Document ym4zDB6KNZ92damRq873b9rq2

ROCZNIKI AKADEMII MEDYCZNEJ la. JULIANA MARCHLEWSKIEGO In BIALYSTOK Supplemont 24 INFLUENCE OF POLYVINYL CHLORIDE (PVC) BUST ON RAT RESPIRATORY SYSTEM by J. Popov BIALYSTOK 1969 . -- * t'T Ovi:... ,:ch TOspv-oriy " v. r-* *" * ; v- ucc 065193 Telephone Welwyn Gwden 23400 (STD Code 07073). STD Code from London Area 96 Telex 264251 leiplast Welwyn tnousiriet* . ^ Limited Plastics Division Mr B N Wheeler Jr _ Project Manager Environmental Protection and Occupational Health Onion Carbide Corporation P0 Box 8361 South Charleston Vest Virginia Your ref. Our ref JS/AM/DS0-107 Tel ext 3162 hegeve* AUG 6 1979* KK * Date 20 July 1979 Dear Nick PVC-DOST Thank you very much for your letter of July 6. I have pleasure in enclosing our translation of the paper by Popow which you requested. I do not know whether this will be of any interest to you in the liability case which you have. As you will see when you read it, Popow1 s experimental conditions were utterly extreme. 1 think any biological system will be overwhelmed by 97 g/m* of FVC or any other fine dust. These conditions are a long way from our TLV of 10 mg/m*.. I have just got back from my annual vacation and your letter was on the top of my pile. 1 have not given copies of this Popow translation to Ted Torkelaon. Maurie Johnson or any of my other American friends. It may be some littl time before I get around to doing this. If you could run off some quick copi s f r them, I would be grateful. With best wishes 'Tours sincerely J Stafford Division Manager Health and Environment Protection Enc ucc 065194 CONTENTS I. INTRODUCTION " II. PURPOSE OF THE WORK AND ASSUMPTIONS III. RESEARCH TECHNIQUE t IV. RESULTS OF INVESTIGATIONS 1. Control group 2. Group I. Early changaa 3. Group II* Later changaa A. Croup III. Changes after cessation of exposure to FVC dust V. INTERPRETATION OF RESULTS AND DISCUSSION VI. CONCLUSIONS VII. SUMMARY VIII. REFERENCES 3 (5) 8 (8) 8 (8) 10 (10) 10 (10) 12 Ul) 15 (16) 20 (25) 25 (32) 35 (38) (39) (45) ucc 065195 1. INTRODUCTION The pathological changes occurring in tha respiratory system under the Influence of inspiration of air contaminated with particles of various dusts have been described for about 100 years aa- dust disease - pneuxsoconl sis. Initially pathogenic action was only ascribed to silicon dust. Therefore the investigations undertaken mainly concerned silicosis. On the basis f clinical studies (Levin [73], Sokolov at al. [109], Vlglianl et al. [122]) and experimental studies (Cabafiski et al. [13], Gross et al. [37], Policard et al. [95]) It vas found that in tha lungs ail iron 4nst causes formation of fibrous nodules, composed of thick strands of collagenous fibres, undergoing hyalinlzatlon. Sometimes there are necrotic masses at the centre f such a nodule. The discovery of the pathogenic properties of silicon dust had the result that many authors turned their attention to the problea f dust diseases. Clinical and experimental investigations made it possible t determine the action of individual types of dust. As a result of this research it was established that eoal dust accumulates in the lungs, damages the pulmonary alveoli and causes formation of dust nodules with the character of giant-cell granulomas. These nodules are of a constant character vith susceptibility to fibrous atrophy (Niepolomskl et al. [80], Sehepers [106], Worth et al. [121], Sofnlerz et al. [110-112]). However, tali: dust causes so-called intraparenchymatous focal pneuaonla, In Which collagenous fibres appear at a very late stage in the inflammatory foci and there Is no f rota tion of pneuaoconiotic nodules (Rakovskl [100]). In the course of asbestosls ve can distinguish an early stage, called the vaso-histlocytic stage, and a late stage, called the fibroblastlc-collagenic stage (Avril [3]). A charac teristic feature of this coniosls is diffuse fibrosis and hyaliniration * without formation of nodular lesions. Sometimes so-called a*best s bodies OCC can be detected among the striae of c nnective tissue (Banes [40]). Cotton dust causes chronic bronchitis (Fetisova [25]), whereas cement dust causes acute tracheitis and bronchitis, and then chronic atrophic inflammation of these regions. In the lungs there Is development of what Is known ms catarrhal-intraparenchymatous inflammation, leading to atrophy of the Inter alveolar septa. Fibrosis Is not very pronounced and Is of a constant nature (Niepoloaski et al. [81]). Berylliosis is included among the toxle dust * diseases in view of the mechanism of its development, and In the early stages there is exudative pneumonia, which quite quickly changes to a productive phase. There is formation of nodules composed of histiocytes lymphocytes- These nodules axe oftan surrounded by striae of collagenous fibres, undergoing hyalinizatlon. Sometimes giant calls, similar to v Langhans N cells, are to be found in the centre of such a nodule (Msrchand [75], Ruttner et al. [104], Stofer [114]). There is no doubt concerning the existence of^conlosiskts a distinct nosologic unit (Kleczefiski [61], Zahorskl [123]). Research undertaken so far has endeavoured to establish the mechanism of its genesis (Aooudru [1], Ottovies [93]). Many authors (Ebert et al. [24], Hamas et al. [40], Heppleston [44], Folicard [95]) consider that pneunoconiotic changes in the lungs only develop with participation of living cells. In the oplnl n f the above authors these cells absorb many particles of dust end then carry them to the connective tissue around the vessels, to the wall of the bronchi and alveoli and to the lymphatie vessels. However, there are those (Gr as [36, 37]) who assert that the dust particles reach the connective tissue without the participation of living cells, as a rasult of tha respiratory movements of the lungs. In recent years tha lltaratuTa has contained reports on tha possibility of pathologic changes developing in the respira tory system reminiscent of eonlosls, but caused by the action of plastics OCC (Koltsov [10], Roussel [102]). These reprts drew ay attention to plastics which are now In general use and have entered many spheres f dally life (Markievicz [76], Kastlerlna et al. [57]( Porejko at al. [97], Schlldknecht [107]). On account of their plasticity, resistance to the action of adds and alkalies, ease of shaping and relatively low production costs, plastics products have also found application in biology and medicine [Frsnkowskl [29], Jaslfiski et al. [53], Ksveckl [58], Kauecki et al. [59], Kuf et al. [69, 70], Kowak [83,. 84 , 85 , 87], Olefiski et al. [89], Bob et al. [101], Rzepecki [105], Staniszewska [113], Szyma&ska et al. [116], Crabowskl et al. [35], Kfdra [60], Komezyfiskl et al. [64]). One of xbe most .important and first synthetic thermoplastic macro-- molecular compound produced on an Industrial scale was polyvinyl chloride (PVC) (Franty et al. [30], Vanderberg [119]). Pure polyvinyl chloride has the form of a white, tasteless and odourless powder. In industrial produc tion, material made from it can be given various forms, with varying elasti city and hardness. Therefore these polyvinyl chloride products have found application in the meat Industry (Bohosiewlcz [9]), pharmaceuticals (Chwlaikowska et al. [15]), in sport (Kopczydskl [65]) and In medicine (Coetzen [34], Homrowski et al. [47, 48], Jankowska [52] and others). The introduction of various new chemicals and various products made from them In dally use has given rise to the problem of the action f these compounds on the human body, both of the producers and of the users. This problem has been dealt with in many works In the national and foreign literature (Crlstea et al. [16], Bartanov et al. [4], Bervieux [45], Kalinin [54], Kalldska [56], Koelseh [62], laehnlt [71], lefaux [72], Markievicz [76], Moeschlla [78], Kowalska et al. [66], Xallnowska et al. [55], Smollk [108], Trosfln [117], Colow et al. [17], Deyanowa et al. [20]). The problem of the toxicity of plastics, and especially polyvinyl chloride. Is ucc 065198 still open, despite the feet that various investigations In this direction have been undertaken (Quooss [99], Russel [103], Fennarola et al. [94]). The opinion expressed in the vast majority of published works Is that polymers are physiologically inert compounds, and the harmful effects are caused by auxiliary chemicals in the