellular accumulations Occa- sional eosinophile infiltrates were to be seen The lungs of animals surviving to 24 months showed no abnormality a condition suggest ing either a complete recovery or a lack of chronic response in the first instance The intratracheal introduction of serpen- tine in guinea pigs provokes within the first month bronchial epithelial hyperplasia with submucosal and adventitial cellular infiltra- tion and scattered alveolar koniophores By the end of a year this condition has sta- bilized as a chronic bronchitis with bronchiolectasia and distortion There is considerable epithelial desquamation with some papilloma formation Talc When introduced into the rabbit by the intravenous route tale produces within 319 J. ... ARCHIVES OF INDUSTRIAL HEALTH one month numerous focal areas of alveolar macrophage catarrh and pleural thickening through superficial fibrocytic and macrocytic hyperplasia The tale spicules are universally distributed throughout the pulmonary parenchyma but avoid the lymphoid tissue and the alveolar macrophages do not yet show much tale At the end of two years this tale is still present in the alveolar bronchial and vascular walls and the alveolar macro- phages now also contain some tale Isolated foci of marked vascular muscular proliferation may be seen More usually there is a perivascular alveolar reaction Endangiitis proliferans is commonly seen in the smaller blood vessels Alveolar walls are thickened through cellular proliferation A moderate degree of chronic bronchitis and bronchiolar dilatation is seen together with bronchopneumonic foci displaying a high proportion of macrophages The pleural cellular pro- liferation shows no advance on that seen at the end of the first month The rat hung is apparently immune to the effects of tale introduced by the intravenous route No reaction is demonstrable at the end of the 1st month and at end of the 15th month a few laden macrophages may occasionally be seen in the alveoli Practically all the tale introduced is still readily demonstrable in the lumina of blood vessels by means of polarized light When introduced into guinea pigs by the intratracheal route particulate tale calls forth within one month perivascular and peribronchiola,, focal intramural cellular accumulations comprising histiocytes fibrocytes plasma cells and rare eosinophiles containing macrophages form irregularly distributed confluent pneumonic patches Fig 1 Within eight months multiple foci of filled koniophores in alveoli surrounding bronchioles and arterioles may be seen but dust cells may also effectively occupy pulmonary alveoli over extensive areas producing a solid effect Some eosinophile and fibrocyte infiltration into peribronchial tissue is seen and there is some fibrosis with bronchiolar distortion and epithelial proliferation Where laden macrophages reach 320 Fig Pulmonary effects of tale injected intratracheally Experiment guinea pig lung reaction one month after injection Focal accumulation of filled koniophores within pulmonary alveoli the pleural surface a fibrocellular sclerosis with subpleural deposits may supervene At the end of the first year the pleural reaction is well established consisting of an outer fibrocellular layer a cellular inner zone and interposed foci of pigment macrophages The dense perivascular sheaths of cells are now seen to be spilling over into the proximal alveolar walls Immediately adjacent to the blood vessels is a zone of lympho- cytes and somewhat further afield are some fibrocytes The hypertrophy of the bronchi- olar mucosa has advanced further and there is now some epithelial desquamation and muscular hypertrophy At the end of the second year the dominant residual change caused by the tale is the bronchiolectasia and bronchiolitis with epithelial catarrh Marked focal cellular deposits and peribronchial fibrosis occur Fibrocytes may now be seen to be intersecting the massed koniophores and delicate web of EFFECTS OF TALC DUNT ON ANIMAL TISSUE collagen is being laid down vade these areas Capillaries in- When particulate tale and quartz of the same particle range are combined in the ratio of 3 the essential additional effects in the guinea pig on intratracheal injection of the mixture are perceptible within the first month The effects consist essentially of a greater prevalence of masses of filled koniophores with numerous eosinophiles at the edges of the alveoli Fig 2,4 There is a distinct tendency to alveolar septal cell proliferation and in the cellular masses alve- oli may survive as cuboidal spaces At the end of the first year the combined quartz lesion may be defined as a fibrocellular granuloma Fig 2B and now numerous multinucleated giant cells occupy alveoli at the periphery of the koniophore masses There is a distinct increase in lymphoid tissue not only in the parenchymal nodes and hilar nodes but also