Document rp7V8JO8pNo2Lxx20e1oB8L6V

GEORGE E. BEST VICE PRESIDENT SECRETARY-TREASURER INFORMATION COPY APPENDIX MAM MANUFACTURING CHEMISTS ASSOCIATION 1*25 CONNECTICUT AVENUE, N.W. WASHINGTON, D. C. 20009 (202) 483-6126 January 25, 1974 Marcus M. Key, M. D. Director National Institute for Occupational Safety and Health Public Health Service Department of Health, Education and Welfare 5600 Fishers Lane Rockville, Maryland 20852 Dear Mark: As you well know from our meeting in July 1973, MCA has a deep interest in research into problems which have arisen concerning vinyl chloride monomer (VCM). We now understand that NIOSH has immediate plans to initiate further action resulting from the voluntary report to you by B. F. Good rich of possible health hazards at its Louisville, Kentucky, facility. We wish to reaffirm our strong desire to work with NIOSH as you see fit and pledge our full cooperation and support. Naturally, we would like to meet with you and participate in any ongoing program at the earliest possible time* We believe the technical expertise within MCA member companies could be particularly helpful in the areas of defining health hazards asso ciated with VCM production, workplace and medical surveillance and work practices necessary to limit exposure. 1 am writing offering our services because of my former responsi bilities as technical director. These duties now have been assumed by Mr. A. C. Clark. I trust I will hear from you scon and that you will then have the opportunity to meet Mr. Clark. Sincerely, VVC 000006615 73-12-27 Deutsche Medizinische Wochenschrift, 2S (43) P* 2034-20373 1973 "On the So-called Vinylchloride Disease" By S. Jtthe, G. E. Lange, G. Stein, and G. Veltman University Skin Clinic of Bonn director: Prof. Dr. Leinbrock Since 1958, when the first information on the hazardous health aspects to workers in the vinylchloride manufacturing industries was found, and especially since 1?63> when the same effects were found affecting workers in the polyvinylchloride industry (PVC), and through further reports on this subject (.3* 4t 7, 8, 12, 28), attention has been drawn to this branch of the chemical industry. This deals with a disease similar to a skin and bone affecting scleroderma, but a disease un explainable in etiology and pathogenesis. The main symp toms of this have been the Raynaud syndrome, nodular to large area dense skin alterations and band--like osteolysis in the finger phalanges. We could report our first observations on this., disease type in Germany in 1972 (I5i 16, 17). Ac the clinical picture was at first comparable to a specialized form of progressive scleroderma, we submitted all employees to' a painstaking vve 000006616 internal examination to determine if visceral participation was also present. Recently, we reported completely (18) on the results found up until the end of 1972. These reveal new aspects to be used in the judgement of this disease and, as we believe, also may give new suggestions in the research. The 13 workers examined in the April-December 1972 time period were 29 to 52 years old (average age: 39 years), and had worked at least two, and at most 18 years (average period: 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 anamnetical details are increasing sensity to coldness in the hands and feet, a feeling of deafness, and crawling parietosis. In addition, pressure pain in single fingers, a thickening of the end finger joints and weakening of the nails as well as general complaints of excessive tiredness, forgetfulness and slowing down, syncopal dizziness, nauseau during work, increased perspiration and upper abdominal pain. A major role in the diagnosis of this disease is played by the alteration of the skin: Seven patients proved to have drumstick-like (clubbed) thickened finger end phalanges (club procurements and shortening, watch-glass nails, shortening of VVC 0000066X7 3 the nail plate). We saw scleroderma-like skin alterations in 8 patients: small knots or more spread out; very coarse and relatively sharply defined, usually covering the surface skin projecting infiltrate on the outstretched hands, the distal third of the arms under the elbow, and the area of the cheeks. Three patients had no clinical skin alterations. The histology findings of the excision specimens (from the left or right hands) of all patients were relatively uni;- form. Besides hyperorthocytosis