Document DDpk0rQoQ70zbzjxQ4vBEKjVa

A ' t. n ii - O') !b d/Ur<iTicc; Translated "by Janet Englund . ($/ (i fV Internationales Archiv fiir Arbeitsmedisin, Vol* 32, PP. 1-32, (1974). ''The So-called Vinyl Chloride Disease - An Occu pational Systematic Sclerosis?"* By C.-3. Lange, S. Jtthe, G. Stein, and G. Veltman, Univ 30 fi (/> _L w -J. a<ot "4 ersity Skin Clinic, Bonn. (Director, Prof. Dr. A, LeinSubmitted: April 30,1973; Accepted: May 3, 1973* trock) This study was awarded the Franz Koelsch Prize for 1973. Key words: Occupational disease; polyvinyl chloride pro duction; vinyl chloride; scleroderma-like skin changes; Eaynaudfs syndrome; Vascular changes; Acroosteolyses; Thrombocytopenia; Splenomegaly; Esophageal varices; Liver fibrosis; Pulmonary ventilation disturbances* Summary: included in original copy (in English).. " VINYL CHLORIDE DISEASE" I, Introduction In the past year, we could observe- for the first time a disease in Germany which occurred in autoclave workers in the polyvinyl chloride (PVC) manufacturing industry. We have designated this disease system as the "so-called vinyl chloride disease." This disease has become known as "occupational acroosteolyses syndrome" and "occupational acroosteolyses" from foreign publications. R&S 131698 Z In 1963* the frequent appearance of the following symp toms in PVC-employees was described: narcotic syndrome, neurasthenical complaints, hepatomegaly, Raynaud's syn drome, dermatitisj and scleroderma-like skin changes as well as transformed functions of the thyroid gland (33). Before that, in 1958, the appearance of "chronical angioneurosis" had been determined in employees of a PVC-manufacturing plant (12). In 1966 in Belgium, two workers were observed to have Raynaud's syndrome, neurasthenia, scleroderma-like skin * changes and in addition, band-like osteolyses of the fin- j gertip phalanges was observed for the first time. A year later, two such cases became known in England (16). Likewise, in 1967 a report entitled "Acroosteolyses Syndrome of an Occupational Origin" was published in France of similar clinical and x-ray alterations found in five autoclave employees (3). Three thousand employees in the PVC-manufacturing industry were examined in 1967 in North America (36). In this examination, 31 employees were found with acroosteolyses, with and without Raynaud's syndrome. In addition, drumstick-like thickened' finger tip phalanges ana knotty skin alterations were present in eight employees. These symptoms became known as "occupational acroost olyses." This designation was kept in later occupational Anglo-American research. In the results of later epidem- ologic examinations, the terms Raynaud's syndrome and R&S 131699 acroosteolyses were promoted for the diagnosis "occupation al acroosteolyses" (9). The main symptoms - Raynaud's syndrome, skin indura tions, and bone lesions, even if only seldom occurring in the form of band-like osteolyses, are also found in pro gressive scleroderma* At this point, a search for further organ manifestations of the "so-called vinyl chloride dis ease." was considered opportune. Therefore, we have given careful internal examinations to all patients. The follow ing organ systems were considered: skin, circulatory sys tem, bone system, blodd building system* liver, spleen, lung, nervous system, digestive tract. Furthermore, the examinations were carried out to the final determination of an autoagressive disease. XI. Our Examinations Since Feb., 1972, we have examined ten patients, ages ranging from 29 to i+6 years. All were employed as auto clave employees in a PVC-manufacturing plant. Their jobs included, in addition to cleaning the autoclaves, also working at times on the separator, the dryer and the screening installations and in packaging the finished dry PVC. The employment period was between 1 3/k and 12 years (average: 5years). The first disease alterations occurred in 7 patients in one and one-half to two years, 4I and in thr e patients, two to three and one-half years after initial employment. The average latent period was about two years. Seven patients listed increased cold sensation in V ^ the area of the fingers or hand as the first disease symp tom, and this was coupled with deafness and "Kribbel1 par esthesia. In one case, the first symptom appeared as an increased painful pressure of the finger tips and par esthesia, in a second loosening of the nails, and in a third, the first symptoms were a club-like expansion of the individual finger joints. In addition, the follow ing generalized complaints were ascertained: 7 patients complained about increased perspiration, 5 about frequent dizziness, 3 about occasional nausea at work, 3 about re duction of vision, 3 about poor hearing, and 2 about headaches. 1. Skin Clinically, we determined a participation of the skin in the symptoms of 8 patients. We observed knotty infil trate . a shortening and drum-like expansion of the fingertin phalanges, and a transformation of the nails to "watch glass" nails. This is in addition to the almost regular, partly constantly present, partly recurring, and mostly cyanotic swelling of the finger or the entire hand, which lead to a feeling of tension and in some cases to a clear loss of motion. Likewise, as a result of outer circulation disturbances in the skin, an increased sensitivity to the . 5. k cold occurred in the hands and usually in the feet of 7 patients. In k of these patients, repeated Eaynaud phenomena could even be provoked by cold exposure experi- . ments. Drumstick-like club expansion of the finger-tip pha langes of one or almost all fingers were visible by sight in 7 patients. This correlates well with the x-ray alter ations, presented later in this article, mainly ozTthe right hand. The nails of the affected fingers were "watch-glass" shaped, with the exception of one patient, in which case a koilonychia had formed. In contrast to "true" drumstick fingers, we found not only an expansion * but. also a distinct shortening of the end phalanges and the fingernails (Fig. 1). This is certainly connected with the delayed fingernail growth reported by 3 patients. The presence of scleroderma-like skin changes was very characteristic in 8 cases. These changes were rela tively sharply defined but very rough, white to ivory in color, and usually an infiltrate projecting somewhat above the surface skin. Size and shape varied from the size of grain to small knots, or even more flatly shaped. These type of indurations were observed mainly on the finger joints and in direct proximity to the Proc. styloideus, .on the ulna side of the hand and the distal third of the under elbow (Fig. 2), with a distinct lessening X) CO GO -sl R&S 131702 . Big, 1, Scleroderma-like knotty skin infiltrate on the outstretched fingers and into the hand joints* Drum stick like club expansion and distinct shortening of the end phalanges* Also, watchglass curvature of the nail plates. Big. 2. Projecting infiltrate on the distal third of the bent side of the right underarm: sheetlike, coarse and relatively sharply defined, yellowish, and pro jecting somewhat above the surface skin. 7i towards the proximal side. Less often observ d were mor phologically similar changes on the sides of the outstretched fingers, distal of the olecranon, and in the face (cheek and cheekbone region). A noteable fact is that the first symptom reported by 6 patients concerned fingers 1-3 on the right hand, only in three of the patients did the first complaints arise from the second or respectively second and third fingers of the left hand. A breakdown of the respective skin changes of the individual patients is found in Table I. R&S 131703 Table I. Summarized Representation of skin * changes in 10 patients with so-called Vinyl Chloride Disease. Nr. l*ntk*nt Kiiitr(tnipfimliirlikrit (mil ItiivimmlSyndrom = It) ,,Trommel- UhrplnuniiRcl lliigw" Sklrroclermiekhniirlio Hniit- vcriiiidcningrn 1 N. <:. 1 O.K. 3 D.X. 4 - J.K. A II. II. 0 A. W. 7 II. A. 8 M.C. 0 R. \V. 10 K. II. 1 -1- + <K) + <R) -- -- + (H) + + (R) -- 4 4* + + Koilnnyrliici -1------ -- ---- + -4- + 4- + + 4- + 4* 4- + ----+ +++ Summp 7 768 Cold "Drum "Watch- Scleroderma-like Sensitiv stick glass skin changes ity fingers' nails" (With Ray naud Syn drome = R) 8i Sample excisions were made in the left or right hands .of all patients. In all cases - even those, in which patients exhibited clinically "only" Raynaud syndrome with out actual proven infiltration - similar changes, for the most part, were shown. The histological changes and their values are shown in Table 2. It was also determined that the changes in the skin, as an organ system, undoubtedly played an important role in the framework of the ''so-called Vinyl Chloride Disease." Eight of the examined patients proved to have distinct clinically visible and protruding rough, sclerodermalike infiltrate. All ten patients exhibited different characteristics, but for the most part had similar his tological changes. The clinical image, with Raynaud syndrome, pale, very rough and usually plate-like infiltration of the skin and the histological results included in that (as previously described) are suggestive of the edematous to infiltra tive stage of progressive scleroderma. Also, we found in both disease images a shrinkage of the epidermis with the passing away of the "reteleisten" and simultaneous hyperorthocytosis ("hyperorthokeratose"), an often con siderable widening of the cutis by means of an increase of mainly nucleus poor and swollen and/or homogenous collagen bundles by means of a ''walling up" of the skin connecting tissue (25), respectively , the raising of R&S 131704 9 Table I* Histological changes in the skin of 10 patients with so-called vinyl chloride disease. I o 43 0 JU CO >> H O -H 43 Nr. Patient E Jh CO ft *4 O O 0} ft-P U a >> >-P WPHiPi3i 0<43i3i I S.G. ft b 2 o.s. .1 D.Z. 4 J.F. a K.D. 6 A.W. 7 H.A. K 1LC- 8.W. in K. H. --b ft b ft b 'ft b ft b ab -- ft C rt M t0 <3 *r-f Q IQ 3 ri tl 0) H <3 fcO OhOC too O O H C O *H 44 * W PS 44 a i-- ii ii o^ $ 43 ft b ft b --1 -- * ft b ft b ft -- ft b ft -- ft b i os h ra (3 44 44 u w c (0 <3 (0 (3 (0 43 <3 E (H -H P MC ta <o *h o a o H a? *H 44 Q fa 44 a ro O'--' n it (1$ 43 ft b --b --b ft b ft b ft b ft b ft b ---- ft b /> (0 iH to <0 ' 0) (Q> H 44 * C iA O'-' - c o O 4r4t C ;H <0 Tf to c H O E-i O im subepid. Gren<tBtreifen Cap. mit Endothclschwellg. Odem im mittl. Cor., perivasculare Infiltrate normal oklerotiach normal kollag. Bindegew. sehr dicht gepackt im oh. Corium vereinzelt normal enreiterte Capillaren GefHSwande im tnittleren starkcs Coriumodem u. oberen Cor. geschwollen normal Coriumodem, lockcres, voriricgend lymphoc. Ir.filUa: normal spdrl. lymphocytiites Infiltrat mitt!, u. tiefercs Corium miiBiges Odcin, lockeree deutl. Wandrerdickung lymphocyt. Infiltrat teila Wandrerdickung nonnal obarcH Corium: Capill. rermehrt u. erweitert tiefercs Corium eklerotisch Nr. Cutis (3. Vessels) Tissue Condition 1. Endothel swelling in sub- Edema in middle corium, epid. borderline capillaries perivascular infiltration .2 normal sclerotic 3. normal collag. tissues closely packed 4. single widened capillaries normal in upper corium 5. vessel walls swollen in . middle and upper corium 6 normal 7. normal strong corium edema coriumedema, loose, mainly lymphatic fluid scanty lymphatic fluid 3J SB CO -_L W ^4 >1 CoJ1 R& s 131706 10 Nr, Cutis (3. Vessels) 8. distinct wall thickening in middle and deep corium 9* walls partially thickened 10. upper corium: capillaries increased in number and enlarged in size Tissue `Condition moderate edema, loose lymphatic fluid normal sclerotic lower corium Fig. 3. Hyperorthocytosis and initial decrease of epi dermis. In the upper corium, enlarged and increased (in number) capillaries with endothelium swelling and moder ately loose mainly lymphatic infiltrate. In the middle corium edema, slight swelling and initial homogenization of the collagen fibers (H.E. Color). R&S 131707 11 * sweat glands (24). Likewise,`we observed a mainly moder ate intercellular edema and. a loose, mainly lymphatic infiltrate between the collagen bundles and around the blood vessels. In the subepidermal border, numerous widened capillaries with endothelium swelling were ob- served, and the vessels of the middle and deep corium occasionally showed a distinct wall thickening. In spite of the numerous items in common, there appears to be an important difference to progressive scleroderma with regard to the changes of the elastic fibers. Although in progressive scleroderma splitting and fragmentation of the elastic fibers occurs, these remain, for the most part (and also in view of the num ber), relatively protected . Indeed, often one has ob tained the impression of an increase of .elastic fibers as a result of the increase in skin atrophy. In addition to fragmentation, an indicative to considerable rarefication of the elastic fibers is most noticeable of the histological results in the so-called vinyl-chloride dis ease (Fig. 3-5), 2. Circulatory System Seven of the patients complained of an increased sensitivity to the cold in the hands. This was also re ported as the first disease symptom. Four of these patients-reported recurring whitening of single or all fingers in connection with strong pain and deafness in 12 I Fig, h. Characteristic swelling and homogenization of the nucleus-poor and widened collagen bundles, separated by a thinned eden&in the lower cerium. Fjg. 5. The elastic fibers show an increase of distinct to complete rarefaction, a splitting and dismembering in the lower corium (Elastica color). R&S 131708 13 cooler environments. Of these pati nts, two reported this type of symptom in their toes. In order to make the above complaints in all the patients objective, the skin temperature of the arm was measured, the arm and leg measured with an oscilloscope, and the arm examined with a piethysinograph (at rest), and exposure of the arm to cold was made after previous adaption to room temperature. In this last experiment, the underarm was held in flowing water for 15 minutes, and subsequently the time required for rewarming was deter mined. In five patients with acroosteolyses and scler oderma-like .skin changes, a two sided arm-hand arteriograph was made in the transfemoral pathway (Priv. Doz. Dr. Beltz, Radiologic Clinic, Director, Prof. Dr. P. Thurn). In two other patients, arteriographs were carried out in an outlying hospital (once through direct punc ture of the A. brachialis, the other time through a transfemoral entry) due to the existing Raynaud syndrome (By Prof. Dr. Schtlssel, Prof. Dr. Schober, Siegburg City Hospital). A capillary microscopic examination of the fingernail grooves was made in four patients, in which the fourth finger, left, was used. An examination of the eye background of all patients was made -because of suspicion of general angiopathy. An opthalmodynamometric measurement was made (University Eye R&S 131709 Clinic, Bonn, Prof. Dr. W. Straub). * Finally, the blood pressure of all patients was made with the patients lying down. The skin tennerature was considerably lower in the hands of 6 patients (up to 10C below normal). In the cold expo sure test, the rewarming -period was lengthened in 9 cases (up to 60 minutes longer) and in four of the patients, Raynaud syndrome allowed recovery in single or all fin gers of both hands. No indication of inferior circulation of the extrem ities was observed oscillographically and plethysmo- graphically. All arteriographed patients exhibited pathological vessel build up. Five of the patients examined in the Radiological Clinic showed an arterial decrease in circu lation in the fingers and in certain cases even in the hands. Minor changes were evident in the finger arteries by a slight narrowing of the vessel opening of the Aa. digit, vol. propr. and the Aa. digit, vol. communes. Segmentary localized stenosis was also found. In more advanced stages, a delayed filling of the finger arteries was determined. These showed an almost total diffuse and R&S 131710 relatively uniform stenosis. High degree stenosis to subtotal closure were found in the area of the base and middle phalanges, foremost on the fingers with acroosteo- lyses, while the rest showed a clear dense vessel net. > T5 The tissue in the end finger -phalanges appeared notice ably thickened in that area. A shortening of the end fin ger phalanges results from this substance defect. This may be related to an effect which is caused by a compression of the arteries localized there. In patients with character istic changes, the filling time of the finger arteries was clearly retarded. The circulation of the finger arteries was greatly limited - the opening plugged partly to the periphery, and collateral was not evident. In theses cases, segmentary closings of the finger arteries or even a deficiency in the filling of the arteries in the entire finger were apparent next to the high degree stenosis. Both v/rists likewise exhibited narrowed openings and _ side branches were absent to differentiated degrees. The circulatory changes described didn't allow a certain correlation to be made as to the number and size of the acroosteolyses. In fingers without acroosteolyses, the circulatory changes were, as a whole, less marked. In two cases concerning patients with Raynaud syndrome without acroosteolyses, outer arm arteriographs proved the existence of a two-sided narrow calibered Aa. radiales et ulnares. The finger arteries were to some extent greatly restricted, segmented or even completely closed off, so that the middle and end phalanges were only incom pletely maintained. This finding was more evident on the right than on the left. In the arteriographs of the R&S 131711 R&S 131712 left hands of the other patients (transfemoral entry) showed a closure of the A. interossea, 3 transverse fingers proximal to the hand. The hand arteries were considerably constricted, and the Aa. radiales et ulnares proved to have a conspicuously narrow caliber. A com plete representation of the angiographic results are in the preliminaries. In the microscopic capillary examinations, nail grooves of the examined four patients exhibited an amnulla-like widening of the capillary loons,as have been described for the Raynaud syndrome (20). This result was brought about by patients, who although clinically exhibited circulation disturbances, proved to have no Raynaud syndrome. In the eve background, two patients were observed to have an increased circuitry of the vessels, aid in third patient a Fundus hypertonicus (blood pressure 145/85 mm Hg) was found. In a fourth, a distinct constriction of the arteries with cross connections of light congested veins was apparent. In the rest of the six patients, no pathological results were found. The oothalmodynamometric measurements were pathologically examined in two patients. In one patient, in a lying position, this lead to an inclin ation to an intracranial vessel resistance. The blood pressures of 9 patients were in the nor- 17 mal range (systolistic between 100 and 12*0 mm Hg, diastol ic between 60 and 85 nun Hg). One patient proved to have a low hypertonic value betv/een 150/95 and 140/105 mm Hg. Circulation disturbances in the hands represented a main symptom of the examined patients. These symptoms would, be most strongly represented by the Raynaud syndrome. Four patients, who exhibited no Raynaud symptoms clinic ally proved to have capillary microscopic results as described for Raynaud syndrome. The objectivity of these complaints was achieved through a determination of the rewarming time required after exposure to the cold and by measurement of the skin temperature after adap tion to room temperature. The oscillograph and plethysmograph results, nor mal in all cases, leads to the suspicion that the origin of the given complaints is not in the area of the large arm arteries. Indeed, the arteriographic results show changes especially in the area of the finger and hand arteries. This corresponds to the changes which occur in the Raynaud syndrome of different types (19), but are even less distinct than that of progressive sclero derma. As far as is yet possible to judge from the small number of patients examined, a relationship exists between the amount of exposure and the extent of the angiographic results. Thus, the most complex changes were seen in a patient who was exposed for 30 0) 03 03 R&S 131714 t 18 over eleven years. The eye backgrounds of six patients were insignifi cant, and those of the other four patients could not be uniformly intrepreted. The opthalmodynamometric results, indicating intra cranial spasms or respectively vessel resistance, in two of the four patients examined could represent the fact that similar vessel changes as described for the extremi ties are also present in the brain. 