around the small blood vessels At the fringes of the lymph nodes there is considerable macrocytic infiltration The bronchiolar distention and distortion produced by exposure to pure tale though present are less marked when the quartz is added There is however more marked epithelial desquamation and there is more peribronchial and perivascular fibrosis Tremolite reaction of the rabbit and the rat to the intravenous introduction of particulate tremolite 3 and less in size either of the soda or soda varieties is essentially negative Most of the tremolite remains in circulation even at the end of the 19th month though some particles may be demonstrable in alveolar walls and lymph nodes However even in the latter locations the dust may be within the capillaries Very few macrophages are to be seen and they are limited to minute perivascular infiltrates of macrophages and fibrocytes When tremolite of similar particle range is introduced into the lungs of guinea Fig Pulmonary effects of the intratracheal injection of tale combined with quartz Experiment guinea pig lung f reaction one month after injection massed accumulation of filled koniophores obscuring the alveolar pattern B. reaction 12 months after injection ; persisting macrophages; granuloma with slight fibrotic changes and some capillary infiltrations EFFECTS OF TALE DUST ON ANIMAL TISSUE goblet cells are now present in greater profusion There also now more cellular infiltration and fibrosis of the bronchial walls with macrophage discharge into the bronchial lumina Fig Pulmonary effects of tremolite injected intratracheally Experiment guinea pig lung reaction one month after injection Commencing crypt formation in a bronchiolar wall at the end of the first month under the influence of tremolite fibers 3 in length pigs many of the bronchioles are observed to have undergone erosion at the end of the first month with peribronchiolar fibrocytic and macrocytic accumulation The epithelium tends to be proliferated and to be desquamated Giant macrophages filled with tremolite particles occupy the alveoli immediately adjacent to the alveolar ducts and some scattered eosinophiles are to be seen among these cells The reaction may however be limited to slight bronchiolar evagination Fig 3 At the end of the first year there may be residual periarteriolar and peribronchiolar lymphocytic infiltration and isolated islets of particle macrophages Eosinoplfiles lie scattered among them The bronchiok^rmucosa also shows considerable eosinophilia When the tremolite is introduced in the form of particles up to 20... in length the spicules may be seen to be well dispersed and closely applied to the alveolar walls of the guinea pigs at the end of the first month Numerous macrophages may also be seen containing such particles but these dust cells are by no means comparable in size to the giants seen in the preceding instances There is a great abundance of cosinophiles and commencing fibrocytic infiltration of alveolar walls The bronchioles are a little distended and distorted and show incipient crypt f^,r- mation The latter change is seen to have advanced appreciably at the end of the first year and 322 The intratracheal introduction of tremo- lite fibers 20 to 50 long produces marked disease rapidly and extensively Within one month the guinea pigs show complex masses of tremolite fibers trapped within the bronchi and bronchioles There is considerable bron- chiectasia and distortion with peribronchial fibrosis and cicatrization Many of the long fibers may be observed to have penetrated into the walls of the respiratory passages Fig 4 At the end of 18 months the result- ant lesion is a marked fibrocellular diffuse pneumonitis with marked bronchiectasia and epithelial destruction Fig 5 and vascular and perivascular damage Fig 6. This extensive lesion is directly comparable to the mature human lesion and is even replete with tremolite bodies e tremolite fibers sur- rounded by a brown containing protein sheath showing typical terminal clubbing and some measure of segmentation where it covers the shaft of the tremolite fiber Many metaplastic cells are also found among the macrophages Fig 7 There is also a characteristic pleural and subpleural fibrocellular reaction Fig 8 When particulate tremolite 3...and less in size is mixed with quartz dust of the same size range in ratio of 13 and introduced into guinea pigs by the intratracheal route the immediate effect is much greater than that observed with either the tremulite or the quartz alone A permanent lesion comparable that which may be expected with quartz alone is however not established Apparently the healing process seen when tremolite alone is introduced also mitigates the quartz effect Within the first month there is an exuberant koniophore and multinucleated giant reaction which obliterates all semblance of preexisting pulmonary