and epidermidosis, there was an expansion and increase of capillaries in the upper cutis. An increase, widening and homogenation of the collagen bundle and a clear rarefaction and fragmentation of the elastic fibers was evident. The same findings in the epi dermis and the fibers of the upper cutis were proven to exist in the patients without clinical skin alterations. The histology alterations in the epidermis and the collagen connective tissues are similar to the edematosis to.infiltra tive stage of progressive scleroderma. Here, however, a clearly defined border is seen between that of possible but to some extent considerable injury of the elastic fibers and the vessel alterations. So far, circulation disturbances are the most common symptoms: Nine of thirteen patients complained of this, and in fact eight of them gave this complaint as their first symptom. The degree of complaint ranged from increased sensitivity to the cold and "akrozyanose" to the Raynaud VVC 000006618 syndrome (four patients). The circulation obstruction could be judged objectively with the aid of temperature measure ments, determination of the time required to rewarm after exposure to the cold, capillary microscopy, and arm-hand arteriography. In no case did oscillography and plethysmo graphy result in a certain pathological prognosis* From this, one can ascertain that the origin of the circulation obstruction is in the periphery and not in immediate range . of the large blood vessels* This consideration is supported by the angiographic and capillary microscopy results. Four patients with sensitivity to the cold were proven to have 'ampule-like widenings of the capillaries in the nail joints -Just as described in the Raynaud syndrome (14). All seven patients who underwent arteriography showed pathological vessel images. The alterations ranged from a slight narrow ing of the Aa. digitales palmares propriae et communes with ^single segmentary localized closure^ to a high degree of stenosis and segmentary closures, and even to the extent of :the loss of contents by the arteries in the entire length 'of the finger and clear stenosis of the entire hand joints. After the examination until this point, it appeared that a direct relationship existed between the length of exposure and the amount of vessel damage. The most obvious x-ray results of this disease were the band-like osteolysis between Processul unguicularis and the phalangen on single or all fingers in six of the patients. VVC 00000661 5 In addition, fragmentation and border defects of the Pro cessus unguiculares could be found in six patients. It is al60 possible to determine different degress of bone alter ation: in light cases only a small lytic zone is visible, and in the advanced stage the phalange is almost fully de stroyed and the Processus unguiculares mounts onto the basis of the phalanx cap-like. A full restitution of the bone is not to be expected based upon the facts at this time (23,24). Remarkable herein is the solid correlation Of acroosteolysis and the club-like expansion of the end phalanges. Thus, the drumstick fingers" are an expression of the lytic bone process and not of an internal disease. 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 H9,GCO/pcJ2_ (under a normal limit of 130,000AaJc) * In ;a -sternal puncture given to six patients in search for. an explanation, there resulted in no case a reference to the ^obstruction of the 'thrombosytopoese", osteomyelofibrosis, or osteomyelosclerose. The other examinations showed no deviations from the norm, except for a slight reticulocis in eight patients (between 16 and 26 %), and a slight leu kopenia in five patients (2350 to 3950 leudocytes/^ JL ). Reticulosis and leukopenia may be caused by the splenomegaly in the twelve patients. At this time, it is not clear if VVC 000006620 the thrombopeny is also so caused, but it is probable that it deals with a turnover disturbance or an increase in disin tegration in the periphery. It was observed in the anamnese that three patients re ported recidivisic pain in the left upper abdomen and 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 not * discerned. However, three patients without the scleroderalike skin condition and acroosteolysis had record histories pointing to a chronic liver ailment (Esophagus varices bleed ing, splenoral anastomosis;portal hypertonus; esophagus