Document 7R8r1KJrpbm44R1KpM6VRoM88

Lay translation which should be verified by .medical translator. .. DeutEche Medizinische Wochenschrift, ^8 (43) P 2034*2037> 1973 "On the So-called Vinylchloride Disease" By S. Jtthe, G. . Lange, G. Stein, and G. Veltman University Skin Clinic of Bonn Director: Prof. Dr. Leinbrock Since 1958, when the first information on the hazardous health aspects to workers in the vinylchloride manufacturing industries was found, and especially since 1963* when the came effects were found affecting workers in the polyvinylchloride industry (PVC), and through further reports on this subject (3 4 7, 8, 12, 28), attention has been drawn to this branch of the chemical industry. This deals with a disease similar to a skin and bone affecting scleroderma, but a disease un explainable in etiology and pathogenesis. The main symp toms of this have been the Raynaud syndrome, nodular to large area dense skin alterations and band-like osteolysis in the finger phalanges. We could report our first observations on this disease type in Germany in 1972 (15 16, 7). As the clinical picture was at first comparable to a specialized form of progressive 1 scleroderma, we submitted all employees to a painstaking BOR 009804 2 internal xamination to det rmine if visceral participation s was also present. Recently, we reported completely (18) on the results found up until the end of 1972. These reveal new aspects to be used in the judgement of this disease and, as we believe, also may give new suggestions in the research. The 13 workers examined in the April-December 1972 time period were 29 to 52 years old (average age: 39 years), and had worked at least two, and at most 18 years (average period: m * 7. years) in a PVC-manufacturing plant at alternating jobs, although mainly as autoclave cleaners. The first disease symptoms appeared one and one-half to three, and one-half years after first working there in eleven patients, and in two cases seven and eleven years after first working. % Symptoms and Findings i. . The most frequent initial symptoms of the anamnetical details are increasing sensity to coldness in the hands and feet, a feeling of deafness, and crawling parietosis. In addition, pressure pain in single fingers, a thickening of the end finger joints and weakening of the nails as well as general complaints of excessive tiredness, forgetfulness and slowing down, syncopal dizziness, nauseau during work, increased perspiration and upper abdominal pain. A major role in the diagnosis of this disease is played by the alteration of the skin: Seven patients proved to have drumstick-like (clubbed) thickened finger end phalanges (club procurements and shortening, watch-glass nails, shortening of BOR 009805 4. the nail plat ). We saw sclerodenna-like skin alterations In 8 patients: small knots or more spread out; very coars and relatively sharply defined, usually covering the surfac skin projecting Infiltrate on the outstretched hands, the distal third of the arms under the elbow, and the area of the cheeks. Three patients had no clinical skin alterations* The histology findings of the excision specimens (from the left or right hands) of all patients were relatively unij form. Besides hyperorthocytosis and epidermidosis, there was an expansion and increase of capillaries in the upper cutis. An increase, widening and homogenation of the collagen bundle and a clear rarefaction and fragmentation of the elastic fibers was evident. The same findings in the epi dermis and the fibers of the upper cutis were proven toexist in the patients without clinical skin alterations. The histology alterations in the epidermis and the collagen connective tissues are similar to the edematosis to infiltra tive stage of progressive scleroderma. Here, however, a clearly defined border is seen between that of possible but to some extent considerable injury of the elastic fibers and the vessel alterations. So far, circulation disturbances are the most common symptoms: Nine of thirteen patients complained of this, and in fact eight of them gave this complaint as their first symptom. The degree of complaint ranged from increased sensitivity to the cold, and "akrozyanose" to the Raynaud BOR 009806 1- ^ syndron (fcir pati nts). Th circulation obstruction couldbe judged objectively with the aid of temperature measure ments, determination of the time required to rewarm after exposure to the cold, capillary microscopy, and arm-hand arteriography. In