3. X-Ray Examinations X-rays were made of the skulls, thoraxes, and upper and lower extremities as well as of the shoulder and peovis. The pathological results are reproduced in Table 3 The most noticeable alterations - which until now have been determined to be the main symptom of the "occupational disease acroosteolyses" - were present in the hands: Six patients exhibited typically striped or band like osteolyses in the end phalanges. In some cases the Proc. unguicularis, separated by osteolyses, proved to have additional fragmentation (Fig. 6). In these cases, fingers 1-3 of both hands were primarily affected. Six patients proved to have bone defects on the edges of the proc, unguiculares and five had a diffuse bone atrophy of the hand skeleton. One patient had acroosteolyses in addition to clear fungus-like widening of the Proc. unguicularis, widening of the shaft and shortening of the end phalanx of the finger. Furthermore, thickened 19 ft Table 3 Bone changes in ten patients afflict d with the so-called vinyl chloride disease. R&S 131715 y. S ps*ss>sf,j:s k < p> ^ p N! 7- P 9 + + 1 + 1 1 1 ++I +9 1 1 -t- + 1 H t+ 9 . + 1 + + 1 +' 1 | + + Jf m 35 c3 ^JSp' S iff fj-l H3 3 0l0 OB ^ 23 c. pc0I0of3--ort1 Osteoporosis (Atrophy) Edge defects (Proc. ung.) Band-like osteo lyses (end pha langes) M 1 ! 1 1 ! 1 1 1 1-1 Osteoporosis ^ (Atrophy) oo ft 11it 1 + II 1i & Edge defects Mo (Proc. ung.) 0ft w 9 S'9 1 1 1 1 1 1 1 1 1 1 *2 c. g-4-? Band-like osteo lyses (End pha langes) * H 1 1 ++ 1 1 1 + 9 t + 1 1 + 1 1 1 ++ 0 fjbt f-tr iS` l-> 0 .4? 7\ O 0 CO a r2 n 1 PC ft 0 3 Cl H 01 Arthritis Bone cysts 20 Jig. 6* Band-like osteolyses of the fingertip phalanx 1-3 of both hands and cystic brightening of the end phalanges ia the region of the Proc. unguicularis of the fourth finger, left. R&S 131716 S 21 I areas existed cn the transition of the Proc. unguicularis to the shaft. In the foot skeleton, unspecific changes as atrophy and small side defects were apparent in four cases in the Proc. unguicularis. In one case, typical edge separation existed in both big toes of the Proc. unguiculares* The iliosacram Joint of four patients exhibited indistinct conture and sclerosis. In five cases, numerous cystic bright spots in the area of the Caput humeri and the Proc. styloideus ulnae were appar ent. In addition to this,, skeletal x-rays of 72 other FVC employees were evaluated. In these x-rays, three cases of bone atrophy, respectively osteoporosis, were revealed, as well as four cases of small edge defects of single Proc. unguiculares. A complete representation and discussion of the x-ray skeletal alterations were published in another work (32). Band-like osteolyses found in PVC-employees has been described by countless authors (5,7,9, 10, 16,36). This impressive picture has given this disease its Anglo-American name. Acroosteolyses has, in addition, been described in numerous other disease. These occur in familiar osteolyses, daktylolyses spontanea (Ainhum), Lepra mutilans, syringo myelia, mutilating arthri tis psoriatica and acroosteolyses described by von Harnasch. Here, however, they may be neglected, differentially R&S 131717 22 diagnostically (31* 32). Although band-lik acroosteolyses has also been described in progressive scleroderma (2), the borderline is clearly possible to determine (31). There is also data existent for the aforementioned bone edge defects, for osteoporosis, and the sclero derma of the ileosacral joint (10, 16). However, due to the small patient collective, it is not possible to judge if the striking amount of bone cysts found in our patients is characteristic of this disease descrip tion. As .to the idea of the "Question of Reversibility" of acroosteolyses, this has already been discussed and published as a result of the ten-year course of this disease in a patient (23 31). According to those results, the osteolytic process in the end phalanx progresses from the distal to the proximal. At the same time, this re sults partlalljjin a bone build up in the area of the Proc. unguiculares and the sintering into "fractured pieces." The end phalanx remained shortened and did not result in a Restitutio ad integrum. 4. Blood producing and Coagulating System The following examinations were carried out on all patients: Hb, HbE, erythrocyte count, reticulocyte count, leukocyte count, differential blood picture, thrombocyte count, coagualogramm (Institute for experimental Hema tology and Blood Transfusions, Director: Prof. Dr.H.Egli). R&S 131719 23 Sternal punctures were made in 5 patients (Medical Clinic, Director: Prof. Dr. H.-J. Dengler). No pathological changes were evident in the red blood picture. Seven patients proved to. have a slight reticulocyte between 16 and 26 % The leukocyte count was under the normal (between 3200 and 3950 leukocytes^l) in four patients. The differential blood picture was hot certainly pathologically changed in any patient. The bone mark examinations offered no indication of dam age to the blood building systems. Especially here, the signs of an osteomyelosclerosis, respectively fibro sis, were missing. All ten patients proved to have a clear thrombocyto penia. The values repeatedly lay between 63000 and 119,000, with one under the normal of 150,000^11. Mainly normal values were found in the determination of the plasma coagulating factors. In one case, Factor VII was slight and Factor X was moderately lessened. The most noticeable, result of these examinations was the decreased thrombocyte count of all patients. The bone mark examinations, with entirely normal results, gave no indication as to the disturbance of thrombocytopoiesis. The thrombocytopenia must therefore at least partially be traced back to the regularly present splen omegaly. Even so, the light reticulocytosis in 7 cases 24 and the indicated 1 ukopenia (in 4 cases) may be indicated in the sense of hypersplenism* A substantial disturbance of blood coagulation may not be established due to the .nature of the examined factors. 5. Liver and Spleen Three patients complained of repeated pulling or biting pains in the left upper abdomen, and one patient reported pain in the right abdomen and a "feeling of fullG? ness". Four patients denied totally the use of alcohol, and the rest of the phtients reported occasional use of ^ beer and wine. No patient had taken long-term medications. 0 In the clinical examination of all the patients, no liver was noticeably enlarged* The spleen was distinctly discemable in the right side, in or around the height of the left rib. The following laboratory tests were carried out as a control of the liver function: BSG, Electrophoresis, Takata reaction, bromsulphalein (BSP.-Test), SGOT, SGPT, alkyl and acidic phosphatase, LDH, cholinesterase, direct and indirect bilirubin, and plasmatic coagulating factor, immunoglobuline, complement fraction beta ^A. A stomach-intestinal passage intigraphy (Radiolog ical Clinic, Director, Prof. Dr. P. Thurn), and a liver and spleen intigraphy (Dr. Schneider, Institute for Clinical and Experimental Nuclear Medicine, Director: Prof. Dr. C, V/inkler) were conducted on all patients. 25 In two caseEf a laparoscope with aimed liver punction (Med ical Polyclinic, Bonn, Committee Chairman: Prof, Dr, Kessler) was carried out. With the help of x-rays of the esophagus, stomach and small intestines, esophagus varices were found in one patient. The scintigraphic examination showed a clearly enlarged (7 patients) and slightly enlarged (2 cases) spleen. The spleen was normal sized in only one patient. In no case was the liver enlarged. The activation distribution pattern wab loosened in all patients in the area of the liver. The BSG was normal in numerous controls. The electrophoresisdiagram was unobtrusive in the normal total albumen of seven patients. In the other three patients, a slight decrease of the beta globulin fraction was observed (5-7 relative %). The Takata-sample was normal in all ten patients. As a result of the plasma coagulating factors, there was no indication of a decrease in liver synthesis perform ance in 9 cases. One patient proved to have a slight decrease of Factor VII and a moderate decrease of Fac tor X. The cholinesterase showed a moderate activity in all cases. The transaminase values of 9 patients were in the upper borderline area, or slightly increased. In one case, they were normal. In two patients the basic and acidic phosphatase was increased, and in one patient R&S 131721 26 th LDH and direct bilirubin were simultaneously in creased. This was noticeable because the slight to clearly increased BSP retention is quite contrary to the relatively low dgree alterations. In the histological examination of the liver punc tures, one patient was found to have a slight periportal fibrosis, and another a slight liver parenchyma damage. No indication Of a floride infection or a cirrhotic reconstruction was present. The important results are assembled in Table 4. With the summarized considerations, complete with respect to the liver functions, we could determine: Al most regularly, the results show the serum-transaminase is slightly increased. This may well be a sign of slight liver parenchyma participation. This is particularly true because no deviations whatsoever from the normal were found in the electrophoresis (with the exception of a decrease of the beta globulin content of some patients), the plasmatic coagulating factor, the enzymes (LDH, alkyl and acidic phosphatase, cholinesterase), and in the bilirubin content of the serum of 8 patients. In two cases, an interim increase of alkyl and acidic phos phatase with one patient and LDH and alkyl phosphatase with a weak positive proof of bilirubin in the other patient could be proven to be a sign of liver parenchyma involvement. However, normal albumin-gammaglobulin R&S 131722 27 Table A. Clinical, chemical, serological, and histologi cal results of the liver and spleen of ten patients afflicted with "co-called vinyl chloride disease." 