cytoarchitectonies around the bronchioles Many of the trapped bronchioles are distended and distorted with epithelial desquamation and pro- EFFECTS OF TLC DUST ON ANIMAL Fig Pulmonary effects of tremolite fibers 20 to 50 long injected intratracheally Experiment guinea pig lung reaction one month after injection I bronchiole choked with fibers and debris showing breakdown of its wall and peribronchiolar cellular reaction in relation to trapped tremolite fibers F. power view of parenchymal pulmonary reaction showing tremolite fibers macrophages fibrocytes plasma cells and occasional lymphocytes Fig Pulmonary effects of tremolite fibers 20 to 59... long injected intratracheally Experiment guinea pig lung reaction 18 months after injection 4 interstitial pulmonary fibrosis with prevalent cellular elements and trapped tremolite fibers R. distortion distention partial mucosal hypertrophy partial epithelial desquamation and peribronchiolar fibrosis Experiment Fig 6. Vascular damage caused by tremolite fibers 20 to 50 long pig lung reaction 18 months after injection ) 4 periarteriolar fibrosis Experiment 995 guinea fibers sparsely present B venule almost completely obliterated by fibrotic reaction around trapped fibers Fig 2 Fate of tremolite fibers 20 hung result 18 months after injection mencing clubbing of the fiber ends R some extracellular to She long in lung tissue ( Experiment 995. -guinea -guinea pig 1 tremolite fiber engulfed by macrophages with comhirefringence of trapped fibers some intracellular and ay. LTH = NS EFFECTS OF OF OF TALC DUST ON ANIMAL TISSUE Fig Pulmonary effects of tremolite fibers 20 to 50 long Experiment guinea pig lung result 18 months after injection Pleural sclerosis and subpleural dominantly cellular reaction around tremolite fibers liferation Foci of necrosis are present and fibrosis is commencing at the periphery The majority of alveolar walls are infiltrated with macrophages and there is some perilymphatic koniophore accumulation as well At the end of the first year there has been a measure of recovery from the initial exag- gerated reaction Foci of massed koniophores may still be found but there is very little reaction around these cells Necrosis is still seen at some areas Small lymphocytic sheaths accompany some of the bronchioles and arterioles and the bronchiolar epithelium has recovered in large measure Anthophyllite Anthophyllite The intravenous introduction of particulate anthophyllite less than 3... in size produces minimal pulmonary lesions only in rabbits The lesions are limited to macrophage proliferation and plasma cell accumulation at pericapillary and intra- alveolar sites and the reaction should be classified as inert An intratracheal introduction of antho- phyllite in this particle range was performed in spite of the essentially negative intravenous result At the end of the first month areas of intramural and alveolar cellular accumulation occur Most of these are filled macrophages but there are several eosinophiles among them After one year areas of irregular fibrosis may be seen to surround distorted and distended bronchi- oles Numerous areas of bronchiolar epithelial desquamation with necrotic cellular plugs in the lumina may be found There are also massed peribronchiolar accumulations of koniophores with commencing inter- stitial fibrosis The effects of the introduction of antho- phyllite fibers in the less than 20... length range are comparable to the effects produced by the 3 particles with the exception that fewer macrophage masses are formed at points distant from the bronchioles There is a greater tendency also for diffuse alveolar wall thickening through cellular infiltration and a higher proportion of fibrocytes to macrophages where cellular reactions are provoked especially in the peribronchial tissues The birefringent particles all seem to lie in relation to the fibrocytes Bronchiolec- tasia and catarrhal bronchiolitis reach a some- what more advanced degree Fig 9 The fiber anthophyllite 20 to 50 has an enhanced and even more rapidly injurious effect on the guinea pig lung Within one month it produces a marked and extensive focal peribronchial fibrotic and cellular reaction consisting mainly of macrophages fibrocytes and eosinophiles with areas of lymphocytosis ( Fig 10 Anthophyllite fibers and spicules are embedded within these cells and some may be partly engulfed by giant cells Areas of necrosis occur Bronchitis and bronchiolitis with distortion and disten- tion are present and the lumina of such passages contain necrotic cellular debris At the end of 12 months a more advanced stage of essentially the same lesion may be seen with however more central and irregular fibrosis within the nodules of reaction There is now some bronchiolar stenosis as well as ectasia 325 ARCHIVES OF INDUSTRIAL HEALTH Fig Pulmonary lesions caused by anthophyllite