polymer manufacturing process (initia tors, catalysts, emulsifiers) or taking part In forming the physical pr par ties of the polymers/ (stabilizers, plasticizers) (Danlshevskll et al. [19], Nowak [S2]). Some authors (Filatova [26, 27], Gervals [32], Wltnauer et al. [120]) ascribe harmful action to vinyl chloride, the toxic properties of which are already recognized and measures to prevent poisoning have already been taken In many factories (Beusnel [7], Broltman [11], Bugajska 112], Saitreva 121], Gabor [31], GQnther [39], Krivoglaz et al. [63]).' However, many authors consider that certain plastics may have pathogenic properties and as confirmation of their viewpoint they cite the harmful effects of massive inhalation of polyamide dust. This dust causes acute catarrhal pneumonia with formation of granulomas of the type around foreign bodies (Giovacchini [33]), and sometimes even changes of the nature of storage disease (Medve et al. [77]). There are also those who ascribe carlnogenic action to plastics (Fltzhugh [28], Hueper [51], Nowak [88], Kesswetha et al. [79], Oppenhelmer et al. [90], Russel et al. [103], Bates et al. [5], Druckrcy et al. [22, 23], Oppenhelmer et al. [89]). As a result of these investigations it was found that after implantation of plates there is nearly always appearance of neoplasms [Guess et al. [38]), after implanta tion of a thread they only develop occasionally (Kogan et al. [63]), and neoplasms are never found after implantation of powder (Oppenhelmer et al. [92]). Although most authors are of the opinion that polyvinyl chloride Is a physiologically neutral compound. In recent years the literature has UCC 065A99 contain d occasional rap rts on tha occurranea of various bodily disorders and changes in tha organs of workers employed in fact rles manufacturing polyvinyl chloride or products made from this material, vis: in the liver (Fushln [98]), especially in older women (Troshlna [117], in the phalangeal bones of the hands and in the skin (Harris and Adams [42]), and la the vas cular and nervous system (Suciu et al. [115]). Bugajska at al. [12] have drawn attention to the possibility of toxic action of PVC. Roussel et al. [102] found posthumous atypical changes in tbs lungs and were unable to assign these changes to a set of known nosologic units. These authors assume that these changes should perhaps be associated with work done for many years by this worker in a PVC factory. In addition to descriptions of clinical observations, the literature also contains experimental works conducted with polyvinyl chloride. Bernt (quoted by Danlshevskll [6]), for example, fed animals an oily suspension of ground PVC and shoved that it I ---------- - '-------------------- ------------------------ 1 ! does not have any toxic properties, but he also ascertained that the material is soluble in the gaatTlc and intestinal Juice. Boitsov [10], however, mentions the possibility of development of conlosis in animals after intra tracheal administration of PVC resin. He found that in their lungs, there is thickening of the Interalveolar septa and also peribronchial and perivascular inflammation. My preliminary investigations on rats (Popov [96]) submitted . to the action of polyvinyl chloride slso indicated that this dust is a noxious agent for the lungs. Lymphocyte-like cells multiply under the influence of Inspiration of this dust. They accumulate In the form of cuffs around the blood vessels, and there is also Intumescence of the muscles and proliferation of collagenous fibres In the wall of the bronchi, and pulmon ary emphysema. UCC 065200 s II. PURPOSE OF THE WORK AMD ASSUMPTIONS As follows from this review of the literature, the problem of the effect of plasties on the living organism has not yet been solved completely. Because polyvinyl chloride Is one of the most frequently used plastics, ve decided to conduct investigations of the respiratory system after long term action of polytvinyl chloride and establish the nature of the resulting pathomorphological changes. Moreover, we tried to determine whether th changes in the lungs after cessation of exposure to FVC dust recede, wh ther they stop developing, or whether they still oceur. Another interesting problem worthy of consideration is whether the changes occurring in the lungs promote the development of complications, as occurs for example la the course of silicosis. In the literature available to me I have not come * across reports on this kind of experimental investigations on animals. III. RESEARCH TECHNIQUE The experiments were conducted on 60 white rats of both sexes of the Uistar strain. A control group comprised 10 rats. The age of the animals at the start of the experiment ranged from 3 to 4 months. The rats weighed from ISO to 220 g. The anlnals remained In separate cages. In a well-lit room which was aired every day, with its temperature maintained in the range from 16* to 20*C. The animals were given mixed, nonstandard food regularly. The test animals were divided into three groups. Croup I comprised 16 animals exposed to FVC dust from 1 to 4 months. In this group I observed the picture of all pneumoeonlotlc lesions. Cr up II comprised 22 rats, exposed to the dust from 5 to 12 months. In this group 1 observed the picture of late pr.cumoconlotle lesions. Group III o comprint! 22 rnts which, after 12 months of exposure to the dust, were kcpr^> n'i?rvatlon for a oerlod of 8 months. This group was employed for 06S20f investigating ch* behaviour of the pathologic changes that ar sc under the Influence of p lyvinyl chloride after Its action had ceased. The c ntrol group comprised 10 animals. They were kept under observation for 20 months, 2 rats being killed by decapitation every 4 months. Exposure to polyvinyl chloride dust was effected in the following way: ^- * the rats were placed in a special chamber with dimensions 1.46 m x 0.56 m x 0.38 m and were submitted to the action of polyvinyl chloride dust every * day for 1 hour. A rubber hose was led Into this chamber, and the other nd of the hose was in a glass vessel with capacity of 2000 ml (mixer). Every day 30 g of FVC powder was poured into the mixer once. The mixer was connected by another rubber boss to an alcctrle blower. When the blower mas switched on, the PVC powder was mixed with air. Then using the outgoing rubber hose, the FVC-alr mixture was led into the chamber where the animals were. The concentration and size of the FVC dust particles were nonit r d with a Zeiss conioDeter during exposure to the action of the dust. At the start of the experiment, on average about 9000 dust particles were f und 3 in 1 mm . As time passed, this figure gradually fell, es follows (figures given after rounding off): 7000 dust particles after 15 minutes, 5000 dust particles after 30 minutes and about 1000 dust particles In the final phase of dust exposure. The size of the dust partleles was as follows: smaller than 1 urn - 1Z, lass than 5 j - 92X, from 5 urn to 10 ym - 4X, larger than 10 pm - 3Z. The concentration by weight was 97 g/m^. After exposure to the dust for 1 hour the rats were put back In the cages, where they remained for the rest of the time. The control group of animals was placed In the chamber for 1 hour every day' and movement of air was created with the aid of the electric blower, but FVC was not Introduced. All the animals vers killed by decapitation. ucc 065202 From each animal lung segments were taken from the perlhllar and subplaural regl n for microscopic Investigation. The segments taken were fixed In Camoy fluid, embedded In paraffin bloeks and stained: hematoxylin and eosin, orcein according to Weigert's method for elastic fibres, accord ing to Goaorl's method for argentaffins fibres, according to Beldenhain's modification of Mallory's method (with "assn") for collagenous fibres, according to Turnbull's method for divalent Iron and Peris' method for trivalent iron and with muelcarmln for the presence of mucus. In addltl n the following hlstochemical tests were effected: paS for neutral mucopoly saccharides (supplementing It with control acetylation according to Gersh and employing blocking with dlmedon), txlpaS for addle protein and 'Bale's test for sddic mocopolyssccharldes. In addition, atalnlng with toluldlne blue at pH 3.4 and S.6 was affected for the purpose of investigating metachrocasia and