5 <b oc *> ss. as* c ++ . + 11 1 (9 ^ |g U 0 S-* v SS M --3 to to * tmoi 4k s S 3 IS M --*4 e e> 4> m s > D* is SJ'C b P Oa cc ** iNUin ner Patient + '+4. ++ + 1 + T Splenomegaly Cscintigraph.) 1 + mi 1 1 Esonha_gus varices u Sg SK3S to X (n IgG (mg %) IS c I-A (mg%) tis to -- to 4k SSii is to 5 IM (mg %) r -- to to J *4 tO *4 Beta 1-A Complement fraction (mg %) 3 s u ! h SGOT (mU/ml) to --*4 -- X --to 3 <4 SGPT (mU/nd) 3 tSoI to to J s p.qp Pffi-.g.n-M *5i -- ^ " X T- Q.*d 00 g Si H 3y H- nW aCD yCq CD Cl Cf 1 H<j CD J ^ .. H- CD M o4O'yH-J-WsM-* 01 O ft H-y 01 rt P Plasma. Coag. Factors. Jl'7 pnoresis, bilirubin, : alkyl and acidic phosphat.. j LDH, ChE. Liver biopsy results R&S 131723 u. C/3 CO I~Ovi ----------- :"aamF)" ' - - ...... - --. 28 * relationships with normal eggwhite in the chemical laboratory results are evidence against chronic liver damage, and also against cirrhosis. Because of the totally normal parenchyna structure, at this point there is no histological basis for a fattening or cirrhosis recon struction of the liver. The moderate increase of BSP-retention of 12-26 % found in five patients is unexplainable in connection with the remaining liver function values. This is not explainable solely through the small increase in SGOT and SGPT. According to a differential diagnosis, a fatty or congested liver would be possible. But clinical indications for both diseases are absent, and in addition, a congested liver resulting from right heart insufficiency may be eliminated as a result of x-rays and on the basis of the previously discussed histolog ical examination. The BSP secretion gave information about the excre tory liver cell performance. But, as this is also depen dent on liver circulation, the following may well be true: a decrease in circulation originally resulting from a periportal fibrosis leads to an increase in BSP retention in the "so-called vinyl chloride disease." In addition, splenomegaly (regularly present with only one- exception) must be seer^losely connected with the changes in the liver, in our opinion. Indications R&S 131725 of a splenomegaly, in the framework of acute infections, are completely missing* A closer representation would be splenomegaly with intrahepatic conditioned portal hypertension, a so-called hepatic block. Due to the above considerations of the histologic results of periportal fibrosis, this may deal with an intrahepatic presinusoidal block. Pressure measurements (blocked liver vein pressure and intraspleen pressure) were not conducted, it is true, but for the most part the scarcely or only slightly diminished liver functions and the regular parenchym construction of the liver as well as the ab sence of heart insufficiency speak against the presence of a postsinusoidal block. It may be presumed that the pressure in the portal vein in all patients except one is not substantially raised,as a hepatofugal circulation with esophagus varices only came to the forefront in one patient. In spite of this, the changes in the liver could already lead to a presinusoidal block with secondary splenomegaly, as no strict relationship exists be tween pressure and spleen size. No splenomegaly may be proven when as yet no portal tension is present (4). A hypersplenism results by means of the splenomegaly, that is, a strengthened blood moulting with a cell decrease in the periphery, which is indicated here by a strength- ening of the existing thrombocytopenia, a tendency to- R&S 131726 30 wards leukopenia, and now and again a slight reticulocytosis. On the basis of the previously considered re sults, it can not be explained if the splenomegaly causes only a presinusoidal block or if the fibrosation occurrences in the spleen itself are also a result of this. 6. Lungs A complete anamnesis was made of all patients, with consideration given to. the smoking habits, A clinical examination was carried out and x-rays of the thorax * completed. In all ten patients a resting spirometry and a plethysmography of the entire body was made, and a blood-gas analysis conducted for nine patients (Prof. S. Schwabe, Medical Clinic, Director: Prof. Dr. H.-J. Dengler). In the clinical examination we determined a deep percutaneous emphysema in one patient and slight breath delay at the lung borders. In one patient the x-rays of the thorax exhibited a strengthened lung picture on both sides and a thickened Hilus left. The thorax xrays of the other nine patients were normal. Indications of primarily restrictive changes in eight patients were found in the examination of the lung functions (spirometry, plethysmography of the entire body). In five patients, a slight to moderately heavy hypox emia with a decrease of the Pn up to 62 mm Hg resulted . u2 R&S 131727 31 from the partial insufficiency. The presence of a partial insufficiency in connec tion with the spirographlc results indicating primarily restrictive changes speaks for the presence of a diffusion disturbance, as is found in beginning diffuse lung fibro sis. This then raises the question that similar changes may occur in the lung tissue as are shown in the colla gen and elastic fibers of the skin tissue. 7. Immunology Results The serogical examinations were carried out on all patients: determination of immunglobulin IgG, IgA, and IgM as well as the complement fraction beta ^A, with the help of radial immune diffusion; examination of antinuclear factors (Medical Clinic, Director, Prof. Dr. H, J. Dengler) and LE-cells; examination for the. presence of CEP, streptococcus antibodies (ASL-Titer), rheumafactors (Latex and Waaler-Rose test), and cold agglutinin. Furthermore, the direct and indirect Coombs test and Lues seroreactions ('.Va.-R.: KBR with cardiolipin, KBR with beef heart extract; flocculation reactions: VDHL test, MKR II) were carried out. As is shown in Table all patients were found to have deviations in the immunglobulin fraction: in one patient, the IgG was increased; the IgG and IgM in three patients; the IgG,` IgA, and IgM in two patients; in a further 32 patient only the IgA was increas d. ` * One patient had a slight IgA increase with a simultaneous slight decrease of IgM, and in one case the IgA was decreased. In three cases, the complement fraction Beta ^A was on the lower normal borderline, and in one case was slightly decreased. Antinuclear factors and LE-cell phenomona could not be proven in any case. All other examinations had normal results. As antinuclear factors, LE-cells or positive rheu- maserology were not found in any patient, and in addition, BS6, electrophoresis and Crp gave no indication of acute infection, one can consequently eliminate the- possibility of an autoimmunity disease. The deviations in the imrnunglobulin fraction could best be connected with existing liver parenchym damage. Moreover, the IgA and IgM values attained were as those R&S 131728 from patients with an uninfectious fat liver or respective ly inactive alcoholic liver cirrhosis (13* 14). In contrast to these disease descriptions, the IgG is clearly increased and achieves values which could also be attained with active alcoholic liver cirrhosis. Accordingly, the changes of the imrnunglobulin fractions were indicated in connection with the chapter ''Liver/ Spleen" as an expression of a chronic-toxic damage to the liver with a gradual differentiating infectious partici pation of the mesenchym. The low values of the comple ment -33. fraction Beta ^A found in four patients `are particular ly worth noting. From these values, and on the basis of the other results, a complement fixation process can not be considered. A closer approximation would be that this globulin is formed in decreasing amounts because of the respective liver parenchyin damage. 