no case did oscillography and plethysmo graphy result in a certain pathological prognosis. From this, one can ascertain that the origin of the circulation obstruction is in the periphery and not in immediate range . of the large blood vessels. This consideration is supported by the angiographic and capillary microscopy results. Four patients with sensitivity to the cold were proven to have ampule-like widedings of the capillaries in the nail joints -just as described in the Raynaud syndrome (14)* All seven patients who underwent arteriography showed pathological vessel images. The alterations ranged from a slight narrow ing of the Aa. digitales palmares propriae et communes with ^single segmentary localized closure^ to a high degree of 'stenosis and segmentary closures, and even to the extent of ?the loss of contents by the arteries in the entire length of the finger and clear stenosis of the entire hand joints. ^' After the examination until this point, it appeared that a direct relationship existed between the length of exposur and the amount of vessel damage. The most obvious x-ray results of this disease were the band-like osteolysis between Processul unguicularis and the phalangen on single or all fingers in six of the patients. BOR 009807 5 In' addition, fragmentation and border defects of the Pro cessus ungulculares could be found in six patients. It is also possible to determine different degress of bone alter ation: in light cases only a small lytic zone is visible, and in the advanced stage the phalange is almost fully de stroyed and the Processus ungulculares mounts onto the basis of the phalanx cap-like. A full restitution of the bone is not to be expected based upon the facts at this time (23,2if). Remarkable herein is the solid correlation Of acroosteolysis and the club-like expansion of the end phalanges. Thus, the 'drumstick fingers" are* an expression of the lytic bone process and not of an internal disease. 4n examination of the blood building system and coagu lation- draws our attention to this remarkable finding: all thirteen patients showed light to serious thrombopeny. The thrombozytic count lay repeatedly between 30,000 and Y\9t000/fxJi (under a normal limit of 150,0C0Ati). In a sternal puncture given to six patients in search for an explanation, there resulted in no case a reference to the ^obstruction of the 'thrombosytopoese", osteomyelofibrosis, or osteomyelosclerose. The other examinations showed no deviations from the norm, except for a slight reticulocis in eight patients (between 16 and 26 %), and a slight leu kopenia in five patients ,(2350 to 3950 leudocytes/i<4. ). Reticulosis and leukopenia may be caused by the splenomegaly In the twelve patients. At this time, it is not clear if BOR 009808 4 6 the thrombopeny Is also so caused, but It Is probable that i it deals with a turnover disturbance or an increase in disin tegration in the periphery. It was observed in the anamnese that three patients re- # ported recidivisic pain in the left upper abdomen and on. patient reported pain in the right upper abdomen and a feel ing of fullness, as earlier diseases of ''Leber and Milz," yet long-time intake of medicines or extreme alcoholism were not discerned. However, three patients without the scleroderalike skin condition and acroosteolysis had record histories pointing to a chronic liver ailment (Esophagus varices bleed ing, splenoral anastomosis;portal hypertonus; esophagus varices, splenomegaly.). The bromosulfaline retention was w clearly increased, but by comparison the values for serumtransaminase and-phosphates were for the most part nothing out of the ordinary. This discrepancy could also be proven in the other ten patients. Four patients had esophagus varices, and in twelve cases splenomegaly was proven scintallgraphically. The laparoscopic and liver biopsy results of five patients, which were available to us at the end of 1972, showed remarkable agreement: surface area of the liver clearly or finely waved, capsule fibrosis, increased bloodand lymph-vessels, histologicaly a slight to clear fibrosis of the portal system and indifidual cell necrosis, and slight coarse fat droplets. The result, that we could further ver ify at this tine let us express the following theory: Except V" BOR 009809 7 for th slightly toxic alterations of the liver cells, Jhis results from the expansion of the connective tissues In the portal system into the diffuse circulation in the liver. In