detection of mast cells. Polyvinyl chloride, designated by the symbol ED, was obtained from the Zaklady Chcmiczny (Chemical Works) in Ofvifci?.. The results of the microscopic Investigations relate to lung segments taken exclusively from animals that were killed at the scheduled tine. IV. RESULTS OF INVESTIGATIONS 1. CONTROL CROUP Macroscopic picture. The animals In this group were killed at 4-monthly Intervals. On dissection. In all the rats the lungs collapsed slightly after opening the thorax, and they were pale pink and airy on the external surface and on section. During cutting they crackle In the characteristic ucc 065203 way. No bronchiectasla and no nodular foci were found in the lungs of these animals. Microscopic picture. The pulmonary alveoli are fairly regular, the Interalveolar septa are of Identical thickness with occasional slender elastic fibres (orcein staining). Around the thin-walled capillary vessels In the interalveolar septa ve observed some' lymphocyte-like cells (Fig. 1). The basement membrane of the capillary vessels contains slender thread-like collagenous fibres (staining with Aran) and slender argentaffine fibres (staining by Gomorl's method), but do not contain paS-positlve bodies, end stain yellow in the tripaS test. pMt lobar bronchi are lined with simple cylindrical epithelium, which is aultirowed with occasional beaker cells, and the ciliary apparatus is retained. In the cytoplasm of the beaker cells there are occasional, extremely minute mucus granules (staining pink with muclcarmln) and als paS-positlve bodies (staining reddish-violet). Neither the cytoplasm of the cylindrical cells nor of the beaker cells contains acidic mucopoly saccharides (Bale's test proves negative). In the wall of these bronchi the muscle fibres run across circuitously in bundles and are separated by collagenous fibres (staining with Azan). The elastic fibres also run circuitously, slightly undulating (staining with orcein), and argentaffine In the form of tanglus (staining by Gomorl's method). Furthermore, in the wall of the bronchi there are a few lymphocyte-like cells and histiocytes. * In the submucous membrane we can observe occasional glandular tubes with narrow lumen, containing neither mucus nor mucopolysaccharides (staining with muclcarmln; paS, tripaS and Bale's tests prove negative). The lumen of the segmental bronchi and bronchioles is lined with eylindric cells, but beaker cells are not found among them (Fig. 1). The cytoplasm of the eylindric cells stains yellow in the tripaS test and d es ucc 065204 doc contain any granules: neither f mucus, nor of me polysaccharides (staining with muclcsrmln and the paS and Hale*s tests prove negative). The vail of the segmental bronchi has structure similar to the lobar bronchi. Ko phagocytes with granules of haemosiderln vers found in the cytoplasm in the rats of the control group. Occasional mast cells appear under th pleura (having fine-granular, reddish-violet cytoplasm vhen stained with toluidine blue). 2. CROUP I. EARLY CHANGES (EATS Nos. 1-16, PERIOD OP EXPOSURE TO DUST - 4 MONTHS) Among the 16 animals in this group, 2 rats (Nos. 1 and 2) died at the scart of the 4th month of experiment. Pulmonary emphysema and a con siderable degree of passive congestion are found id all internal organs on dissection. A further 2 rats (Nos. 3 and 4) died in the last days of the 4th month of exposure to the dust. The macroscopic picture was similar t that of the 2 previous rets. The surviving 12 rats (Nos. 5-16) were kill d at 1-month intervals (3 rats st s time). Mnrror.coplc picture. After opening the thorax, in all the rets of this group the lungs do not collapse but fill the whole thorax, and they ar fluffy and pale. During cutting, they do not crackle as characteristically as normal lungs. On the cut surface they are pale pink and dry. A small quantity of mucous mass is dischargad from the large bronchi on cospressl n. Microscopic picture. The pulmonary alveoli ere inflated like balloons, the septa betvaen than art of reduced thickness, ere disrupted in places, as a result of which there is formation of large cysts, and the residues of the septa project in the form of spines into their lumen. In the first ucc 065205 few months of experiment the Interalveolar septa are f und to have aggregates of hlstl cyte-like cells, the cytoplasm of which possesses minute, diffuse goldcn-br vn granules of haemosiderln containing trlvalent iron (they stain greenish-hlue according to Peris' method. Fig. 2). Sometimes in the vicinity pf the blood vessels in the foeally thickened Interalveolar septa there are aggregates of cells of this kind, profusely charged with haemosiderln (Fig. 2). Towards the end of the 4th month of exposure to dust, cells with haemosiderln granules arc seldom found. However, thicken ing of the septa persists. In the first few months of this period the lobar bronchi, lined with cylindrical epithelium, have an irregular lumen. On the surface of the epithelium there are scant, amorphous, pink mucous masses (which stain pink with mucicarmin), containing minute granules of mucopolysaccharides (which stain reddish-violet in the paS test). Between the cylindrical cells there are occasional beaker cells, the cytoplasm of which contains mucus (which stains pink with mucicarmin) with a few, fine granules of neutral mucopoly saccharides (staining reddish-violet in the paS test). In the final phase of this period of the Investigations the lumen of the lobar bronchi becomes roundish. * In some places the cylindrical epithelium undergoes flattening, and in some places there is even complete destruction (Fig. 3). This destruction is not restricted to the epithelium, but effects deeper layers of the bronchus. Between the lymphocyte-like cells filling such a defect in the bronchial vail there are no elastic fibres, or they have undergone frag mentation and have the form of fine, very thin brown filaments In rceln staining. On the other hand the argentaffine fibres undergo thickening r fragmentation as well (staining according to Gomorl's method). The rather *mall number of lymphocyte-like cells in the wall of the lobar bronchi in ucc 065206 the initial phase increases as tine passes, and by the end of the fourth sooth such cells are quite numerous. In this period there is also an increase in the number of beaker cells among the cylindrical cells of the epithelium of the lobar bronchi (Fig. 4). The cytoplasm of the beaker cells contains mucus in the form of spherical pink granules when stained with muciearmln. The composition of this mucus Includes neutral mucopolysaccharides (staining reddish-violet in the paS and tripaS test). These granules are located in the basal part of the beaker cells, near the nucleus. In addition, the cylindrical calls lining the lumen of the lobar bronchi undergo mucous degeneration and exfoliate Into the lumen of these bronchi, which is filled with mucous mass (Fig. 5). The mucous masses mentioned above are stained pale pink by muciearmln, but the paS and tripaS test proves negative. In the submucous membrane there are occasional glandular tubes, which have e narrow lumen and contain neither mucus nor mucopolysaccharides (staining with muciearmln, and the paS, tripaS and Hale's tests prove negative). In the initial phase of the period of investigation, with staining with Azan, a small number of slender, bluish collagenous fibres are noted in the wall of the lobar bronchi. The reddish-violet striae of muscle fibres are fairly vide in comparison with the control group. By the end of the fourth month, here and there the bluish collagenous fibres In the wall of the lobar bronchi have become "scattered", and nearby there are agglomerations of lymphocyte-like cells. On the other hand the muscle fibres are tumefied. The vail of the blood vessels located near the lobar bronchi has focal thickening as a result of considerable swelling of the muselc fibres, which is revealed by Intense reddish-violet coloration in staining with "Azan". However, the adventitia appears ss s very thin blue stripe. In places in the well of these vessels we can see small amorphous, violet calcic lamellae. uce 065206.01 In the peripheral part the lung juat under the pleura, ar 12nd the capillary v ssels with softened and thickened wall, ve can detect "cuffs** vlth numerous small, rounded cells with