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V R&S 025493 73-12-27 Translated by Janet Engiund Deutsche Medisir.ischc V/ochenschrif 1973 8 (43), P. 203/4-20j ( "On the So-called Vinylchloride DiEcn.cc" By S. JUhe, G. E. Lanya, G. Stein, and G. Veltcan University Skin Clinic of Bonn Director: Prof. Dr. Lcinbrock Since 1958, when the first information on the hazardous health aspects to workers in the vinylchloride- manufacturing industries was found, and especially since 1?c3j when the same 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 tc this branch of the chemical industry. Tins dears witr. a aiscase 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 Paynaud syndrome, nodular to large area dense skin altomelons and band-like osteolysis in the finger phalanges. We could resort our first observations on this disease type in Germany in 1572 (' 5, 16, 1?). As the clinical pic cure v.vtr, '1s L first c: 0:: ramble' 1 a spec Lai J sod form of progressive sc'l orod 0rm a wo i` 4 ^ r\, - , * \ rv rS ai: cm': eye os to a minstakin/; 2 Internal examination to dotermino if vir.ccral participation waG also present. Recently, we reported completely 08) on the rccultG found up until the end of 1972. TheGC reveal new aspects to be used in the judgement of this disease and, as we believe, alco may /live now suggestions in the research. The Ip workers examined in the April-Decomber 1972 time period were 29 to 52 years old (average age: 59 years), and had worked at least two, and at most 18 years (average period: 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 The most frequent initial symptoms of the ar.amnetical 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 slewing down, syncopal dizziness, nausoau 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: hover. patients proved to have drumslick-11ke (c .1 ubbcu) thickened i'i: pger end phalanges (club procurements and si) or t e n i jig, wetck-gl' ms nni];;, shortening of R&s 025495 3 the nail plate). Wo saw scleroderma-.!ike shin alterations in 8 patients: email knots or more spread out; very coarco and relatively ehai'ply defined, usually covering the surface skin projecting infiltrate on the outstretched hands, tho distal third of the arms under tho 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 wore relatively unir form. Besides hypororthocytosis and epidernidosis, there waG an expansion and increase of capillaries in the upper cutis. An increase, widening and homegenation of the collage:*, bundle and a clear rarefaction and fragmentation of the elastic fibers was evident. The same findings in the epi dermic and the fibers of the upper cutis were proven to exist in the patients without clinical skin alterations. The histology alterations in the epidermic and the collagen connective tissues are similar to the edomatosis to infiltra tive stage of progressive scleroderma. Here, however, a clearly defined border is scon 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: Nino of thirteen patients complained of this, and in fact eight of them gave this complaint as their first symptom. Tho degree of complaint ranged from increased sensitivity to the cold and "nkronyanoso" to tue h'aynaud syndrome (four patients). The circulation obstruction could be judged objectively with the aid of temperature measure ments, determination of the time required to rowarm after exposure to the cold, capillary microscopy, and arm-hand arteriography. In no cane did occillography 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 widenings of the capillaries in the nail joints just as described in the Raynaud syndrome (Uf)* 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 closures, 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 exposure and the amount of vessel damage. The most obvious x-ray results of this disease were the band-like osteolysis between Proconsul unguicularic and the phalanges on single or all fingers in six of the patients. If? R&S 025496 f 5 In addition, fragmentation and border defects of the Pro cessus unguicularcs could be found in six patientc. ,It in alco possible to determine different degrees of bone alter ation: in light canes only a small lytic zone is visible, and in the advanced stage the phalange in almost fully de stroyed and the Processus unguicularcs 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 (23i24). Remarkable herein is the solid correlation Of acrooctcolysis 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. An 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 11 9,CCO/pcJ2_ (under a normal limit of 150,000^-0.. 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'thrombocytopocse", osteomyelofibrosis, or ostoomyclcsclerose. The other examinations showed no deviations from the norm, except for a slight reticulocis in eight patienms (between 16 and 26 %), and a slight leu kopenia in five patients (2350 to 3950 leudocy tcsO JL ). Reticulosis and leukopenia may be caused by the splenomegaly in the twelve patients. At this time, iu is not clear if R&S 025497 1! 6 the thrombopcny is alco cc caused, but it is probable that It dcalc with a turnover disturbance or an increaGC in disin tegration in the periphery. It was observed in the ananmese that three patients re ported recidivisic pain in the left upper abdomen and one 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 no^ discerned. However, three patients without the sclcrodcralike 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 clearly increased, but by comparison die values for serumtransaminase and-phosphates wore 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 inciifidual ceil necrosis, and slight coarse fat droplets. The result, that we could further ver ify at this time let us express the following theory: Ex cent R&S 025498 Us' ? ? for the slightly toxic alterations of the liver cello, this rcculto 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 intcrhepatic block (most like ly because of the hinderanecs in the heicht 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 tho lung functions (anamnese, x-rays, spirometry, entire body plethysmography, and blood gas analysis) after references pointed to mainly restrictive alterations, eight of these patients showed partial insuffi ciencies. 