8. Further Results In addition to the previously mentioned examinations, the sober blood sugars, Rest-N, creatinin, uric acid, sodium, potassium, calcium, and chloride were deter mined in all patients and the urine tested for protein, sugar, bile color and pH-values as well as urine sedi mentation. Only normal results were obtained. The results of the thorough neurological examination' of the patients will be reported at a later date. 9. The so-called vinyl chloride disease without acro- osteolyses and clinical skin changes. The internal results of the ten previously examined patients helped us become aware of three other patients whose symptoms, although exhibiting no clinical skin changes and no acroosteolyses, indicated obvious con currence with the previously determined internal results found in this disease. .The most important results will be placed in a short casuistic. F.S.. 52 years old, employed since 1937 in the autoclave R&S 131729 34 I room of a PVC manufacturing plant. Sine' the beginning of Ahe 60* s, has experienced increased dizziness and numb ness, and in the last year strong pressure in the upper abdomen. Dislike for fatty foods. -About two years ago, distinct sensitivity to cold in the fingers, slightly less in the feet. -May 16, 1972, esophagsl varices bleeding, May 18, 1972 received in Surgical University Clinic, Bonn. The laboratory results obtained there: thrombo cytes 73,0004*1, electrophoresis o.B., slight decrease of plasma coagulating Factors V, VII, and X. X-ray re sults: MDP and esophagus: esophag^L varices in middle and lower third esophagus. Stomach fundus varices. PercutanGus splenoportography: intrahepatic block, collat eral circulation over the vena coronaria ventriculi. -June 8, 1972 - splenectomy with establishment of a splenoral anastomosis. Intraoperativ raised liver and spleen diagnosis: spleen clearly enlarged, the liver surface slightly uneven, but not representative of a typi cal cirrhosis. No distinct signs of high pressure in the portal vein. Only slight degree raised pressure in arteries, veins, liver, spleen. Macroscopic and micro scopic diagnosis of liver and spleen (Pathological Insti tute, Director, Prof. Dr. P. Gedigk): Liver - a slight fibrosis of the portal fields, next to an insignificant flock-like fat increase. Any statement concerning the R&S 131730 R&S 131731 35 ` tiology of th fibrosis is no longer possible. No clues were present indicating a chronic hepatitis or cirrhotic alteration. Spleen: a 300 g heavy, 15x 7 cm large spleen. Histologically, this deals with a chronic blood congestion in the spleen (so-called fibroadenia of the spleen). In section cuts of the spleen hilus,* there are recent obstructive thrombus within the spleen veins. Postoperatively, the thrombocyte count rose to $0^,000/ 1.* We have carried out control experiments since Oct. 5 1972. Thrombocyte: 97,000/ 1, totsp. protein electro phoresis o.B., transaminasis in upper normal range (SGOT 17 and 19 mU/ml, SGPT 15 mU/mi), acidic and alkali phos phatase 79 and 83 mU/ml). BSP test, 16.7 % retention after 45 min. Serological Examination: CUP slightly positive, IgG 2960 mg %, IgA 820 mg %t IgM 220 mg %t complement fraction Beta 99 mg%. Lung function and blood analysis: indicates a moderately restrictive ventilation obstruction, slight lung emphysema, partial insufficiency. Temperature measurements (arms): on both sides, distal of the hand joint, a temperature deficit, which was 4-7 C on the end phalanges Histol ogical results of a sample excision of the right hand: Narrowing of the epidermis and basophile degeneration * Y/e thank the Surgical Clinic, Director: Prof. Dr. A. GUtemann, for their willing relinquishment of the case histories. R&S 131732 36 * of the collagen fibers in the upper corium, a sign of senile degeneration. In the middle and lower corium, no far reaching alterations of the collagen and elas tic tissues were evident. L.M.. 51 yehrs old, employed for 11 years in all rooms of the PVC manufacturing plant, has cleaned autoclaves only seldom. -1962, period of medical tretaraent due to heart pains and lumbago. At that time, no pathological liver and spleen diagnosis was clinically obtained. Since 1968, increasing pain in left upper abdomen and since this time, spleen enlargement is evident. In 1969, diagnosis in the Medical Polyclinic and Surgical Clinic. Medical Polyclinic: splenomegaly, . liver function disturbance with BSP retention of 1.0 % after minutes, but otherwise with unobtrusive liver chemical values. Thrombocytopenia of Mf,000 thrombo cytes/ 1 and slightly extended bleeding period. Of the other laboratory values, only the electrophoresis showed a deviation from normal values with a moderate increase of Beta-globulin to 15*4 rel. %. Sternal punctures unobtrusive, x-ray examination of the extrem ities: no indication for osteomyelosclerosis. The origin of the splenomegaly could not be explained. Surgical -University Clinic: intrahepatic block, R&S 131733 37 * probably with liver parenchyna damage and initial develop ment of esophageal and stomach fornix varices (spleno portography, liver and spleen scintigram). In 1970, the examinations in the Medical Polyclinic resumed: spleen enlarged, as compared to x-rays of 1969* Thrombocytopenia between if6,000 and 81,000 thrombocytes^l, BSP test: 5*3$retentiofi. after 43 minutes. Other labor atory values, including the liver chemistry, had results in the normal range. Laparoscopy: Distinct spleno megaly. As a whole, the liver was not enlarged and exhibited a brown-red color. A fine - wavy surface relief was impressed, which resulted in a somewhat colorful picture due to capsule fibrosis as well as a clearly increased blood and lymph vessel picture. No certain signs of parenchyma structural alteration were present. Liver histology: moderately strong periportal fibrosis. A statement concerning the genesis is not possible. Esophagoscope: beginning esophageal .varices. Ster nal puncture: o.B. In October, 1972, examinations in the above named clinic: Anamnesis: further pain in left upper abdomen, especially with bending and at mealtimes. Dizziness and feeling of unsteadiness which emerged daily and lasted up to one-half an hour. Hearing loss, strong inner unrest. Clinical Results: spleen extended palpatori- 4 38 cally almost to the left pelvic ridge. Dth rwis no clinical deviations from the norm. Laboratory Results: normal red blood picture, a reticulocytosis of l6/oo, leukopenia of 2350 leukocytes^.1, normal differential blood picture, thrombocytopenia of 30,000 thrombocytes/^d. Liver Chemistry: total protein, electrophoresis, Takata-Ara reaction, SGOT, SGPT, alkali and acidic phos phatase, direct and indirect bilirubin in the normal range. BSP test, 13 % retention after 45 minutes. Coagulating factors: .slightly extended thrombin period, prothrombin, Factors VII and X moderately decreased. Serological Examination: IgA 600 mg %t IgG 1600 mg %t Igl-l 200 mg complement fraction Beta ^A, 84 mg%. No proof of LE-cells, anti-nuclear factors or cold agglutinen. CEP, ASL, latex fixation, Waaler-Rose test, and the classical Lues-Seroreaction o.B. Lung function exam ination (spirogram, entire body plethysmogram, blood-gas analysis): indicates a restrictive ventilation obstruc tion with slight partial insufficiency. MPP: indicates a low-degree esophagus varices, esophagastric hiatus her nia, deformation of the Bulbus duodeni, large spleen, no proof of a ulcer or tumors in the stomach or duodenum. Histologic results of a sample excision of the right hand: thickened collagen fibers here and there in the lower corium and strong rarefication of the elastic fibers. Otherwise, no noticeable results. R&S I ' l l 7nA 39 B.K.. ^7 years old, employed since 1954 in a PVC manu facturing plant. In 1954-56, employed as autoclave clean r for one and one-half years, and again in 1968 again for three months. Otherwise mainly employed at the screen ing installations. Experienced cold sensitivity and much shaking in the hand for 1 to 2 years. Experienced synco pal-like dizziness and numbness for 2 to 3 years. Notice able tiredness, slowing down, and forgetfulness, slack ening of libido for 4 to 5 years. In 1969, bleeding duodenal ulcer with "tar" stools. Nonsmoker. In April, 1970 and Oct., 1972, renewed "tar" stools. Due to numer ous bleedings during the stationary treatment on Oct. 31 1972, a two-thirds resection of the stomach according to 'Billroth II was carried out; sufficient emptying of ascites. Liver: macroscopic: cirrhosis-like changes; microscopic (Pathological Institute, Director: Prof. Dr. P. Gedigk): slight increase of the tissue and a thin round-cell infiltration of the portal field. No proof of chronic hepatitis or cirrhotic structural alteration. From Dec. 11 to 21, 1972, stationary at the Skin Clinic. Clinical Examination: spleen clearly palbable underneath the left rib joint, otherwise no important pathological findings. Laboratory Examinations: Light hypochiomic anemia with a normal differential blood R&S 131735 pictur JfO thrombopenia with 90,000^1 wit.h slightly- lengthened thrombin period and a decrease of Factor X In the blood diagnosis. Liver Chemistry: BSP test, 15*6% retention after 1+5 minutes; electrophoresis, trans aminase, LDH, alkali and acidic phosphatase, bilirubin, iron, and copper in the serum, all in normal range* Other Examinations: Electrolytic, Rest-N, classical Lues-Seroreaction, all normal. X-Ray Examination (MDP and Esophagus): esophagus and stomach fundus varices. Liver and spleen scintigraphy: strong atypical config ured liver with enlarged left lobe. Spleen significantly enlarged with straigl^increased colloidal storage. Lung function and blood analysis: small lung emphysema, partial insufficiency. Temperature measurement: Temp erature deficit distal of the hand joint on both sides, on the end finger joint of both sides, deficit of 10 C, Histological Results: from a sample excision of left back hand: orthohypercytosis, constricted epidermis. The entire collagen fibers in the middle and lower corium showed a significant insufficiency of nucleus and homo genization, which increases in the deeper corium. In contrast to that, the elastica coloring shows an unob trusive structure of the elastic fibers. R&S 131736 * All three patients had worked between 11 and 18 years that is, !tong-term-at the same PVC manufacturing plant in various capacities. Their main subjective complaints r &S 131737 41 * during the past years included numbness, dizziness, pressure or pain in the upper abdomen, and increased sensitivity to the cold in the hands. Some of these complaints were also reported by the other ten patients. ' In the recorded internal results, a great deal of concurrence was seen between the group of ten patients and the above three patients. On the basis of skin temperature measurements, two patients proved to have a lessened circulation in the hands. All three exhibited a decreased arterial 0^ saturation as the expression of a partial Insufficiency in the lungs, which gave an indication for the existence of a re strictive ventilation disturbance and lung emphysema found in the lung function examinations. The clear thrombocytopenia (and in one patient, a simultaneous leukopenia resulted), liver damage, and the