a dark nucleus and a narrow fringe of cytoplasm (Fig. 61. The endothelium that was tumefied at the start exfoliates into the lumen of the vessels in the final phase, and sometimes closes it completely. The cytoplasm of the cells lining the lumen of the segmental hr nehl and bronchioles, which for the most part Is not widened, is not found to contain granules of mucus, neither after 1 nor after 4 months of dust exposure. Also no beaker calls appear between the cylindrical cells f The epithelium of these bronchi, or of the bronchioles. In this period of the Investigations, under The pleura wa observe e few. Isolated meat cells, which have reddish-violet, fine-granular cytoplasm In staining with t luidina blue. 3. CROUP II. LATER CHANCES (RATS Nos. 17-38, PERIOD OF EXPOSURE TO DUST - 8 MONTHS) s Among the 22 rets in this group, 2 died (Nos. 17 end 18) In 6 months of exposure to FTC dust. On dissection they were found to have pulmonary emphysema and bronchlectasla in a suppurativa state, end in e further 4 rets which died in 7, 8, 9 end 10 months of exposure to the dust (Nos. 19-22) there were smell, scattered foci of suppurative pneumonia. Two rats died in each of the 11th and 12th months of exposurs to the dust (Kbs. 23-26) as a result of bronchiectasis and pulmonary suppuration. The surviving rats were killed in two's at monthly intervals, starting from the 5th month of observation. ucc 065207 Macroscopic picture. In the rats after 5 and 6 months of exposure to the dust (K a. 27 to 30), after pening the thorax the lungs do not c llapse but protrude froa the thorax, they are moderately fluffy hut do not crackle during cutting as markedly as normal lungs. Minute slate-llke specks show through the'pleura. On cutting the lungs are pale pink, and dry. Br nehi with widened lumen protrude froa the cut surface, and on compression the ropy contents are discharged froa them. In the lungs of rats after 7, 8, 9 and 10 months of observation we found nodular foci protruding above the surface, which had a honeycomb appearance on the cut surface. Theae f cl contain a ropy, milky-opalescent fluid. In addition to these foci there were large formations, with the features of single-cell cysce filled with mucoatheromatous mass. These large eystold formations were surrounded by a distinct undulant reddish fringe. Sometimes the eystold formations were so large that they occupied the entire lobe of the lung. In rats after 11 and 12 months of exposura to FVC dust the nodular'foci had enlargad to such an extent that sometimes they occupied the entire lobe. On the other hand there were fewer large eystold formations, and they were also smaller. Xicrr'tcoplc picture. Marked pulmonary emphysema Is noted, more pro nounced than in the animals of group 1. However, in places the interalveolar septa are thick, and the blood vessels in them have Irregularly thickened wall and tumefied endothelium. In the wall of these vessels, after 9 months of exposure to the dust, eollsgenous fibres sppear instead of the muscle fibres, which Is indicated by blue coloration of the vessel valla as s result of the action of Azan and orange coloration when the trlpaS test Is carried out. Cuff-llke aggregations of lymphocyte-like cells and histiocytes are observed around these vessels. Sometimes these aggregations are connected to the aggregations of such cells around the segmental bronchi, forming a single complex. The lobar bronchi have a widened lumen and are filled with UCC 065208 mucous masses with numerous granulocytes submerged in them. The muc us masses give a strongly p sltlve paS reaction (Intense reddish-violat staining) and are closely adjacent to the surface of the epithelium. Between the cylindrical cells lining the lumen of these bronchi there are very many beaker cells. Their cytoplasm gives a weak reaction with mudcarmln: pale pink, but the reaction of paS and trlpaS is very strong: Intense reddish- violet. After blocking with dimedon, there was no change In the e 1 rati n of these masses In the paS test. Furthermore, in the cytoplasm of th cylindrical cells there are minute paS-positive granules. As time passes, the collagenous fibres in the vail of the lobar bronchi become thicker and thicker (staining blue with Azan), and the elastic fibres undergo fragment - tion and are visible as short, thin brown filaments (staining with realm). In addition. In some bronchi there is metaplasia of the cylindrical epi thelium to stratified pavement epithelium (Figs. 7 and 8) In the immediate vicinity of the bronchi we can see aggregations of lymphocyte-like cells and histiocytes. Sometimes we gain the lmpr sslon that the cylindrical epithelium of the lobar bronchi forms In layers or grows In the shape of a tongue deep Into the well (Fig. 9). In 11 end 12 months of exposure to PVC dust, the epithelium of the dilated lobar bronchi is low and flattened. The collagenous fibres In the wall of these bronchi have the appearance of thick, broad, uniform blue stripes (stained with Azan). The submucous membrane is greatly widened. The glandular tubes located In it ere either dilated like cysts (Fig. 10) and filled with pale-pink contents, giving a weak reaction with mudcarmln, and stronger paS reaction, or have the appearance of solid tubular f cl without a lioien, composed of malleolar epithelium (Fig. 8). Sometimes the dilated, eyst-llke tubes are filled with paS-posltlve*masses located just under the metaplastlc, stratified squamous epithelium, into which their ..iitj.oli./ duct i probably set (Fir.. 7). ucc 065209 Between these tubes we find quite numerous scattered lymphocyte-like cells end hist! cytes (figs. 8 end 10) end quite wide bands of c Hagen us fibres, which stain blue with Axan. The changes described above are observed starting from 7 months of exposure to the dust. The segmental bronchi undergo dilatation after 8 months of experiment. In this period the cells of their epithelium undergo flattening, and beaker cells appear between them. The cytoplasm of these beaker cells gives very weak reaction s with muclcarmin, but the paS test is strongly positive - there is intense reddish-violet coloration of the cytoplasm. paS-posltlve granules also appear in the cytoplasm of the cylindrical cells. In addition the epithelium of.these bronchi becomes stratified (Fig. 11), and sometimes even undergoes metaplasia into stratified squamous epithelium (Fig. 12). Then in the lcaedlate vicinity we can see aggregations of hlstlocyte-llke cells and occasional bands of hyallnizing connective tissue. As tine passes, the collagenous fibres in the wall of the segmental bronchi become thicker and thicker and have the appearance of broad blue stripes in staining with Azan. By the end of 12 months of experiment, the collagenous fibres undergo hyalinization (Fig. 13), and the epithelium undergoes atrophy. There is also atrophy of the glands located in the sub mucous membrane. Starting from 8 months of exposure to the dust, round some segmental bronchi we observe profuse euff-llke aggregations of lyaphocyte-lika cells. Pathologic changes do not appear In the bronchioles until 9 months of experiment. They result from enlargement of histiocytic and lymphocyte-like cells towards their lumen and intussusception in the vail of the bronchi le In the form of warts. Some vart-llkc formations are deprived of br nchlal epithelium. As time passes, around the bronchioles there is accumulation of marc and more lyaphocytc-llke cells and histiocytes (Fig. 14), which ucc 065210 fill defects In the epithelium of the bronchioles (Fig. 15). The elastic fibres in the wall f the bronchioles in defective regions undergo dis integration, and whan stained with orcein th y are visible as slender, short, isolated brown filaments. The microstructure of the nodular foci with honeycomb appearance, which was found in rats after 7-12 months of exposure to PVC dust, can be described as follows: they contain cystold formations lined with cylindrical epithelium. In places we can see wart-like protuberances, composed of connective-tissue stroma (thick blue stripes when stained with Azan) covered with cylindrical epithelium, which creates the impression of focal strati fication or undergoes metaplasia into stratified squamous epithelium (Figs. 16 and 17). Squamous-epithelial metaplasia of this kind also occurs in lobar and segmental bronchi. Between