varices, splenomegaly.). The bromosulfaline retention was clearly increased, but by comparison the values for serumtransaminase and-phosphates were for the most part nothing out of the ordinary. This discrepancy could also be proven in the other ten patients. Four patients had esophagus varices, and in twelve cases splenomegaly was proven scintallgraphically. The laparoscopic and liver biopsy results Of five patients, which were available to us at the end of 1972, showed remarkable agreement: surface area of the liver clearly or finely waved, capsule fibrosis, increased bloodand lymph-vessels, histologicaly a slight to clear fibrosis of the portal system and indifidual cell necrosis, and slight coarse fat droplets. The result, that we could further ver ify at this time let us express the following theory: Except VVC 000006621 7 for the slightly toxic alterations of the liver cells, this results from the expansion of the connective tissues in the portal system into the diffuse circulation in the liver. In advanced stages this leads to an interhepatic block (most like* ly because of the hinderances in the height of the portal system, possibly similar to a sinusoidal block), with esophagus varices. It remains to be found if the splenomegaly is only is a secondary condition or if this primarily the direct .result . of toxic changes. Of nine patients examined in the lung functions (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) thrcmbopeny,splenomegaly, toxic liver damage, ventilation blockage, circulation obstruction, and skin and bone alteration. This complex of symptoms has not yet been VVC 000006622 been assigned to a known syndrome* It is unexplained etioiogically and pathogenically. Is it possible to obtain a certain insight in the etiology and pathogenesis by a comparison of our results with those previously recorded in literature? What is then possible to be the initiating factor? At a simultaneous pressure and temperature increase, liquid vinylchloride is polymerized to polyvinylchloride with the addition of water and various additives, depending upon the different properties desired* In different countries, independent of the additive type, the Raynaud syndrome and acroosteolysis was present in workers cleaning autoclaves* The symptoms appear so characteristic that it lead in the past year tc the disease designation of "occupationallyconditioned acroosteolysis" and was advanced to a diagnosis position (28). It is not assumed that the additives, differ ing by type, country of production and methods, play an import ant role, but the harmful combination of these with the vinylchloride can not be completely excluded. Therefore vinylchloride, the substance present in the largest amount, be comes the main point of our interests* The monomer vinylchloride is pumped over a closed system of an autoclave. The exit possibilities of the gas - and thus the inhalation possibilities - consist then in more places within the pro duction process: 1, Permeability of the autoclaves (intake and offtake) / VVC 000006623 9 during polymerisation and recovery processes* 2. In the discharging and opening of the autoclaves as well as in the drying process of the finished polyvinylchloride. The residual gas consists of up to 90% vinylchloride (6) and often leads to leaden tiredness and short-lasting disorientation in the employees. 3, From the polymer precipitation on the walls of the kettles. Therefore, from the technical viewpoint, it is completely possible that vinylchloride initiates the hereby described disease. Some facts are already known about the effect of vinyl chloride on human and animal organisms. The narcotic effects have long been recognized (22). Since 1958, reports have repeatedly been made concerning the angioneurotic obstructions and the Raynaud syndrome in workers (1, 10, 21). In the literature one finds single references to the intoxication of vinylchloride, wherein a reversible dizziness, light to very noticeable giddiness, disorientation, skin appearing as a 2-degree burn, and lessened blood coagulation have been determined symptoms (6, 9 11). One worker died as a re sult of poisoning. With the use of experiments involving animals, lung odem, blood congestion in the lung% liver, and kidneys, as well as decreasing blood coagulation could be proven (20). In long term experiments it was possible to produce cent'rolobular degeneration in the