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) thrembopony, splenomegaly, toxic liver damage, ventilation blockage, circulation obstruction, and skin and bone alteration. This complex of symptoms hue not yet boon been assigned to a known syndrome. It is unexplained etiol- r Ig it possible to obtain a certain insight in the etiology and pathogenesis by a comparison of our results with thoce previously recorded in literature? What 'in then poccible to be the initiating factor? At a simultaneous pressure and temperature increase, liquid vinylchloride ic polymerized to polyvinylchloride with the addition of water and various additives, depending upon the different properties desired. In different countries, independent of the additive typo, 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 "occupationallyconditioned acrocstcolysis" and was advanced to a diagnosis position (26). 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) *> CO 0 0M1 ocn o R&S 025501 9 during polymerization and recovery processes. 2. In the discharging and opening of the autoclaves as well as in the drying process of the finished polyvinylchloride. Tho residual gas consists of up to 90% vinylcnloridc (6) and often leads to leaden tiredness and short-lasting dicorientation in the employees. 3* From tho polymer precipitation on the walls of tho kettles. Therefore, from the technical viewpoint, it is completely possible that vinylchloridc initiates the hereby described disease. Some facts are already known about the effect of vinylchloride on human and animal organisms. The narcotic effects have lone been recognized (22). Since 1953, 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 vinylchloridc, wherein a reversible dizziness, light to very noticeable giddiness, disorientation, skin appearing as a 2-degree burn, and lessened blood coagulation have been determined symptoms (6, 9, 1l). One worker died as a re sult of poisoning. With tho use of experiments involving animals, lung odem, blood congestion in tho 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 tlie liver and necrosis with foamy vacuolization as well as periportal cellular infiltration (26). 10 Recently, reports were made concerning skin, lung, and bono tumors and obstrucLi ons in the bone structure (27). These results, based on animal experiments, lead again in 1970 to a depression of the MAK (maximum occupation concentration) to 100 ppm (1j>). It is not yet knov/n to us the regulations concerning gas concentrations at the occupational cite. The symptoms related in the framework of this disease (Raynaud syndrome, toxic liver changes, obstruction in the . bone compositions am! pronarcotic syndrome) may then be pro duced by vinylchlori.de. 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 "occu pationally-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 vinylchloriuc disease" for this syndrome because this disease, influenced by the participation of numerous organs, obtains the character of a system disease. Pathorencsis The pathogenesis is, as before, unexplained. On the bacis of our research we discussed the theory that the disease as a pathogenetic principle in the furthest sense is caused by an obstruction or. ike connective tissue or the vessel connective; tissue. in addition, as our theory shows that the toxic agent is effective not onily per inhala lionem., but 3J do in 11 a] go pcrkutan, the fact exists that only uncovered ma.cn artciac... exhibit c c 1 c r ode rmn--1 i.kc coatings and tnat the sand--line os teolysis in only found on the finder phalanges. We caw ccloiOdcrca-likc skin alterations an well an acroosteolytoci^ only in workers who had 'worked a lone period with the cleaning oi autoclaves. This can perhaps be explained by tn<~ iact that 600-1000 ppm of vinylchloride could be measured in the area of tho autoclave walls (5). As an indication based upon the obstruction of the connective tissues, we saw the qualitative and quantitative alterations of the skin and the multipli cation of collagenic fibers in the portal system of the liver. The increase and expansion of the capillaries was visible by capillary microscopy and histology in the upper cutis, in addition to the peripheral circulation obstruction proved clinically, angiographically, and thcrmographically. Even the alteration of the bone (osteolysis as a result of trophic obstruction by damage to the vasa nutricia) and the lunc (restrictive .and obstrictive ventilation olockagc) can be synonomoucly explained. The prognosis of the disease judged quite optimistically by earlier literature-appears quite serious to us, especially with respect to thrombopeny, 'splenomegaly, and portal hypertension. According to our observations of alterations in the bone, this disease should be judged with reserve. C o:m r,n'1 it f' nfov i i ' P.'V c i.ee The triassic forma lion of disease system, Gcraou s R&S 025503 t i ! t*. 1 * 12 prognosis end relatively high mortality (from our investiga tier, certainly more than \0",l) has led prevailingly your, men to colicit UG to place the following suggestions: 1 . Execution of epidcmologic and preventative medical experi mental tests. In our opinion, it in not sufficient any more to ccarch for only Raynaud syndromes and knotty skin alter ations: because thcco symptoms , as characteristic as they are, already chow the advanced stage of disease. Perhaps more important, controls to determine the thrombozytic count in regular tine periods should bo given to all employees of PVCproducing industries, 'fills should toko workers with a con stant thronbopeny out of this branch of the industry, as this appears to bo the first objective symptom, before further and more serious internal damage occurs. 2. No employment given to those v/ith liver diseases or circu latory problems. 3. Regular gas concentration measurements in different work sites to avoid exceeding the KAK limit. Experienced tech nical improvement with the goal of greatest possible automation, andimprovemont of the ventilation conditions to reduce the possibilities of gas inhalation to the lowest amount possible. h. Compensation to diseased workers and recognition of this disease as liable to indemnity by, inclusion in the list of BKVO. 3. 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Med inrcru S-'** ) IS Vtt*. L\V Ttoiclv n, T h * F. (>rrn, V K. hi* tf 1 .'<c t 011,7 t*l i"*i s>'ofi.le at ,! " 1 1 * ' r 1 11 y t - pc j * fy1. e 'V- re (*> .<> i' , > J. A 're f I;t, h,)' A 1 * 7,' j *, ;;t*en m M1 '1 ?m, h l . h ! , / c'' mm , I I I'.L.-omo IiOi,L;li'eT inj ` Xe mji ulj %y ..Lotion jiol n*; tjf : iCs cr A in\i<r04;:i l`***4', P 1' V ... Jl rum, V C'oso i'l 1*1 >V,n, I'X1. I v` v'v/r-n,! Or. Mi : * M: ( J'ffif !': M \ ' :.t I'o.f*. . 1'. S 1 1, \ f