the cylindrical cells without cilia there are quite numerous beaker cells, the cytoplasm of which give a strongly positive paS reaction - it has intense reddish-violet staining. paS-positive masses also fill the lumen of these cystold formations and arc stained pale pink by mucicarmin. However, the large cystold formations filled with "mashy" masses , in rats with the same period of exposure to dust, have a different microstruc ture. These are large thin-walled cavities, end the wall is composed of hyallnized connective tissue, without epithelial ependyma. In the lumen of these cavities there ere amorphous, fine-granuler masses, and granulocytes are only seen among them in a few pieces. Hale's test proved negative in all the animals. The number of mast cells, the cytoplasm of which is stained reddish-violet by toluidine blue, does not increase; only e few f them are encountered under the pleura or near the dilated bronchi. The granules In the cytoplasm of the phagocytes, located in the lnteralve lar septa near the blood vessels, contain neither divalent nor trivalcnt iron (staining according to the method of Turnbull and Peris prove* negative). ucc 065211 4. CROUP III. CHANGES AFTER CESSATION OF EXPOSURE TO PVC DUST (RATS N a. 39-60, OBSERVATION FROM 1 TO 8 MONTHS) Of Che 22 rats in this group, by Che end of che first month of observation after cessation of exposure to PVC dust, 6 rats died (Nos. 39 to 44). Upon dissection, in the lungs of all the rats In addition t emphysema and bronchiectasis ve detected the presence of numerous nodular or cystold formations filled with thick, creamy, ropy contents mixed with "washy" masses. Sometimes the entire lung was composed of thin-walled, cystold formations. The surviving 16 rats (Nos. 45-60) were killed at monthly Intervals (2 rats at a time). Macroscopic picture. Among the surviving 16 rats, during dissection of 8 animals killed at the scheduled time ve determined the presence f apneusatic, fine-lobular, hard nodular foci (Fig. 18), as in the lungs f the animals in Croup II. In addition, we observed large, quite soft cyst id formations (Fig. 18), and when cut they were found to have a thin wall and were filled with "mashy" masses mixed with mucilaginous, partially creamy contents. The changes described above were observed in rats both 1 month and 8 months after cessation of exposure to the dust. In the other 8 rats, after openin'; the thorax the lungs do not collapse, they are excessively fluffy, pale pink, and during cutting they do not crackle as characteristically as normal lungs. The surface of the cut is pale pink, and dry. Bronchi with widened lumen and roller-shaped wall project from the cut surface. Mucila ginous contents are discharged from them on compression. Scattered slate like and dot-like foci show through the pleura. Microscopic picture. Pulmonary emphysema Is found in all the animals In this group, chough with less Intensity than in the rats of Croup IT. As time passes, blood vessels surrounded by a cuff of lymphocyte-like cells VJCC 065212 are observed less and less fr qu ntly In the lnteralve lar s pta. In the eighth month of bservatlon after the end of the experiment, only Isolated lymphocyte-like cells are to be seen around the blood vessels. The lumen of these vessels Is brosd, the endothelia ere flattened. In the veil ve can see thinner (In comparison with Group II) 'thread-like blue collagenous fibres (staining with Azan). The lobar bronchi have a much widened lumen and for the most part filled with coagulated albuminous, acidophilic fluid, mixed with numerous neutrophilic granulocytes. The albuminous fluid contains mucus (distinctly pink In staining with muciearmin) and a much smaller amount of paS-posltlve substances in comparison with group II (in the paS test It Is pale reddish-violet). These bronchi are lined by a low cylindrical epithelium with numerous beaker cells, 1 month after cessation of exposure to the dust. Minute paS-positive granules appear In the cytoplasm f the cylindrical cells. As time passes there is a gradual decrease of the number of beaker cells, and there are only Isolated ones by the end of 8 months of observation. At first the cytoplasm of the besker cells contains very little mucus (it is stained pale pink with muciearmin), hut a large amount f paS- positive substances (it Is stained intense reddish-violet). However, by the % end of observation there is a pronounced mucus reaction, whereas th paS reaction is weakly positive (staining pale reddish-violet). At this time the minute paS-positive granules also disappear from the cytoplasm of the cylindrical cells, and their squamous-epithelial metaplasia is rarely encountered. In two rata (Kos. 59 and 60) killed 8 months after cessation of exposure to the dust, it was found that there were numerous greenish-blue granules of acidic mucopolysaccharides (Hale's test) In the cytoplasm f the cells of the epithelium of the lobar and segmental bronchi and also in the glandular tubes of the submucous membrane of these bronchi. Similar granules were present In the epithelium of the microlobular nodular foci. IL'ile's test proved negative In the ocher animals. ucc 065213 The c llagenous fibres in the vail of the lobar bronchi are thick* homogeneous* and stain dark blue with Azan throughout the period of observa tion. Staining according to Gomori's method indicates lnspissatlon f argentafflne fibres - thick black bands. On the other hand there are few elastic fibres* in the form of thin* discontinuous brown threads (staining with orcein)* or they are completely lacking in the regions of defects In the bronchial wall. The submucous membrane is vide* in it there are numerous glandular tubes with a vide lumen, filled vlth contents giving a weak reaction with mucicarmin* and strongly paS-positive (staining intense reddish-violet). Aetween the glandular tubes there are extremely numerous lymphocyte-like cells. After 5-3 months from the time of cessstlon to exposure to the dust* the lumen of the glandular tubes seems to collapse. Cells of new connective tissue and numerous collagenous fibres appear between the tubes (with Azan, staining in the form of broad blue bands* which surround these tubes) (Fig. 19). In places the connective tissue grows as broad bands* and between them there are numerous lymphocyte-like cells and histiocytes* either scattered or in aggregates. Among the bands of connective tissue there are argentaffine fibres (staining black according to Comori's method), and thcr are no clastic fibres (staining with orcein). Some glandular tubes are enlarged in cystoid manner and filled with pale pink* homogeneous masses* giving a weak positive reaction with mudearmin (they stain pale pink), and negative pcS reaction (they do not stain). One month after cessation of dust exposure, the rounded or oval lumen of the segmental bronchi is lined with cylindrical epithelium with quite numerous beaker cells* indicating exe sslve secretion of mucus. This mucus contains a large amount of neutral mucopoly saccharides (Intense reddish-violet staining in the paS reaction). There arc alia* minute paS-posltlve granules in the cytoplasm of the cylindrical ucc 065214 cells. A broad bend of fibrosing connective tissue Is evident In the vail of the segmental br nchl (stains blue vlth Azan, and black according to Gonori's method) (Fig. 20). As time passes. In the epithelium of the segmental bronchi there is a fairly rapid decrease of the number of beaker cells containing paS-posltlve _ bodies; these cells are no longer visible A months after cessation of exposure to the dust. At this time the minute paS-positive granules also disappear from the cytoplasm of the cylindrical cells. Fight months after cessation of dust exposure, the broad band of connective tissue Is still present in the wall of the segmental bronchi and does not display signs of hyalinizatlon. Between the cylindrical cells of the epithelium, the cytoplasm of which Is atained yellow in the tripaS test, only isolated beaker cells are visible, with their cytoplasm containing mucus (stains pink with muclcaroin), but not containing paS-positive bodies. In 1 rat (No. 53) we observed several segmental bronchi alongside one another with cystold enlargement, which were lined with considerably flattened epithelium. Around these bronchi there was growth of fibrous connective tissue, still containing quite a number of lymphocyte-like cells and histiocytes^ The lumen of these bronchi is empty. The pulmonary alveoli in the vicinity of these enlarged bronchi are apneuaatlc, often copiously infiltrated with granulocytes, sometimes occupying some 10-20 alveoli each. Decay is found in the centre of these infiltrates. In all the animals we observed slight, gradual decrease of the number of lyapliocyte-like cells surrounding these bronchi like a cuff. By the end of the experiment (in 12 months of exposure to the dust), numerous histio cytes and lymphocyte-like cells had accumulated round the bronchioles, t such an extent that la places they lntussuscepted the vail of the bronchi le in the form of a wart. Two months after cessation of dust exposure, the ah ve-rentioned c 11s ore still r.ulr!plyirv: and now intussus.