fibers less than 20... long Experiment guinea pig lung result 12 months after injection A. A. mixture of filled macrophages fibrocytes occasional plasma cells and collagen strands B bronchiolectasia within an area of fibrocellular reaction multiple evaginations create a cystic effect When anthophyllite fibers and quartz are mixed with each other in ratio of 11 and introduced into guinea pigs a marked subpleural cellular reaction confluent mural proliferations and perivascular cellular accu- mulations may be found within one month Solid foci of macrophages occur and there is commencing distention and distortion of Fig Pulmonary effect of anthophyllite fibers 20... to 50 long injected intratracheally Experi- Experiment 993 guinea pig lung reaction one month after injection Section shows rapid degeneration of bronchiole peribronchiolar dominantly cellular deposit in relation to trapped fibers but failure to involve the lymph node bronchioles By the end of a year the lungs are occupied by multiple masses of cellular reaction consisting mainly of fibrocytes though some macrophages are still present Advanced multilocular bronchiectasia may be found within these cellular zones An inter- esting feature of the reaction which shows forcibly the modifying influence of the anthophyllite on the quartz is the fact that though such cell masses may encroach on and surround the lymphoid nodules they do not involve them Small foci of acellular necrosis occur in some of the larger cell masses but there is no distinctive tendency to fibrosis such as may be seen in pure quartz lesion at comparable stage COMBINED EFFECT OF TREMOLITE ANTHOPHYLLITE AND TALC The purpose of this experiment was to at- tempt to define the relative influence of quartz on a mixture of components which simulates the natural tale product mined in upper New York State The study was there- EFFECTS OF TALC DUST ON ANIMAL TISSUE oreconducted in two stages viz with and without the quartz When no quartz is included the initial reaction to tale tremolite and anthophyllite is very mild At the end of one month there is slight bronchiolar epithelial catarrh and some plasma cell infiltration into the bronchi- olar mucosa Isolated small foci of filled macrophages may be found At the ead of a year the area of reaction around the pigmented macrophages is somewhat more extensive and includes some capillary hyper- emia Such areas may occur in relation to the bronchioles and subpleurally A little bronchiolar distention and distortion may be seen The addition of 14 quartz to the tale tremolite and anthophyllite mixture rapidly provokes massive focal lesions consisting of macrophages and fibrocytes with scattered giant cells Multiple foci of diffuse alveolar wall thickening due to macrophage invasion and septal cell proliferation also occur In the air passages there are incipient epithelial hyperplasia and submucosal plasma cell or lymphocytic infiltration At the end of a year this exuberant cellular response still persists but fibrocyte accumulation is limited almost to being a fringe phenomenon The distortion and distention of the bronchioles and epithelial catarrh have also progressed somewhat but the degree to which this has oecurred is by no means comparable to the lesions which may be provoked by either fiber tremolite or anthophyllite alone COMMENT Though one must acknowledge at the outset the limitations of the techniques employed in this series of experiments the diversified results obtained not only by exploiting different minerals but also through modifying their particle sizes or varying the route of introduction or the species of experimental animal justify the inference that at least some progress has been made in eluci- dating the role played by components of commercial tale in producing disease and the mechanisms by which the terminal results are achieved Thus it seems that the basic reaction to the presence of any of these dusts is a macro- phage catarrh into the alveoli the cells becoming engorged with large particles so rapidly that they remain immobilized and fail except in rare instances either to return to the tissues or to be extruded from the lung via the respiratory passages It is possible that this is merely a mechanical result due to their large size On the other hand it is possible that the koniophores are actually paralyzed They certainly do not tend to undergo necrosis nor are collagen or other types of fibrous elements stimulated to invade the cell masses in the majority of instances except when the component fibers are long The degree to which fibrosis supervenes depends on the length of fibers rather than on their chemical composition Thus when the minerals have been reduced to S and less in maximal dimension they have practically no fibrogenic effect On the other hand the 20... to 50 length tremolite and anthophyllite fibers produce