liver and necrosis with foamy vacuolization as well as periportal cellular infiltration (26). VVC 000006624- 10 Recently, reports were made concerning skin, lung, and bone tumors and obstructions 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 (13). It is not yet known to us the regulations concerning gas concentrations at the occupational site. The symptoms related in the framework of this disease (Raynaud syndrome, toxic liver changes, obstruction in the - * bone compositions and prenarcotic syndrome) may then be pro duced by vinylchloride. Thus, in the knowledge of the occu pational site we can express the conjecture that long term exposure to vinylchloride is at least a, if not even the disease-initiating factor. The fact that the name "occu pationally-caused acroosteolysis" hints only at a not necessarily determining symptom shows that a new name should be coined. Y/e have proposed the designation "so-called Vinylchloride disease" for this syndrome because this disease, influenced by the participation of numerous organs, obtains the character of a system disease. Pathogenesis The pathogenesis is, as before, unexplained. On.the -basis of our research we discussed the theory that the disease as a pathogenetic principle in the furthest sense is caused by an obstruction on the connective tissue or the vessel connective tissue. In addition, as our theory shows that the toxic agent is effective not only per inhalationem, but 00OOO6625 11 also perkutan, the fact exists that only uncovered main arteries exhibit scleroderma-like coatings and that the band-like os teolysis is only found on the finger phalanges. We saw sclerOderma-like skin alterations as well as acroosteolytosis only in workers who had worked a long period with the cleaning of autoclaves. This can perhaps be explained by the fact that 600-1000 ppm of vinylchloride could be measured in the area of the 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 thermographicallyi Even the alteration of the bone (osteolysis as a resiilt of trophic obstruction by damage to the vasa nutricia) and the lung (restrictive and obstructive ventilation blockage) can be synonomously 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. -Consequences for the Practice The triassic formation of this disease system, serious VVC 000006626 12 prognosis and relatively high mortality (from our investigation C? v certainly more than 10%) has led prevailingly youn men to sol icit us to place the following suggestions: 1 Execution of epidemologic and preventative medical experi mental tests* In our opinion, it is not sufficient any more to search for only Raynaud syndromes and knotty skin alter ations because these symptoms , as characteristic as they are, already show the advanced stage of disease* Perhaps more . important, controls to determine the thrombozytic count in regular time periods should be given to all employees of PVC- producing industries. This should take workers with a con stant thrombopeny out of this branch of the industry, as this appears to be the first objective symptom, before further and more serious internal damage occurs. 2. No employment given to those with liver diseases or circu latory problems. 3* Regular gas concentration measurements in different work sites to avoid exceeding the MAK limit. Experienced tech nical improvement with the goal of greatest possible automation, andimprovement of the ventilation conditions to reduce the possibilities of gas inhalation to the lowest amount possible. 4. Compensation to diseased workers and recognition of this disease as liable to indemnity by inclusion in the list of BKVO. 7 / 5* More research, especially with animals, using vinylchloride with special consideration to the skin, bones, lungs, liver, and spleen. VVC 000006627 13 BIBLIOGRAPHY: Uteratut^ (l| Anghelescu, !* M. Otmu. E. DuhrtfKivU. L. Hsg'pira'-chu-DinMos, C Dohnnascu. V. Clares: Co(i\ilcratii sirkularion. ForschungtheftAte del Lan> des Nordrhein-Wevtfalen, Nr. ISMS (Ws*tdeu(*ihcr Verlug. ke!n 1964). (lj) Jiahe, S.. C. Vcltman. Zu: kimik tlinico patngeniLe j%uprj l.imminului Raynaud la iTiunaiorii din mdustru pwhcloruni de 'nil. Med. interna Jcr sog. VinyKIilorid-Krink.-.eit I. Inter nationales Symposium der "Serksame dcr dicnusdien Industrie, 27. 4. 1972. (Sue.) 21 (1969), 473. (16) Jiihe S., C.