-ept the wall ucc 065215 of the bronchioles In numerous pieces (Fig. 21). Among the lymphocyte-like cells end histiocytes th re ere cceslonel thin collagenous fibres (they stein blue with Azan end brown eccording to Comorl's method). After 7 months ' from the end of the experiment, the lumen of the bronchioles Is merkedly constricted and distorted as e result of Intussusception of the wart-llke formations described above. In their subepithellal layer the connective / tissue undergoes hyalinlzation (steins a uniform blue with Azan), and the surface is partially covered with flattened epithelium. In addition to the changes described above, 1 month after cessation of .exposure to the dust ve may. find, bands of partially fibrosing connective tissue around some bronchioles, with lymphocyte-like cells and histiocytes between these bands (Fig. 22), or profuse aggregations of lymphocyte-like cells filling the defect in their wall. Four months after cessation of the experiment, sometimes the bronchioles have an Irregular, stellate lumen and are lined with low epithelium (Fig. 23). Into these bronchioles thara is intussusception of bands of connective tissue containing collagenous fibres (staining blue with Azan) end argentafflne (staining black according t Goaori's method). Moreover, we often observe proliferation of connective- tissue fibres (staining blue with Azan) in the vicinity of the bronchi les. By the end of 8 month* from cessation of the experiment, the picture is similar, but the new connective tissue gradually transforms into fibrous tissue (uniform dark blue staining with Azan). The microstructure f the mlcrolobular nodular foci, observed both 1 month and 8 months after cessa tion of exposure to FVC dust, is similar to that described In Group II, and the lumen of these cystold formations is filled with granulocytes immersed in mucus, which is stained pink with mucicarmin. However, the microstrueture of the large, soft cystoid formations and their contents are the same ns described in Group II. ucc 065216 In the first month of bservatlon after cessation of exposure t dust, under the pleura there is accumulation of, in each case, a few r about a dozen large phagocytes with scattered golden-brown, minute granules in the cytoplasm. These granules do not give positive paS and tripaS reac tion, do not stain with mueicarmin, and also do not contain divalent r trlvalent iron (staining according to the method of Turnbull and Peris), Only toluldlne blue stained them golden-yellow. The appearance of fibro blasts and occasional very thin collagenous fibres (filaments staining blue with Azan) between these phagocytes was only determined after 8 months f observation. Throughout the period of observation the mast cells behave as in Croup 11. V. INTERPRETATION OF THE RESULTS AND DISCUSSION The results obtained in my Investigations indicate that FVC dust is not a physiologically neutral compound. Long-term inhalation of it leads to the development of a variety of pathologic changes in the resplrat ry apparatus. At the earliest, after just one month of exposure to this dust, there is development of catarrhal inflammation of the lobar bronchi with mucoid degeneration of the cells of the epithelium and focal pulmonary emphysema. The development of focal emphysema even in the first month of exposure to PVC dust depends most probably on mechanical obstruction f the small bronchi in the form of a valve. The muscle fibre* and collagenous fibres of the bronchial wall undergo tumefaction, and the lymphatic follicles undergo focal hyperplasia. In this period the segmental bronchi as well as the bronchioles do not exhibit catarrhal lesions, but the basement membrane of the capillary blood vessels in the interalveolar septa undergoes ucc 06S2A1 c apounds have been explained by Opp nheimer et *1. (90}. They c nslder that free radicals are released and react vith the cell constituents. These free radicals repeatedly lead to depolymerization of nucleic acids and so have an influence on the enzymatic processes of the eell. Hedrl et al. (cited.by Homrowskl [43]) and Kowalski et si. [67] deoonstrsted that if dibutyl phthalate is used as a plasticizer in the production of PVC, the finished ?VC has marked toxic properties, probably as a result of Insufficient polymerization. The investigations of Novak [86] and Bober [8] showed that dibutyl phthalate can cause inflammatory reactions. However, Smollk 1108] considers that the toxic properties of macrcoolecular compounds ere associated with aonomer residues. In his opinion .they cause acute chronic disorders of the respiratory passages. On the basis of ay research I cannot ssy with complete certainty whether the FVC molecule undergoes depolycerlzetion and becomes associated with protein, or whether free radicals react with the constituents of the serous fluid of the bronchi, or whether the residues of monomers perhaps exert en action. It is a fact, however, that paS-positive bodies appear in the cells of the epithellio f thu bronchi, in their lumen and in the bronchial glands under the influence of I'VC dust, and the number of Such bodies Increases as time passes. After exposure to the dust has ceased, the paS-positive bodies gradually disappear. This might indicate that PVC duat irritates the bronchial epithelium, causes en Increase of the number of beaker cells end promotes their s cra tion. This secretion does not have the typical nature of mucus (slightly positive result of staining with mucicarmin), but it contains paS-posltlve bodies. This is emphasized by the feet that with the passage of experiment time, this secretion becomes more end more deprived of the constituents that are characteristic of mucus (stslning with muelcamln Is almost nega tive), but it contains more end more paS-positive bodies. After cessatl n ucc 065218 f exposure Co FVC dust, Che peS-poslcive b dies disappear quite quickly from this secretion, and Che constituents that are characteristic of mens appear Instead (staining with mucicarmin Is strongly positive). It Is - a-- significant that PVC administered perorally does not cause any symptoms of toxic lesion of Internal organs (Homrowski et al. [46, 49]). Research by Hervicux, Tessler [45] and Truffert [118] showed that nacroaolecular compounds that are derivatives of vinyl possess toxic properties. Toxic action of polyvinyl chloride Is Indicated by investigations of the liver of rats exposed to Inhalation of FVC dust, undertaken by Cylwlk [18]. In addition to far-advanced degenerative lesions of the liver cells and reac tive hyperplasia of the cells of the reticuloendothelial system, he noted that paS-positive bodies appear In the liver cells during the experiment, but disappear when exposure to the dust ceases. Appearance of paS-p sltive bodies in the bronchial epithelium and in the lymph nodes of test animals exposed to polyvinylpyrrolidone dust (a vinyl derivative) is also described by Lovsma et al. [74], who also note that these paS-posltive bodies are nlr.o found in the lymph nodes of people employed in the production of this polymer. The reports of Lachnit [71] and Lefaux [72] show that nontoxic cacronolecular compounds administered perorally may prove highly toxic n Inhalation to the respiratory system. It seems that polyvinyl chloride can he Included among the macromolecular compounds with such properties. Comparing the morphologic pictures In conlosis caused by FVC dust with the pictures of conlosos that have already been described, it must be