characteristic spleen enlargement were particularly im pressive, The liver damages v;ere also evident in the laboratory examination of all three patients by means of a clearly raised BSP retention, in which only one patient had a simultaneous increase of transaminasis and the alkali phosphatase. The deviations in the coagulating factors and the inmunglobulin fractions, as well as the decrease of the complement fraction Beta jA, -likewise correspond to the results found in the other ten patients. R&S 131738 42 Pathologically-anatomically, the liver of the three patients proved to have a fine-waved surface relief macroscopically, and in one patient, there was capsule fibrosis and increased blood and lymph vessel view. Histologically, a more or less strongly characteristic fibrosis of the periportal fields was found in all > cases which had lead to an intrahepatic block(proven in one patient with a splenoportography) and with that, the formation of esophagus and stomach fundus varices. These characteristic liver alterations, in connec tion with the characteristic splenomegaly and thrombocytopenia as well as the lung function disturbances lead to the conclusion that this likewise deals with the socalled vinyl chloride disease, and shows, in contrast to the other characteristics, the serious prognosis of this disease in the advanced stages. In two patients, this resulted in esophagus, respectively stomach, fundus varices, for which a splenoral anastomosis was performed after a splenectomy in one case and in another case a two-thirds resection of the stomach was undertaken. The disease progression was clearly evident in the third patient, for in that case it has not yet resulted in esophagus varices bleeding. During the past two years, the patient has experienced further enlargement of the spleen, the thrombocytopenia has become more distinct, R&S 131739 43 and in addition, leukopenia has set in. The reason these patients with such deep-lying dam ages of the parenchymatous organs have passed over the clinical and histological skin changes typical for the so-called vinyl chloride disease (no acroosteolyses was proven), may possibly be explained by the type of employment in the PVC polymerization process. This shall be discussed in more detail in the following. III. Job Conditions What is then the suspected origin for the above- described disease? This question can only be answered through an analysis of the manufacturing rrocess of vinyl chloride to -polyvinyl chloride, and the materials used there as well as the by-and intermediate-products and the compounds resulting from these. The end product, vinyl chloride (VC), was first synthesized in 1833 and is a colorless gas at room temperature (b.p. -13.9 C, freezing pt., -154 C). It is heavier than air and has an aromatic odor. In the gaseous state, it is easily inflammable. The narcotic effect was proven early (29). Vinyl chloride may not, however, be used as a narcotic because it leads to a disturbance of the heart rhythym in the concentrations necessary for such an effect (28). 44 A 30-minute exposur of a 30 vol% VC giv n to rats and guinea pigs'lead from a narcotic stage to death. (26) Congested lungs, lung edema, blood congestion in the liver and kidney and a decreased blood coagulation was viewed autoptically. In long-term experiments conducted at low concentrations (200 ppm daily for 7 hours over 6 months) given to rabbits, centrolobular degeneration and necrosis with foamy vacuolization was present in the liver. Furthermore, periportal cell infiltration was also present .(.34)* Recently, it was reported that in long-term (12 month) exposure of rats to VC, tumors of the skin^lung, and bone resulted. (35) .Acute intoxication in industry due to VC has sel dom been observed. Reports of a reversible dizziness, slight disorientation, and burning in the feet have been made by two workers who received 2-5 % VC for three minutes (11). Three cases of poisoning have become known from Canada, in which VC-gas was determined to be the origin in two separate cases (8). Intense stupor and decreased blood coagulation were found to be symptoms. One of the two died. A third died while cleaning a tank for ten minutes. The exact details of death could not be exactly determined in this case. Vinyl chloride leads to a toxic alteration of the skin similar to that of a second degree burn (15)* R&S 131740 \ On the basis of the previously described animal experimental results, the maximum on-the-job concen tration (MAK-value) was set at TOO ppm in 1970 (18) Different methods of production are known for the polymerization of VC to PVC, and in each of these methods there are again countless modifications (6). The most widely used method is the suspension process. In this process, deionized v/ater is added to the reaction con tainer (autoclave or reactor), followed by numerous additives. These additives include suspension materials as polyvinyl alcohol, methyl cellulose, and gelatine; emul sifiers (sulfonated oil); surface reactive materials (sorbitmonolaureate); and buffer solutions (as sodium bicarbonate, for example). Furthermore, trichloro ethylene may be added to give the polymer a lower molecu lar weight. Catalysts are used to initiate polymeriza tion (usually organic peroxide). , After the reactor is closed and evacuated, liquid VC is pumped in under pressure. This reaction mixture is kept in motion by means of a rotating propeller and by the warming of the reactor walls to 50 - 55C. As the polymerization depends upon the addition, it must later be cooled. Depending on the degree of polymeri zation and the desired molecular weight of the end pro duct, the process is interrupted and the excess VC is R&S CO R&S 131742 46 pumped to a gasometer for reuse* Prom the initial steps in the production of PVC up until this stage, the process takes place in a closed system, from which no gas escapes under normal circum stances, In the further production processes of the reac tion mixture and in the cleaning of the reactors, VC and other gas-forming substances may escape, which the workers then inhale. The reaction mixture is pumped into a mixture con tainer after the VC is suction-pumped from the autoclaves. There, the excess VC is again removed by means of a vacuum pump. Afterwards, the mixture is carried to a supply bin, from where it is sent to the centrifuge. The poly mer is separated here from its aqueous phase. Finally, the polymer is dried in kettles, and separation according to particle size takes place in the screening installation. The finished powder-like polymer is then packed in paper containers or transported in tank cars. After the reaction mixture has been removed, the autoclave is opened and sprayed with water with the use of a high pressure handle. If it is not clean after such treatment, the autoclave is again filled with water. After the water is let out, one or two employees enter the autoclave and remove the numerous, very solid coat ing from .the wall with trowels, or sometimes with hammer and chisel. These -so-called autoclave employees are thus R&S 131743 b7 not solely employed in the autoclaves but also work on the centrifuges, the dryers-, and the screening equipment, as well as the packaging of the polymer. In addition to the industrial use of the here-by described suspension process, the emulsion process is also used in plants where some of the examined patients worked. This process serves not only to produce the homopolymer PVC but also the mixed polymer polyvinyl acetate. The polymerization is likewise carried out in autoclaves, but in contrast to the suspension process, other additives (emulsifiers) are added. The reaction mixture is not conducted to the centrifuge and drying equipment after the gas is extracted but sprayed in a nozzle over storage tanks, in which hot air is present. The polymer contained in the sprayed emulsion droplets are thereby directly dried and are precipitated on the filters. The gases contained and the steam formed from the heat are blown free. Screening and packaging of the polymer follows as in the suspension process. In the course of the processes which lead to the polymerization of VC to PVC, VC and other gaseous com pounds enter the air of the work rooms. With each autoclave cleaning conducted with a water pistol, re sidual gas escapes into the working area. Although no measurements of work level concentrations of the gaseous R& s 131744 48 compounds are available, it may be assume that thes^ would be present in significant amounts. At times, con centrations are obtained which produced a pre-narcotic syndrome in the autoclave employees. This syndrome con sists of stupor, dizziness and nausea. However, a moderate amount of odor-perceptible gas also emerges from the centrifuge, the storage and mixing tanks, and the spraying towers as well as the connections carrying to and from and the drying and screening equipment. Also, the cleaning of the inner autoclave walls with trowels and chisels present opportunities for the workers to be exposed to gases diffusing from wall precipitates or those found as underground polymer precipitates. After ventilation of the reactors, 50 to 100 ppm were measured (6). The air analysis in the region of the inner reactor walls, that is, in the region in which the employees' hands and face are exposed, reached concentrations of 500 to 1000 ppm. However, the largest amount of gas is released by leakage (for example, in the ventilation) from the ex posed autoclaves. This can only be eliminated after the reaction process is completed and by insufficient VC recovery after cessation of polymerization. Presently, there have been only single examinations concerning the degree of cleanliness of the utilized VC and the quail- 49 tative and quantitave composition of the*gases present after completion of polymerization in the autoclaves. There is, however, no doubt that the dominant portion consists of vinyl chloride. The chemical analysis of the residual gas from the autoclaves gave the following composition (the method applied vtas not reported): 90 % VC, 8.5 /o CO^f small amounts of vinyl acetate, trichloroethylene and nitrogen, traces of argon (8). IV. Discussion In the previous sections, the examination results of 13 employees of PVC manufacturing industries were re ported. Countless serious diagnoses of the different organ systems, described for the first time, were brought up. (Table 5) From these results, it could be deter mined that the characterized disease symptoms can no longer be sufficiently described by the previously used term "occupational acroosteolyses." A slight to severe thrombocytopenia was found in all of the examined patients. Twelve of them were found to have a slight to defined splenomegaly. On the basis of laboratory-technical examinations, restricted liver functions were proven in 11 cases which histologically corresponds to a periportal fibrosis. Esophageal varices had formed in four patients, caused by the periportal fibrosis and the resulting portal hypertonia. R&S 131745 50 Table 5. Compilation of the important diagnos s of all examined patients, with the so-called vinyl chlor ide disease. 