-E. Lange: SxicfoJermie* (3) Basalaev, A. V.. A. N. Vatin. A. C- Kochetkov: On the pathogenesis of change* developing due to a long term exposure to the effect of vinyl- irtige Hsuivefandcrungen, Raynaud- Syndrom und Akrooi'eolvcen bet Arbcitem der PVC-herstellenden Industrie. Di&ch. med. Wschr. 97 (1971;, 1922. dtlortde. Gig. Tr. prof. Zabul. Id d>n>. 24. (3} Charelain, A., P. Motiilon: Un (17) Jiihe S., C.-E. Lange, C. Stein, G. Veltman: Zur KUmk dcr tog. Vinylehlorid-Krankhett. Jahresraeur.g Deutsche syndrome aacro-oxeoljse d'ori^ine Gescllschaft fur Arbciismcdain, professionclie et de const-won nouvelle 26. 10. 1972. en France. J. Radiol. Electrul. 43 (19(7), 277. (18) Lange, C.-E , S. Jiihe, G. Stein, G. Veltman: Die sog. VinylAiorid- (4) Cordier, j. M,, C. Ficvcz. M. ). Lcfcvrr, A. Scrrin: Acrooxcoiyse Krankheit - cine bcmfsbedxgre System *klcrsc? Int. Arch. Arbeitsmcd., itn lesions cutanees associees chex deux ouvriers affectes au nenoyace d'autnclaves. Cah. Med. Travail 4 <)966|, 3. Druck. (19) Lange, C.-E., 5. Jiihe, H. J. Marstejler, R. Mulier, G. Veltman: Leber- (5) Cook, tT. A., P. M. Ciever, B. D. sdiaden im Rahnien der tog. Vinyl* Dinman, H. J. Magnuson: Occupational acroosteolysis. II. An industrial hygiene study. Ardi. environm. Hlth 22 ehlorid-Krsnkhcit. jahrntagung Deut sche GcscHschalc fur Arbeiaaiedixin 18. 3. 1973. (1971). 74. (f) Darveiger. H.: Accidental poisoning (20) Mastrumacteo, E., A. M. Fisher, H. Christie, H. Dantiger. Acute inha by vinyl chloride. Caoad. med. Ah>c. lation toxicity of vinyl chlor.de to J. 12 (19(0), 829. * (7) Dinman. 0. D., W. A. Cook. V. M. Whitehouse, H. i. Magnuson: Occupational acmoumittic 1. An epidemiological study. Arch, envirunm. Hlth 22 (1971). 61. (!) Dodson, V. N., B. D. Dinman, W. M. Whitehouse, A. N. M. Nasr, H. J. Magnuson: Occupational acroo* laboratory animals. Amer. udustr.s Hyg. At. J. 21 [I960j 394; liuetr in: Malten, K. .. R. L. Ziclhuia (cd.): Industrial Toxicology and Dermatology in the Production and Processing of Plastics (Elsevier: Amsterdam 1964). (21) O'Conner, R. B.: A new occupatii^ nal disease is bom. J. eccup. Med. 12 (1970), 234. ttcolysis. in. A clinical study. Arch, environm. Hlth 22 (1971). S3. * (J) Dublin, L. J-, R. J. Vane: Occupa (22) Peoples, A. S , C. D. Leake: The anesthetic action of vinly ckionde. J. Pharmacol, exp. Ther. 4g '.1933), 284. tional huards and diagnostic science. Bulletin No. Sil (1933). Bulletin No. 41 (1941), U.5.A. Dept. Labor; aifierr in: (13) Seem, C., S. Juhe, C.-L Lange, G. Veltman: Bandformige Oncolysen in den Endphslangcn de* Handskeierw. Danziger (6). Fonschr. Rontgcnstr. Ill (1973), 60. (10) Filatova, V. S., L. J. Balakhonova, E. S. Gronsberg: Hygienic conditions in the production of vinvl chloride. Cig. Tr. prof. Zabol I (1938), 6; xiricre in Public Health Engia. Abstr. 40 (I960) No. 4, p. 6. (11) Harris, D. K.: Health problems in tha manufacture and use of plasocs. Brit. J. indusrr. Med. 10 (1953). 2i$; xirien in: Makes. K. E.. R. L. Zielhuis (cd.): Industrial Toxicology and Derma tology in the Production and Processing 0< Plastics (Elsevier: Amsterdam 1964), 143. (12) Hams. 1>. K.. W. G. F. Adams: Acro-osrenlysis occurring in men engaged its the polymer.iauon of vinyl dilondc. Brit. med. J. I967,j, 7l2. (13) Henschler, H. (Hrsg.): Gciundbcitsichadlikhc Arbeirssinre. Tosikologisdi-arbe:tvmed tmische begrunuung von MAkc-Wrrten (\ .-Hag Ctiemie. Wcmheim 1972). (14) Jacoby. H.: Periphery Durchblu* tunpkrankheiten i.n Spiegel der Mikro- (24) Stem. G.. S. Jiihe. C.-E, Lange, G. Vrltman: SkeletrverandeTURgco bei der sog. Vinyldilorid-Krankjen. Rdncgenpraxis, im Drudc. (25) Suciu. 1., J. Drejmaa. M. Valalkai: Corttributii la srudiul imholnavinior produse de clurura de vinil. Med. interna (Due.] 15 (1563'u 967. (26) Torkelson, T. R... F. Oven. V. K. Rowe: The tuxicisy of vinyl diloride as defermined by repeated eapovure to laboratory animal*. Amer. iadustr. H>g: At>, J. 22 (1961). 3J9-. utseit in: Malren, R. E., R. L. ZieLSois (eJ,): Industrial Toxicology and Dermatology in the Production and Processing of Plastics lEWevicr: Amsterdam 1964). (277 Viola, P. L.. A. Bigotu. A. Caputo: Oncogenic response of rat slua. lungs, and bones to vinyl chlonde. Cancer Res. 31 (1971). $16. (28) Wilson, R. H.. W. E. McCemiiit, C. F. Tatum, J. L. Crecos: Occupational acmcsreolyiis. J. Amer. med. Am. 201 (1967), 377. Dr. Susanne Tiihe. Dr. C.-E. Lange, Dr. G. 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