stated that the changes produced by polyvinyl chloride dust ere somewhat similar to the changes in bsrylllosls, though to s slight degree. This comparison is based on Identical cells in the inflammatory infiltrates. However, in berylliosis there is formation of granulomatous nodules, but pronounced granulomas were not observed In FVC conlosis. In FVC conlosis ucc 0652A9 Chickening and ftening, and the and thellal cells undergo tioefacd n* Ar und the blood vessels chare Is accumulati n lymphocyte-like cells, which surround them like a cuff. Here and there In the Interalveolar septa near the blood vessels we encounter Isolated or small groups of phagocytes, laden with.granules of pigment containing trlvalent iron. After 2, 3 and 4 months of exposure to the dust we observe greater dilatation of the lumen of the lobar bronchi and Intensification of the degenerative changes of the epithelium than after 1 month. The muscle fibres of the bronchial wall are more thickened and swollen than after 1 month, whTas the collagenous fibres undergo disintegration. Devel paent of defects was observed In places in -the wall of the lobar bronchi. Than in this region there was intensive proliferation of lymphocyte-like cells and histiocytes, which filled the defect. In this stage of the experiment, lymphocyte-like cells accumulate in large foci around the segmental hr nchl. The epithelium lining the segmental bronchi and bronchioles maintains Its height, but it is covered with a thin layer of mucus. In this period we did not observe accumulation of lymphocyte-llke cells near the bronchi les. However, they surround small blood vessels in the Interalveolar septa like a cuff. The excessively-inflated pulmonary alveoli exhibit the typical characteristics of emphysema. On the basis of the picture of pathologic changes In the first 4 months of exposure to PVC dust It can be stated that PVC dust reaching the respi ratory system causes mucoid catarrh of the lobar bronchi and pulmonary emphysema In the early stage. As time passes, mucoid degeneration gradually affects the segmental bronchi and bronchioles, but is only slight. In parallel with the degenerative changes In the bronchi, we observe a marked reaction on the part of the lymphatic system. Lymphocyte-like cells accumulate not only around the blood vessels In the Interalveolar septa, b-.it nV - in the bronchial wall. ucc 065220 Among the changes baerved In animals exposed t PVC dust fra further 8 months on top of the first schedule, hyperplastic and metaplastic lesl ns appear. In addition -to Intensification of the degenerative changes. They affect the epithelium of the lobar bronchi and of the segmental bronchi, and even appear in the epithelium of the bronchioles. Against a background of hyperplastic lesions of components of the bronchus, there Is development of cystoid foci, with wart-like protuberances covered with cylindrical or squamous epithelium. The epithelium lining these foci exhibits muc id degeneration. The excessive quantity of mucus accumulates in the liases f these wart-like foci, often there is secondary Infection, which leads to suppuration. The microscopic picture of these foci Is similar to the pic ture of e cystoadenoma. In the vail of the lober and segmental bronchi, with widened lumen, vc find broad bands of connective tissue with lymphocyte-like cells betveen its fibres. The muscle fibres in the vail of these bronchi underg atrophy. The resulting dilatetion of the bronchi often leeds to secondary Infection. Then their lumen is filled with mucopurulent fluid, and the epithelium undergoes strophy. In the final staga of exposura to tha dust, l.e. after 12 months, granulocytes and histiocytes accumulate around the bronchioles. Sometimes the granulocytes and histiocytes lntussusccpt the wall of the bronchioles like warts Into the lumen, distorting and constricting it. There is often mucus with granulocytes in the lumen. Pulmonary emphysema, developing in the initial period of exposure to the dust, most probably depends n mechanical obstruction of the bronchi. The emphysema Increases as time passes. Its development In the later stage is associated with degenerativeinflaraatory lesions In the bronchi and bronchioles; large bullae fora, in which an exudate accumulates, mainly comp sed of neutrophils. The wai's ucc 065221 of the number of beaker cells In the muc us membrane of these bronchi and decline of metaplasia f tha pavement epithelium. Metaplasia of the pavement epithelium deserves further consideration. In the rats of Group II this metaplasia was very pronounced. In Croup III, however, either it was not very marked, or It was completely absent. It would be difficult to accept that the 16 rats In Group III would react so very differently to exposure to PVC dust, l.e. that their reaction charac teristics would differ markedly from the reactivities of the rats in Group II. I assume that in these animals, which after all are derived from Inbreeding, there cannot be marked differences in reactions. Then we should mmsuna chat metaplasia of the pavement epithelium also occurred in the bronchi in these 16 rats, hut after cessation of axpoaurato PVC dust th metaplastic epithelium gradually exfoliated and normal epithelium was com pletely restored. The validity of this idea is supported by the fact that there is metaplasia of tha pavament epithelium in '8 rets out of 16, though this metaplasia was of a low level of intensity. As follows from 8 months of observation after cessation of exposure to FVC dust, some of the pathologic changes in tha lungs recede, but soa show no significant signs of receding. It can therefore be concluded that the pathocorphologic changes in the lungs, produced as a result of tha action of PVC dust, persist even after its action has ceased. Va must then ask what happens to the FVC dust. Is it deposited in the lungs, or is It dissolved in the body fluids? It is not easy to answer this question, for it turns out that PVC dust probably has the same refractive Index as Canada balsam and therefore it cannot be detected. Moreover, PVC dust particles do not retain any pigments which ere employed in the rasearch. It could be assumed that these dust particles dissolve In the tissue fluid In the lungs. That this possibility cannot be rejected Is demonstrated by th ohservarions of Bent 16], CylvtV pi-]. T-nchnit [71] and rtl.--::1-. ucc 065222 The results of investigations of rst lungs after exp sure t PVC dust Indicate that this dust produces lesi ns of the nature f coni sis. [AO] and Harris [41] consider that the type and nature of the pathonorphologle changes developing in the lungs during conlosls depend not only on the biological activity of the dust introduced, but also on the size of the dust particles. Khukhrina [14] proposed a classification of dusts int 7 types* placing highly toxic dusts in first place. Danishevskil [19] con siders that prioarlly macrooolecular compounds (polymers) are toxic to the organism. They are precisely characterized by biological activity. The toxic action of polymers is also reported by Hopkins et al. [50]. These authors described poisoning vith acrylamide* which took place with symptoms of toxic lesion of the nervous system. My investigations seem to show that particles of PVC dust* 92Z of which are smaller than 5 pm* reach the respiratory system and also have a toxic effect* though an Influence elso results from their mechanical action* by obstruction of the small bronchi. The toxic action of PVC is mainly indicated by dilatation of the bronchi and their suppurative Inflammation. According to Ashbel [2]* devel pment of dilatation of the bronchi and their suppurative inflammation are charac teristic features of toxic conloses* defined by French authors as toxic bronchopnthies (Marchsnd [75]). The mechanism of the toxic action f aacromolecular compound* was explained by Huepcr [51] in the following way: after coming in contact with body fluids a macromolecule may underg degradation (dapolymerlzation - my comment) and then he Incorporated in protein or nucleoprotelns aa pathologic granules. A new polymer-protein combination is formad* which may hava toxic properties. On the other hand* Fltzhugh [28] associates the toxic action of polymara vith free radicals* being the residues from initiators. These groups are able to combine vith protein. The