9 loV 1+3 H- Oa' ++ I3JD-1 + n <(3mD : 3 <t> zz 0> c3m o+ 3 3H* 3 O' fr |1 """w*-- N ** 0+3- < + J. CD1 >1 ++ 3JB 3 3 < H(D A2 *H c3m 1i i3c+ e O< 3 + + Number -sex <i xa.eui. rps*g = >sf-rc* Patient s s o > ;g - " n ? - Skin changes a. Clinical b. Histolog, I tt -r + -^ + -r Circulation Disturb ances + I + + -r-r | | + + Bone Alterations ++++ + ++ +. +T+TT+ + -r Thrombocytopenia T + + + + -T*T + | + + ++ ++ Splenomegaly + u & c/) 2sS<Tj^JTOo+o2_al J?51"+I2?<3*|o+_+++!f'l8oL+^o ++| |+ + Liver Changes Ss-Sw 51 CO ; < ? CTU> + + + + + + + I + + Ventilation and/or diffusion obstruc tions 51 The changes in the respiratory tract were conspic uously numerous. The majority of the patients (eleven) proved to have functional disturbances in the sense of partial insufficiencies and gave indications of mainly restrictive alterations. Circulation disturbances of the hands and feet up to the Raynaud syndrome were given as the first symptom by almost all patients and could be objectively judged in eleven cases. The scleroderma-like alterations of the skin in the arm region, typical for this disease, could be observed in 8 cases. No strict relationship existed between the amount of circulation disturbance and the distinctness of the skin changes. Acroosteolyses has given this disease its name, es pecially in American literature, and we saw this in 6 patients. Up until this point, acroosteolyses and Raynaud syndrome had been given the central position in the disease diagnosis. Other authors placed the disease occurrence at 3"5 % of the employees. V/e could confirm this statement, in regard to the Raynaud syndrome and acroosteolyses symptoms. Yet, with re spect to the internal results of our examinations, it may be assumed that the death rate is significantly higher. In our examined patients, this would lie at 10 % of the employees employed at the plant, although R&S GO 4* R&S 131748 51 ' *` The changes in the respiratory tract were conspic uously numerous. The majority of the patients (eleven) proved to have functional disturbances in the sense of ~ partial insufficiencies and gave indications of mainly restrictive alterations. .. Circulation disturbances of the hands and feet up to the Raynaud syndrome were given as the first symptom by almost all patients and could be objectively judged in eleven cases. The scleroderma-like alterations of the skin in the arm region, typical for this disease, could be observed in 8 cases. No strict relationship existed between the amount of circulation disturbance and the distinctness of the skin changes. Acroosteolyses has given this disease its name, es pecially in American literature, and we saw this in 6 patients. Up until this point, acroosteolyses and Raynaud syndrome had been given the central position in the disease diagnosis. Other authors placed the disease occurrence at 3-5 % of the employees. V/e could confirm this statement, in regard to the Raynaud syndrome and acroosteolyses symptoms. Yet, with re spect to the internal results of our examinations, it may be assumed that the death rate is significantly higher. In our examined patients, this would lie at 10 % of the employees employed at the plant, although R&S 131749 52 no previous serial examination has been undertaken. With this aspect in mind, the suspicion voiced by some authors that constitutional factors play an important role in the origination of this disease may be placed in the background. The toxic occurrences should be placed foremost. The high mortality rate of mainly young men indicates on the one hand an entirely special occupational sector, and on the other, the complex nature of the disease. In spite of the differing effects of this disease, in which skin and bone altera tions or conversely internal changes are seen as the main symptoms, a common trait may be found. In all the organ systems we examined, changes in the tissues or respectively the vessel tissues were always found. The tissue alterations of the liver were particu larly impressive. As a result of an increase of collagen fibers, a fibrosis of the portal fields v/ith the remain ing normal parenchyma structure occurs. In comparison with this result, the small toxic changes of the liver parenchyma becomes insignificant. It can not be present ly decided if the observed spleen enlargement should be viewed as the single result of hyperportal tension or if it is also primarily due to a fibrosation in this organ. The four patients with the most definite spleno megaly exhibited esophageal and partial stomach fundus varices. 53 The origin of the thrombocytopenia remains unclear. It is certainly not solely due to the splenomegaly and the liver changes, as this has been determined to be a uniform symptom in one patient with a splenectomy as well as in a patient without liver and spleen changes. According to our results, we would assume the lowered thrombocyte count is the first ob.iective svnrotom. This is all the more Important because the thrombocyte count is. a value that is easily determined and therby offers a possibility of inner-industrial procedural control. The indicated restrictive ventilation disturbances combined with hypoxemia indicate that fibrosation also occurs in the lung tissue. The skin gives evidence of a histological increase and a thickening of the collagen fibers with simultaneous destruction of the elastic fiber network. The corium vessels exhibited only discret changes in the form of edematosis swelling. In compar ison , the caliber constriction and segmentary osteo lyses, particularly in the region of the hand and finger tip phalanges, may be proven angiographically. Possib ly, the osteolysis of the fingertip phalanges may be an indication of a trophic disturbance. Circulation dis turbances in the sense of a Raynaud syndrome - which existed in /f of the patients examined here - were found in addition to numerous internal diseases as well as 54- progressive scleroderma and results of toxic influences 07). The Raynaud syndrome and the clinical and histol ogical changes of the skin are suggestive of this system atic disease. In progressive scleroderma, the vessels and the tissues also become important. Although on one side, the paralells between progressive scleroderma and the "so-called vinyl chloride disease" are very.clear, the two diseases are quite well separate^ on the other side (23). Above all, however, there exists no doubt that the disease described by us is occupationally dependent and has a toxic origin. As it has already been described, the patients have been constantly exposed to gases be cause of their occupation. These gases emerge from the PVC synthesis, and these gases contain a mixture of numerous volatile substances. The main fraction con sists, hov/ever, of vinyl chloride (8). Other substances, as vinyl acetate and trichloroethylene, are only present in trace amounts. The narcotic effects of VC are familiar. The employees examined by us anamnetically revealed that VC periodically escapes in significant amounts in differ ent phases of the production process, and that this pro duced tiredness, dizziness, and nausea. From animal experimentation, it is known that VC has toxic liver effects in significant. This has, among other things, lead to a new determination of the MAK value 08). R&S 131751 % 55 * Furthermore, the em rg nee of Raynaud syndrome has he n observed in plants which produce only the monomer, and not PVC (1, 27) In the most recent period, long-term vinyl chloride exposure in animal experiments produced damages in the bone construction. Various authors have determined the employment in autoclaves to be the deciding factor in the origin of acroosteolyses, Raynaud syndrome and skin changes. At this time there is no known patient afflicted with occupational acroosteolyses who was not at least periodically employed as an autoclave cleaner. It was assumed that the origin of this disease was a result of the coinciding of a perinhalation or percutanous toxic substance, the physical alteration of the hands during the cleaning of the autoclaves, and a disposition factor. We suspect, in contrast to that, that it is not so much the constant microtraumatization of the hands in manual autoclave cleaning which is the main factor for the formation of the osteolysis but the close con tact with the polymerisation precipitate. This contains large amounts of the diffused VC such that the inner reactor walls (even after previous spraying of the autoclave with water) contain 600 - 1000 ppm vinyl chloride. A further indication of the percutanous penetration of VC is indicated by tha fact that we found scleroderma- R&S 131752 like skin changes only in the. region of unclothed skin areas. On the basis of the expounded results and consider ations, we believe that the penetrating suspicion exists that ong-term VC exposure is capable cf producing a com plex disease. This is expressed in the fibrosation of the parenchyma organs examined by us: the lungs, liver, and spleen as well as the circulatory system. With this, the disease obtains the character of a systematic disease in which the prognosis becomes serious in advanced stages. The disease thus is far wider reaching than the previously described disease, "occupations^. acroosteolyses". We would therefore like to eliminate this symptomatic designation and propose the name "vinyl chloride disease." We thank Mrs. E. VoigtlUnder for the production of the clinical and histological figures. R&S 131753 R&S 131754 Literature: 57 1. AngludnuMi, K., Oloiu, M., Dnlirimwii, E.. Ihigi-l'nmwIiiv-DnwiMsi, I... !)o- lirincncu, {., (iniirn. V,: Cnnsiib-mtii rIinici>*|iloK>,nii-c ,-isuprn fcnnincnuliii Itayimtid lit miini-ilorii din indtiHlrin |ilicl(irtirii <li< vinil. Mill, iiiliftm SI, 473 (UMill) 2. ilAmony, T., I'Vim-h. H.: Ilcilriigc zur Rontgenologic dor ,,Akro*klcnr". Fort* selir. Itiinlgeiuilr. 