extensive regional fibrosis Unfortunately tale could not be obtained in this fibrous form so that it is not certain whether this rule applies to tale also It was observed however that tale evokes fibrocytes but the presence of these cells does not tend readily to lead to collagen deposition Attention must be drawn to the triple localization of the lesions produced by tale tremolite or anthophyllite namely at perivascular peribronchiolar and subpleural or pleural sites In addition cellular accumulations having no such apparent topographical relation to the blood vessels air passages or pleura may occur It is possible however that these macules are merely examples of the standard lesion cut at a tangent The lymphatic tissue escapes almost entirely and alveolar walls are not affected except near the focal deposits or when quartz is present too The marked tendency to bronchiolar distention and distortion is readily explained when large masses of sharp elongated fibers are trapped within the bronchioles or when there are extensive peribronchiolar cellular 327 A. M. A. ARCHIVES OF INDUSTRIAL HEALTH masses of fibrotic cicatrization The mecha- nism is less readily apparent when such obvions causes are in abeyance The mineral particles could not be readily demonstrated in the bronchial wall except when advanced disease was present On the other hand it must be granted that we do not yet know the lower size range of particles of those min- erals which may be active The lack of secondary infection in spite of the marked pulmonary changes observed is remarkable Unfortunately the study was not elaborated to include observations on the influence of the tale minerals on the course of tuberculosis Such a project would be worth pursuing in view of the conflicting reports concerning the prevalence of tuberculosis among human tale victims It would however involve a costly inhalation study Contrary to expectation the addition of quartz did not materially enhance the pathogenicity of the tale minerals Indeed there seems to be some indication that the fibro- genic effect of the quartz is reduced by the presence of tale in particular This may be explicable on the supposition that if all the koniophores are effectively occupied and immobilized by the tale the quartz cannot influence them to the contrary and thus does not truly enter the body remaining trapped in the koniophores lying in alveoli and thus truly still outside the body The lack of a lymphoid tissue response favors such a simple and mechanistic explanation On the other hand the difference in reaction may be more subtle and dependent on chemical or physical interaction between the quartz and the other minerals While there are these evidences of oppos- ing or inhibiting actions and as has been shown they are not limited to quartz there is also some suggestion that in certain com- binations separate components may augment one another This applies particularly to the combination of quartz with tremolite or an- thophyllite The successful experimental production of a tremolite body provides strong evidence that the bodies found in human talcosis are truly ponent of were not provoked by the tale dust demonstrable the tremolite com- Comparable bodies in the anthophyllite series There is therefore more than length of fiber required to cause them to develop This feature firmly links the animal pathology to the human disease Indeed this series of experiments elucidates most satisfactorily the nature of the human talcotic reaction and the factors responsible for its production At the same time it sheds further light on the asbestos problem while confirming certain observations previously recorded concerning silicosis Furthermore the rela- tive immunity shown by certain animal types serves to confirm the general concept of vari- able susceptibility of man and animals to disease SUMMARY The pulmonary response of rabbit rat and guinea pig lungs to dolomite serpentine talc tremolite anthophyllite and quartz either separately or in combination was explored by the intravenous and intratracheal techniques Dolomite and serpentine are relatively inert While tale is dominantly cytogenic tremo lite and anthophyllite have both cytogenic and fibrogenic propensities Quartz modifies the effects of these sub- stances The effects of these substances are differ- ent from the effects of the substances in combination acting singly Talc tremolite and anthophyllite all tend to damage the smaller respiratory passages and blood vessels to a variable degree The long tremolite and anthophyllite fibers produce rapid and grave peribronchiolar le- ' sions REFERENCES 1. Schepers W. H. and Durkan T. M The Effects of Inhaled Mining Dust on the Human Lung A. M. Arch Indust Health 12 182-197 1955 2. Dana E. .: Textbook of Mineralogy Ed 4 revised and enlarged by W. E. Ford New York John Wiley & Sons Inc. 1932 328