advanced stages this leads to an interhepatic block (most like ly because of the hinderances in the height of the portal system, possibly similar to a sinusoidal block), with esophagus varices. It remains to be found if the splenomegaly is only is a secondary condition or if this primarily the direct result . of toxic changes. Of nine patients examined in the lung functions (anamn se, x-rays, .spirometry, entire body plethysmography, and blood gas analysis) after references pointed to mainly restrictiv alterations, eight of these patients showed partial insufficieicles. Further research must be undertaken to determine if these disturbances can be traced back to the fact that similar changes occur in the lungs as in the collagen and elastic supporting tissues of the skin, that is, that a beginning diffuse lung fibrosis is the cause of these dis turbances. The initiating Factor This paper is concerned with an industry-caused disease, in which the symptoms include (arranged in order of most common occurrence) thrombopeny, splenomegaly, toxic liver damage, ventilation blockage, circulation obstruction, and skin and 4bone alteration. This' complex of symptoms has not yet been bor 009810 b en assigned to a known syndrome. It is unexplained etioi-. ogically and pathogenically. Is it possible to obtain a certain insight in the etiology and pathogenesis by a comparison of our results with those previously recorded in literature? What is then possible to be the initiating factor? At a simultaneous pressure and temperature increase, liquid vinylchloride is polymerized to polyvinylchloride with ^ the addition of water and various additives, depending upon the different properties desired. In different countries, independent of the additive type, the Raynaud syndrome and acroosteolysis was present in workers cleaning autoclaves. The symptoms appear so characteristic that it lead in the past year to the disease designation of "occupationallycondltioned acroosteolysis" and was advanced to a diagnosis position (28), It is not assumed that the additives, differ ing by type, country of production and methods, play an import ant role, but the harmful combination of these with the vinylchloride can not be completely excluded. Therefore vinylchloride, the substance present in the largest amount, be comes the main point of our interests. The monomer vinylchloride is pumped over a closed system of an autoclave. The exit possibilities of the gas - and thus the Inhalation possibilities - consist then in more places within the pro duction process: 1* Permeability of the autoclaves (intake and offtake) // BOR 009811 9 jarring polymerisation and recovery processes* Zm In the discharging and opening of the autoclaves as well as In the drying process of the finished polyvinylchloride. The residual gas consists of up to 90% vinylchloride (6) and often leads to leaden tiredness and short-lasting disorientation in the employees. 3. From the polymer precipitation on the walls of the kettles. Therefore, from the technical viewpoint, it is completely possible that vinylchloride initiates the hereby described disease. Some facts are already known about the effect of vinyl chloride on human and animal organisms. The narcotic effects have long been recognized (22). Since 1958, reports have re peatedly been made concerning the angioneurotic obstructions < and the Raynaud syndrome in workers (1,10,21). In the literature one finds single references to the intoxication of vinylchloride, wherein a reversible dizziness, light to very noticeable giddiness, disorientation, skin appearing as t, .. a 2-degree burn, and lessened blood coagulation have been determined symptoms (6, 9 11)* One worker died as a re sult of poisoning. With the use of experiments Involving animals, lung odem, blood congestion in the lung% liver, and kidneys, as well as decreasing blood coagulation could be proven (20). In long term experiments it was possible to produce centrolobular degeneration in the liver and necrosis with foamy vacuolization as well as periportal cellular infiltration (26). BOR 009812 10 Recently, r ports w r mad concerning skin, lung, and bone tumors and obstructions in the bone structure (27)- Thes results, based on Animal experiments, lead again in 1970 to a depression of the MAK (maximum occupation concentration) to 100 ppm (13)- It is not yet known to us the regulations concerning gas concentrations at the occupational site. The symptoms related