47. 287 (I IK13) 3. IhMilnrv. A. V., Vuzin. A. N.. Korlirtkov, A. (!.: On t lie pulliogcnrsis of i-liangr* ilovclopiog (inn to a kutg-ferm x|Mwnnt lo lint cIIitI nf viuvlchloride. Gig. Tr. |OT.f, Zitlml. 1C. 24 (1972) 4. Ikgruinnn, II.: Klinisriic liitiiintnlogic. Stuttgart: Thicino 11)70 0. Clintciuiu, A., Moliilon,. 1'.: Uii syndromo d'acro-osteolyso d'origino profceaioncllcetdoconslulion nonvrlle <-n France..!. Radiol. Elect rol. 48,277(1907) 6. Cook, W. A., Gicvcr, J*. M., Dinman, It. 0., Magnuson, 11. J.: Occupational acroosteolysi*. II. An industrial hygiene study. Arch. environm. Hllll S3, 74 (1971) 7; Cordk*r. J. M., Ficvcz, C.,, Ijrfrrm, M. .1., Scvrin. A.: Aero-ostcolyso ct lesions rutnluTM nHnorHT* rhrz deux ouvricrs n licetrs nti nettoynge d'nntnclnvc*. Cnli, Metl. Travail 4,3 (llHili) 8. Danziger, H.: Accidental poisoning by vinyl chloride. Cnnad. med. Ass. J. S3, 838(19110) 9. Dinman, B. D.. Cook, W. AM Whitehouse, W. M.t Magnuson, H. J.: Oceu* pntionnl acroostcolvsis. I. An epidemiological study. Arch, environm. Hlth 32, 01 (1971) 10. Dodson, V. If., Dinman, B. D., Whitehouse, W.M., Xasr, A. N. 51., Magnuson, H. J.: Occupational acroostcoiysis. III. A clinical study. Arch, environm. Hlth S3, 83 (1971) 11. Dublin, L. J., Vane. R. J.: Occupational hazards and diagnostic science. Bul letin No. 582 (1933); Bulletin No. 41 (1941) U.S.A. Dept. Labor; zit. in: Dan- tiger, H. (I960) 12. Filatova, V. S., Balakhonova, L. J., Gronsborg. E. S.: Hygienic conditions in the production of vinyl chloride. Gig. Tr. Prof. Zabol. 1, G (1958); zit.. in: Public Health Engin. Abstr. 40, Nr. 4. S. G (1UG0) IX Gleichmann, E., Doichcr, II.: Quantitative Immunglobulin-Bestimmungcn im Serum bei entzundlichcn Leberkrankiiciten. Klin. Wsclir. 4G, 171 (1908) 14. Gleichmann, E., Dcichcr, H.: Quantitative Immunglobulin-Bestiinnmngen im Scrum bei entzundlichcn Leberkrankiiciten. Klin. Wschr. 4G, 793 (19GS) 18. Harris, D. K.: Health problems in the manufacture and use of plastics. Brit. J. industr. Med. Id, 255 (1953); zit. in: Malton, K. E., Ziclhuis, R. L., Industrial toxicology and denuatology in tlte production and processing of plastics, S. 143. Amsterdam: Elsevier 1DG4 10. Harris, D. IC, Adams, W. G. F.: Acro-osteolysis occuring in men engaged in the polymerisation of vinyl rhloride. Brit. med. J. 19K7/3, 712 17. lteidrirh. H.: Prirnarca und aekundiirM Baynaud-Syndrom. Dtsch. med. J. S3, 370(1972) 18. Hensclilcr. II. (Hrsg.): Gosundhcitsschiidlicho ArbeitsstolTe. Toxikologisch- arlieitsmediziniachn Hcgriindung von MAK-Wertcn. Wcinhoim: Verlag Clicmie 1972 Literature (Cont'd) t 10. llorv&lh, F., Sztnnkay, C., Knkonsv, T.: Anpioumphische Untersuchungen eibrationsbcwirktor GofiiBvcrandcrungen. Rofo 1 13, 1G4 (1070) 20. Jacoby, H.: Periphery Durebblutiincskrankhciton im Spiegel der Mikrozirkulalion. PomchungHliericlilo <lrs Landes Nordrhein-Westfalen, Xr. 1585. Ivoln: WcatdeiilaclH'FVorlng 1900 21. Juho, S., Lnnge, C.-E.: Sklcrodermicartige Hnutvcriinderongcn. Raynaud. Syndrom und Akroostcolvscn bei Arbeitera der PVC-heratellcndcn Industrie. Dtsch. mod. Wschr. 97. 1922 (1972) 22. Julie, S., Ijuigf. C.-E., Stein, G., Wltmnn, G.: Zur Klinik der sog. YinylchlbridKrankhoit. Jalirest.-igung: Deutsche Gescllschaft fur Arbcitsmcdizin, 20. 10. 1072 23. Juho, S.. Veltmnn, G.: Zur Klinik dcr sog. Vinyichlorid-Krankheit. I. Internationnlcs Symposium der Werksiirztc der rhemisclien Industrie, 27. 4. 1072 24. Korting, G. W., Hoiztnnnn, II.: Die Sklerodermie und ihr nahostchende Bindegewebsproblcme. Stuttgart: Thiome 19G7 25. Lever, W. F.: Histopathologic dcr Haut. Stuttgart: Fischer 1058 2G. Mastromattco. E., Fisher, A. M., Christie, H., Danzigcr, H.: Acute inhalation t toxicity of vinyl chloride to laboratory animals. Anter. industr. Ifyg. Ass. J. 21,304 (10G0); zit. in: JLaltrn. K. E., Zielhuis, R. I*, industrial toxicology and dermatology in the production and processing of plastics. Amsterdam: Elsevier 19G4 27. O'Conner, R. B.: A new occupational disease is born. J. occup. Med. 12, 234 (1070) 28. Oster, R. H., Carr. C. J., Krantz, J. C.: Anesthesia XXVII. Narcosis with vinyl chloride. Anesthesiology S. 339 (1947) 29. Peoples, A.S,, Leake. C. D.: The anesthetic action ofvinrlchlorid-J.Pharmacol exp. Ther. 4$, 2S4 (1933) 30. Schur, P. H., Austen, K. F.: Complement in human disease. Ann. Rev. Med. 19,1 (19GS) 31. Stem, G., Juke, S.. Lanre, C.-E.. Veltman, G.: BandiBrmige Osteolysen in den Endphalangen des Handskeletts. Fortschr. Rontzenstr. 11$, 60 (1973) 32. Stein, G., Jiihc, 5.. Lanre. C.-E.. \eltman. G.: Skelettverunderungen bei der sog. Vinyichlorid-Krankheit. Kontgen-BI. 26, 350 (1973) 33* Suciu, I,, Drcjman, I,* \ alaskai. Ma Contributii la studiul imbolnavirilor prodoso do clorara de rinil. Med. interna 15. 9C7 (1963) 34. Torkeison, T. R., Oven, F., Rowe. V. K.: The toxicity of vinyl chloride aa determined by repeated exposure to laboratory animals. Amer. "industr. Hyp. Ass. J. 22, 359 (19GI); zit. in: Malten. K. E., Zielhuis, R, L., Industrial toxi cology and dermatology in the production and processing of plastics. Amster dam: Elsevier 19G4 35. Viola, P. L., Bigotti, A., Caputo, A.: Oncogenic response of rat skin, lungs, and bones to vinyl chloride. Cancer Res. 31, 31G (1971) 36. Wilson, R. H,, McCormick, W. .. Tatum, C. F.. Creech. J. L.: Occupational aeroostcoljsis. J. Amer. mod. Ass. 201. 577 (19G7) Dr. C.-E. Lange Dr.S. Juhe , Dr. G. Stein Prof. Dr. G. Veltman Universitats-Hautklinik Bonn D-5300 Bonn Bundesrcpublik Deutschland X R8.S 131756 Translation No This is the translation which you reauested. If you would like to make comments or offer constructive criticism of this work, please do so on this form, fold, and mail to the address below. Your evaluation is our only way of determining the quality of our translation service. Is the translation written in clear, understandable English? Are the technical portions correctly expressed? Other Comments -- Retuni to: Mary H. P.es lock Dow Chemical Company Library 566 Building Midland, Michigan 48640 Int. Arch. Arbeitsmed. 32,1--32 (1974) by Springer-Verlag 1974 Die sogcnannle Vinylchlorid-Kranklicit-- eine berufsbedingte Systemsklerose ?* C.-E. Lange, S. Jiihe, G. Stein und G. Veltman Universit&ts-Hautklinik Bonn (Direktor: Prof. Dr. A. Leinbrdck) Eingegangen am 30. April 1973 / Angenommen am 7. Mai 1973 Vinyl Chloride Disease Summary. The health status of 13 workers employed for 1.75--18 years in a polyvinyl chloride factory was studied. Eight of them had scleroderma-like skin changes (Fig. 2) characterized histologically by thickening and homogenization of the collagen bundles (Figs. 3 and 4) and fragmentation and rarefaction of the elastic fibers (Fig. 5). In 7 patients, thickening of terminal finger phalanges resembling clubbing was noted (Fig. 1); 11 patients had circulatory disturbances of the extrem ities (4 of them had Haynaud's syndrome) and 6 patients band-like osteolyses of terminal finger phalanges (Fig. 6, Tables 1--3). In addition to these disturbances, thrombocytopenia was observed in all pa tients, in 12 patients splenomegaly- arid in 11 patients malfunction of the liver (increased BSP retention). Histological examination of liver biopsies taken from 5 patients who underwent laparoscopy revealed marked fibrosis of the portal areas. 4 patients had esophageal varices (Tables 4 and 5) and 8 patients showed partial pulmonary insufficiency with signs of predominantly restrictive changes of the lungs. These pathologic changes in a series of different organs are far more extensive than the syndrome of occupational acroosteolysis already known. Long-term ex posure to vapors of vinyl chloride is strongly suspected of eauaeing this complex disease. Therefore it is proposed that this systemic disease be designated vinyl chloride disease. Key word*: Occupational disease -- Polyvinyl chloride production* -- Vinyl chloride -- Scleroderma-like skin changes -- Raynaud's syndrome -- Vascular changes -- Acroosteolyscs -- Thrombocytopenia -- Splenomegaly -- Esophageal varices -- Liver fibrosis -- Pulmonary ventilation disturbances. Zusammen/as*ung. Ea wurden 13 Arbeiter untersucht, die zwischen 1% und 18 Jahren in einem PVC-herstcllenden Betrieb beschaftigt waren. 8 von ihnen wiesen sklerodermieartige Hautveranderungen (Abb. 2) auf, die histologisch charakterisiert sind durch Verbreiterung und Homogenisierung der kollagenen Faserbiindel (Abb. 3 u. 4) sowie Fragmentation und Rarefizierung der elastischen Fasem (Abb. 5). Bei 7 Patienten bestanden trommelschlegelartige Auftreibungen einzelner Fingerendphalangen (Abb. 1). 11 Patienten zeigten Durchblutungsstorungen der Extremitiiten (4 von diesen ein Raynaud-Syndrom) und 6 Patienten Acroosteolysen einzelner Fingerendphalangen (Abb. 6, Tabellen 1--3). * Die, Arbeit wurde mit dem Franz Koelsch-Preis 1973 auagezeichnet. 1 Int. Arch. Arbeitsmed., Bd. 32 R&S 131757