resultent combination is toxic and can even cause tissue to undergo neoplastic proliferation. Such toxic properties of maeroicolcculnr ucc 065223 of these large bullae undergo fibrosis, and then hyalinlxation, and the exudate accumulated in their lumen undergoes deeoap sition ("aashy" nesses). In addition to the hyperplastic and oetaplastic lesions of the epithelium, in this period we also observe growth of the glands in the wall of the lobar bronchi. New solid glandular foci develop, containing high epithelium or typical glandular tubes. Then some of these tubes underwent eystold dilatation. In their luaen we detected aucus containing neutral nuc poly- / saccharides. Between the glandular tubes there were disseminated inflamma tory cells, such as lyaphocytes and histiocytes. On the basis of analysis of the aieroscopic images of the lungs of c exposed to polyvinyl chloride dust from 5 to 12. months it can he stated that xhe pathologic changes produced in this time are aore Intense than after 4 months of exposure to the dust. During exposure to the dust from 5 to 12 months, bronchiectasis develops, with proliferation and meta- *" plasia of the bronchial epithelium. These lesions, are often supplement d by an inflammatory reaction, which affects not only the dilated bronchi, but also the bronchioles, and sometimes even the pulmonary alveoli. To generalize, this period can be called the hyperplastic-inflanmatory stage. The animals in Group III were kept under observation for 8 months from cessation of exposure to the PVC dust. (The aniaals in this group had previously bean exposed to the dust for 12 months). It was found that despite cessation of exposure to the dust, the pathologic changes in the respiratory system display varied development. Some of them continue developing, but others recede. In the dilated bronchi the epithelium undergoes atrophy, but the inflammatory process already In progress around them does not recede. The thick bands of connective tissue in the bronchial wall only undargo partial hyalinlxation, and the catarrhal lesions In the epithelium lining their lumen remain even after 5 months of observation. ucc 065224 In the lumen of s me dileted bronchi there ere copious grenul cytes, sometimes exhibiting signs of deesy. The Inflanmatory pr cess often els effects the nearmst pulmonary alveoli. In the wall of the dilated 1 bar bronchi, the lymphocyte-like cells remain in the fora of a fairly vide ridge up Jo the end of observation. Only, a few glands in the wall of the lobar bronchi undergo atrophy and then connective tissue grows focally between them. Inflammatory Infiltrates mainly of histiocytes also remain in the bronchial wall and between the glandular tubes. The connective tissue around the bronchioles behaves differently. In the first months of observation this tissue grows repeatedly, leading to considerable constric tion of their lumen. It is transformed to fibrous connective tissue only by the end of the 7th month of observation. However, the inflammatory infiltrates mainly of histiocytes remain between the bands of connective tissue. Moreover, bronchioles in a state of exfoliating catarrh ara observed. After cessation of exposure to PVC dust, accumulation of a number of phagocytes with golden-brown granules in the cytoplasm was obssrved under the pleura. These granules contained neither divalent nor trlvaleht iron. Toluldlne blue stained them golden-yellow. It follows that these granules are not haemosiderin in the strict meaning of this word. They can be regarded as so-called old haemosiderin, which Is not synonymous with true haemosiderin. My opinion in this matter is confirmed by the result f e staining with toluldlne blue. By the end of 8 months of observation after cessation of exposure to the dust, fibroblasts appear between the phago cytes. The following lesions undergo regression: disappearance f the cuff-like aggregations of lymphocyte-llka cells around tho blood vassals in the interalveolar septa, regression of mucoid degeneration of the bronchi disappearance of paS-posltlve granules from the cytoplasm of the beaker cell*; i::! cylindrical cells of the lch.tr and segmental broivM, decrease ucc 065225 there i* neither formatl n of flbrouu-hy.il Inc nodules, as In .b:.orv*d la silic sis, nor formation f Riant-roll gr.*inu]on.w( undergo I it): Mhrnofn n atrophy, which are characteristic of nntlirnrosla. w oltio <11l n<n nl.rrvt> the diffusa fibrosis and hyalinlzatlon that occurs in asbostnuln. After long-term application of PVC dust there is development of atrophic hronrhU In like that observed in cement pneumoconiosis. Mention should nlno be made ' of the differing behaviour of the pathomorphologlc changes in the respira tory system upon cessation of exposure to the dust. In pneumoconiosis caused by polyvinyl chloride the connective tissue in the wall of the dilated bronchi is not cicatrised, and doas not hyaliniza around tha bron chioles. Infiltrates of .lyraphoeyte-like cells and M-.tioryt'-n man In 1 the wall of the lobar and segmental bronchi. All this Indicates a repair reaction. In pneumoconiosis caused by PVC dust, proliferation of lympho- * cytes and growth of bronchial glands is more intensive than in berylliosis It follows from all these comparisons that pneumoconiosis caused by PVC dust has s distinct morphologic picture. This is further emphasized by the fact that the pathomorphologlc changes described in the respiratory system in the course of pneumoconiosis caused by polyvinyl chloride dust devel p more slowly. According to Pushin [98], this is typical of diseases caused by maeronolecular compounds. Comparing the results of the changes caused by PVC dust in the respira tory system of rats, the opinion may he expressed that this dust causes pneumoconiosis of a toxic nature. It is also necessary to discuss the fairly large group of animals which died in the course of exposure to the dust. Four rats died in Croup I - in ell of them, in addition to pulmonary emphysema and bronchial catarrh, we found a marked degree of passive hyperaesis in tha internal organs. This might indicate circulatory insufficiency, probably existing prior to the commencement of exposure to the PVC dust. ucc 065226 '.4 Lacr*. under Che Influence of rhe mechanics id toxic action .sc led to the animals' deaths. Ten an is died In Group II. " ' apart from the signs f circuit * sufficiency we onchlectasia in a suppurative state '=* ulmonary suppuration, six rats died in the first month issatlon of the action The pathomorphologie changes In s determined during are similar to the changes described oup II. All the live survived for a further 7 months. In my opinion the `'s before the Intended time of oo on can be explained eace of lesions which were lntensix' > .er the influence of nyl chloride dust. It would have bee. .cult for at tea tlce ring lesions prior to commencement of rperiments. .owing conclusions can be drawn on <:> -is of these experiments i , .is of the pathomorphologie changes prorJ . i in the respiratory rats exposed to polyvinyl chloride dust. ). w ..rt chloride dust introduced into the esplratory system Is .c ,ically t tive, exerting mechanical and *>oxic a ction, and producing the nature of toxic pneumoconiosis yneuaoeonlotlc lesions ere based on: . /elopnent of bronchial catarrh a- chiectasla with the * earanee of postpositive bodies In the cells of their epithelium. 'like hyperplasia of component** ,v bronchial wall with :o: tlon of nodular foci similar to cyst adenomas. ucc 065227 c) multiplication f lymphocyte-like calls and hlati cytas In the bronchial vail and aggregation of these cells in tha fern of cuffs around tha blood vessels in the interalveolar septa, d) development of pulmonary emphysema and chronic inflammation around the bronehioli. 3. Development of pneumoconiosis caused by polyvinyl chloride can be '* divided into two stages: catarrhal-degenerative and hyperplastieinflanmatory. 4. The pneumoconiotlc lesions develop very slowly, are different from ether known conioses and create -favourable conditions for suppurative complications, which mainly affect bronchiectasis. 5. Some of the pathomorphologle changes in the lungs arising in the course of experimental conlosis caused by polyvinyl chloride dust do not display any marked tendency to recede after cessation of exposure to this dust. ucc 065228