in the framework of this disease (Raynaud syndrome, toxic liver changes, obstruction in the . * bone compositions and prenarcotic syndrome) may then be pro duced by vinylchloride- Thus, in the knowledge of the occu pational site we can express the conjecture 'that long term exposure to vinylchloride is at least a, if not even the disease-initiating factor. The fact that the name "occupationally-caused acroosteolysis" hints only at a not % necessarily determining symptom shows that a new name should be coined. V/e have proposed the designation "so-called Vinylchloride disease" for this syndrome because this disease, influenced by the participation of numerous organs, obtains the character of a system disease. Pathogenesis The pathogenesis is, as before, unexplained- On the basis of our research we discussed the theory that the disease as a pathogenetic principle in the furthest sense is caused by an obstruction on the connective tissue or the vessel connective tissue. In addition, as our theory shows that the toxic agent is effective not only per inhalationem, but BOR 009813 f - 11 #> also perkutan, exhibit scleroc t exists that only uncovered main arteries :e coatings and that th band-like os- teolysis is on: on the finger phalanges. We saw sclerO- derma-like ski: zions as well as acroosteolytosis only In vorkers whc ced a long period with the cleaning of autoclaves. T perhaps be explained by the fact that 600-1000 ppm c nloride could be measured in the area of the autoclaobstruction or (5). As an indication based upon the * -nective tissues, we saw the quailtativ and quantitati ations of the skin and the multipli- catlwn of coll' ibers in the portal system of the liv r. The increase a: .sion of the capillaries was visible by capillary micr:.. ^nd histology in the upper cutis, in addition to tkr . _eral circulation obstruction proved clinically, an: --.ically, and thermographically. Even the alteration . bone (osteolysis as a result of trophic obstruction by - to the vasa nutricia) and the lung (restrictive et rictive ventilation blockage) can be synonomously er; ;i. The prognosis of the disease - judged quite o_"__ - really by earlier literature-appears quite serious t- Especially with, respect to thrombop ny, "splenomegaly, s~- ~.=1 hypertension. According to our observations o; .zions in the bone, this disease should be fudged with . Consequences frr ~ zrsctice The triassi r. :'c:z.stion of this disease system, serious BOR 009814 12 * prognosis and r latively high m rtality (from our invests nation i certainly more than 10$) has led prevailingly youn men to sol icit us to place the following suggestions: 1* Execution of epidemologic and preventative medical experi mental tests* In our opinion, it is not sufficient any more to search for only Raynaud syndromes and knotty skin alter ations because these symptoms , as characteristic as they are, already show the advanced stage of disease* Perhaps more ^ important, controls to determine the thrombozytic count in regular time periods should be given to all employees of PVCproducing industries* This should take workers with a con stant throabopeny out of this branch of the industry, as this appears to be the first objective symptom, before further and more serious internal damage occurs. 2. No employment given to those with liver diseases or circu latory problems* 3* Regular gas concentration measurements in different work sites to avoid exceeding the MAE limit* Experienced tech nical improvement with the goal of greatest possible automation, andimprovement of the ventilation conditions to reduce the possibilities of gas inhalation to the lowest amount possibl * 4* Compensation to diseased workers and recognition of this disease as liable to indemnity by inclusion in the list of BKVO. 5* More research, especially with animals, using vinylchloride with special consideration to the skin, bones, lungs, liver, and spleen* BOR 009815 V --4 13 BIBLIOGRAPHY: \ Littretue^ (1) An*h(!<wi( f-( M. Oimu, f- tWKf*- nes.ii, L, Hig-p:fi"-th:-D<****ot, 0. DoHnn^wll. V, Gar c a ConaidcrJIH cliniempstniame* j'Uftfj l.noniiou ui Raynaud (a ffl4nci(t>rii dan inJuiiru policlotum de McJ. interna IBuc.) 11 (1949), -*71. (2) btibn, A, V.. A. N. Vatin, A. C. fcncbetko*: On ihe pithugcresis of dianges developing due to t long term txpot-jn lu th* crieit o( nr.yldilotidc. C.fr Tr. prof. Zabol. 14 (ITH). 14. (I) Chstelain, A., P. Monllon: Un syndrome d'icro-o*<eol)ie d'uriginc pmfeuionallc at dc conuunn nouvellc (1X7). m.cn Franc*. J. Radiol. Elcvxrul. 41 (4) CordKr. J. M,, C. Fievet. M. J. Itftrn, A. Savrm: Ac.-uosicnlyac et Ifaion* curaneea sstocicr* dies deax ouvricts aSecret ju nenoyape dautoalaegs, Cab. Med. Travail 4 (1944), 1. (J) Cask. W. A., P. M. Cwvrr, ft. D. Dinman, H. J. Magnuson: Occupational nctooatcolytii. 11. An industrial hygiene study. Ant. environm. Hlth 21 (1971), 74. (0 Daoiiger, H.: Accidental poisoning bp vinyl chloride. Canad, mtd. Aaauc. J. 12 (1940). 111. . (7) Dinman, b. D., W. A. Conk, W. M. Whitchousr, H. I. Magausons Occupational scmostcol>tfi. 1. An epidemiological study. Atth. environm. Hitt 12 (1971), (1. (t) Dodson, V. N,, B. D. Dinman, V. M. Vhitebouse, A. N, M. Nasr, H. J. Magnuson: Occupational actw tuolysis. til. A clinical itudy. Arch, minwi. Hi* 22 (1971), 12. (9) Dublin. L. 1. J. Vane; Occupa tional haaatdt and diagnostic science. Boflatus No. 3C (IS.'Jl, Bulletin No. 41 (1941), U.S.A. Dope. Labor, aiticrt ini Daaaiiar (4). Mutation. Fonjiungsliend'.te dea Lan des NorJrtiein.'AeMfalen. Nr, 1909 (WcstdcuttJscs Vcrlag; Koln 1X4). (la) Jiihe, S,, C. Veitman. Zu.* Kitnlk dcr mg. Vinyliltlond-kranahcit 1. Inter nationales S> mp->tium dcr 1 crWiintie der diemndita Intlustna, 27. a. 1972. (14) J'ihc 1., C.-E. Lange: SVamltnnie snipe Hauiverandesungen, RaynaudSyndrom und Akroot'colvsen bet Ar* bettem det PVC-betsttlienden Industrie. DisJi. mtd. Wsdir. 97 (\T7Z., 1922. (177 Jiibe S.. C.-E, Lange, C. Stain, G. Veltman: Zur Klimlt dcr sog. Vinyl* dilorid-tirankhtit, JahmisgongDoumtc Ctsclischaft iiir Arbeuimrdsua, 24. 10. 1972. (II) Lange, C.-E., S. Jiihe, C. Stein. C. Veltman: Di* sog. VmyltiondKra.aklieic - cine berufibethr r* Systeom sklert,*? Int. Arch. Arbeicuml., ist Druck. (19) Lange, C.-E., S. Jiiho. H. J. Mar. ttejlet, R. Mailer. C. Veitrear.: Leberadtiden im Rahman dar tog. VinyL dilond-Knnkheit. Jahrcstapang Deut sche Cescllachaft lit Arbeitsacdiaia II. J. 197J. (20) Masrromaneo, E., A. M. Fisher, H. Christie. H. Dsniiger. Acum inha lation toxicity o< vinyl chlor.i* to laboratory animals. Amar. iMwr, Hy(. As. J. 21 (1940) 394; titieft int Malten, K. E-. R. L. Zielbuis (ad.): Industrial Toxiculofy and Dermatology in the Production and Processing o( Flasrio (Eiaavier: Amatcadaot 1X4). (21) O'Conner, R. B.: A M ocoipatkvnal disease it bom. J. occup. Mod. 12 (1970), 234. (22) Peoples, A. S., C. D. Leafcot The anesthetic action of vinly d^loride. J. PharmacoL amp. Thar, at (1923). 2M. (23! Stain, G., S. Juha, C.-E. Lange. C. Vclthian; Bandformige Oncolysca in dan Endphalangan da* Handskelters. Fottsthr. Rbotgcnatr. HI (19731,40. (10) Filanst, V. S.. 1_ J. Balakhonova, E. S. Cionabcrg: Hygienic conditions in * the ptodacnoo ul vinyl chloride. Cig. Tr. prod, Zabol 1 (1931), 4; linen in PuMk Healtk Enpo. Abate. 40 (1940) No. 4, p. 4. (It) Hants, D. K.t Health problems in manufacture and us* si plastic*. Brit. J. induitr; Med. 10 (191)1. 235; airim In- Msl.es. K. E.. R. L. Ziclbuia (adds Induainal TonnoU-gy and Desmemingy to tb* Production and Processing of ?Isaacs (Elsevier: Amsterdam 1944). ML (IS Harris. D. r,, W. C. F. Adams: Acm-osnnlrtit occurring in men engaged In the polymer.iaiiun of vinyl dtlonde. Brit. med. J. 1X7/J. 111. (13) HenscbUr, H. (Hng): Cesundbescaathldlwjtt Arbeusstnre. Tu Iikokj. (isdmariKinotaditinifdie Begtvndung von MAK-Wenc* (Vcriag Chemtt: Wcutbeis 1972). - (14) Jacoby, H.: Xripbasv DgrtbklwNiplrisklnm i.ti Spiegel dcr Miitro- (241 Stein, G* S. J'aha, C.-E. Lang*, C. Veltman: Steletrverlndcrangen M dcr tog. VmylthloriJ-Kjantaeit. Rontgcnpragii, im Drodt. (23) Suciu, L. J. Drejmaa, M. Vilaakai: Contributii la >nid:ul imriolnavmlor produsa da cksnsr* de viml. MX. innnu (Buc.) 13 (1943i, 947, (24! Terkelion, T. R,, F. Oym, V. K. Rowe.' The ruaicity til vinyl chloride as determined by repealed cspottirr t Isbnritoty animals. Amar. asduatr. Hyg. Asa. J. 12 (1941). 339; ameer m: Malten, K. E.. R. L. Zielhuis (cd.lt Industrial Tuxicologv and Dermatology in ihr Ptuducnoa and Priiucssing el Plastic* (Elsevier: Amsterdam IX4|. (27y Viola, P. L, A. Bigocti. A. Caputni Oncogenic rcapunso of rat skio, lungs, and bones to vinyl chloride. Cancer Rrs. 31 11971), J|4. (21) Vtlaon, R. H.. XV. t. McComrii. C F. Tatum, J. L. Crtedt: Occupational acrooaraolysia. J. Amor. med. Am. 201 (1947), 377. Dr. Susarme Jiihe, Dr. C.-E. Lange, Dr. C. Srcin, Prof. Dr. C. Viliman Univertinrs-Hamklinik 53 Bonn 1, Vmusbcrg r. f *f *. #* * o^n **'t>t *4 BOR 009816