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R&S 113312 BIO-MEDICAL-RESEARCH DOCUMENT DESCRIPTION POEM 53 68 69 76 Duplicate .in. all cards: --> /ft# year as-1961- tf/ File number [Right justify [Numeric only] Author(s), as Last Name , FS (No Punctuation) and coden for journal as JAMA preceeded by one blank space 1 ---------- V 20 21 {S/A-Ljntt y&r 40 41 77 78 I Sub-Index Code 51 62 11 12 13 Title of Report; end with space-hyphen-hyphen-space. Follow with Index Terms, separated from each other with comma-space. Avoid other punctuation; do not abbreviate. 12 61 62 1: 21 <0 22 --/zL.Xr/r 7 #_ V 23 24 Source (Journal, Vol., Number, Pages, Date ) *1 62 ~31 . 32 Brief Summary 12 10 SUMMARY: 61 62 61 62 63 64 R&S 113313 4' IMPERIAL CHEMICAL INDUSTRIES LIMITED PLASTICS DIVISION--WELWYN GARDEN CITY From: j STUFORD Division Hmafr Saalth & krtrosaaot Protactloa DSO-16 Srt 3162/3859/2096 3859 - Dr Staff0x4*1 Sac. 2096 - Tolopboso eoataet la T3 To Dr M N Johnson. Mr John Lawrence Dr J T Barr Dr J G Kannnuller Mr J C Thomas Dr J P Tassignon Dr W G F Adams Dr- D P Duffield Dr A P Wright Dr D D Boyson Nr & J Sleddon Dr James P Lyon Dr F W Best Mr L F Hill "Vrtr fUL--t-d c Ii *J VCM - VTNATEX We have come across the attached article on studies of Vinatex workers. This encapsulates much of what we have reported to you already on Milford Ward's work and views on immunological changes. On p206 it introduces the finding of reduced lung transfer factors which needs much more careful examination. The article came from a book entitled "Induced Disease: Drug) Irradiation, Occupation" published this year by Grune Straiton and edited by L Frege wii.h ISHJ number 0-8089-1225-9. J Stafford JS/LJV/DSO 16 10.11.80 4T` Ml mi SUS\lLf ^7Y0W(Lw,.^O'^) 1 CJLtjvfc' M ^UJ 4v, fJU, j^-ULfc- Ijxp /f /u >ZU Ronald G. Grainger Anne E. Walker A. Milford Ward* 11 m!? O-SW-l**?-* Vinyl Chloride Monomer-Induced Disease: Clinical, Radiological and Immunological Aspects The story of vinyl chloride induced disease has been described as a watershed in the history of occupational medicine.1 The understanding of this disease has precipitated new attitudes toward occupational hazards and has made obligatory an immediate response to the first evidence of damage due to industrial processes. Within the last decade, the complicated multisystem symp tomatology, the signs, and the radio!ogica!.,and pathological features have been defined. The toxic chemical, vinyl Chloride monomer (YCM), and the specific industrial processes with which it is associated have been idenlifted. The pathogenesis of vinyl chloride disease (VCD) has been inten sively studied and there is now strong evidence that immunological pro cesses are involved. Since 1974, the levels of permissible exposure to . VCM have been lowered substantially by industrial legislation; there is a good possibility that current exposure levels will not be high enough to ' induce disease in the future. Our own involvement with vinyl chloride came about when workers at a local polyvinyl Chloride (PVC) manufacturing plant developed symp toms of the disease. We present here our clinical, radiological, and immunological studies of workers from this factory. MANUFACTURE OF POLYVINYL CHLORIDE The process of converting vinyl chloride monomer (VCM) to polyvinyl chloride (PVC) by polymerization was discovered in Germany * The authors wish to thank Mrs V. Morris for her assistance in preparing the manu script. 191 'US j---* ii mL e. t ~ F- r fi*v Si-8eu S9U % -'/u 192 Grainger, Walker and Ward in ihe mid 1930s. Production is now world-wide, resulting in an annual output ofapproximately eight million tons. The uses of PVC are many and varial as it is used extensively both in the home and in industry. PVC is manufactured by the polymerization of VCM; 500-toi,500 molecules of the monomer produce one molecule of PVC, depending on particle size.* VCM {monochlgro ethylene, or C,H3Cl) is a liquid gas at normal temperature and pressure. It has a pleasant odor, which can be detected at a concentration of 400 parts per million. ---- Thu polymerization process takes place in a large reactor or auto clave approximately 6 ft. 6 in. in diameter and 11 ft. 3 in. high with a capacity ofapproximately 290cu. ft. (Fig. I J-l). Liquid VCM is dispersed in water with a suspending agent and a catalyst. During polymerization, the mixture is constantly agitated by a central paddle, and1 carefully controlled pressure is upplied within the reactor. As the process Is exothermic, the autoclave is continuously water-cooled, Polymerization takes approximately eight hours, and at the end of this time,': 92-95 percent of the monomer has been converted to polymer. Excess monomer is then drawn off and the thick slurry of PVC in water is rurtfouf of the bottom of the reactor, centrifuged, dried, bagged, and sent for processing. The PVC slurry contains a considerable quantity of VCM: up Jo 500 parts per million. Despite constant stirring during polymerization, some of the thick slurry, of PVC settles on the inner lining of the autoclave and on the central paddle. To ensure the purity of the next batch of PVC, this residual scale has to be removed before the vessel is recharged. Descaling used to be performed manually; an operator would climb into the autoclave Figi 11-1. reactor or autoclave is a cylinder with a domed top and bottom. The illustration shows a worker opening the upper hatch door through which the cleaners climbed to descale the inner walls. The total height of the reactor is 11'3" Vinyl Chloride Monomer-Induced Disease 193 through the hatch in the dome (Fig. ll-t) and mechanically descale the vessel wall with hammer and chisel. The health hazards of PVC manufacture appear to be entirely related to exposure to VCM. VCM gas is readily absorbed by the I tings. Work men have most often been exposed to VCM when the reactors arc first opened after polymerization, during manual descaling or the reactor, and during maintenance work on pipes carrying the liquid VCM. However, 5 the drying of the PVC slurry and bagging of the final PVC powder are not without hazard. The PVC slurry contains approximately 51)0 pails per million of. VCM, whereas Ihe dry powder contains less than live pails per million.. Microscopic examination reveals that PVC particles have a markedly : pitted surface in which unpolymerized VCM may lx: retained. The small-? esl particles of PVC (0.5 (tax in diameter) arc easily inhaled and may' vrv carry unpolymerized VCM into the lungs. p CLINICAL EFFECTS OF EXPOSURE TO VINYL CHLORIDE MONOMER Acute ^ Exposure to high concentrations of VCM gives rise to temporary ' narcosis, dizziness, weakness of the legs, impaired coordination, and sudden loss ofconsciousness. (At one time, VCM was considered for use . as an anesthetic; it is chemically related to chloroform.) Only in the last > four years have environmental levels of VCM been adequately and accu- . rately monitored in PVC manufacturing plants. Current levels are proba- , bly as low as five parts per million, but it is possible that twenty years ago, - levels were as high as 1,000 parts per million, and in 1973 around 500 parts ' per million. VCM has a pleasant smell and an agreeable taste. The initial ' symptoms of narcosis are not unpleasant, and it is probable that some workers have deliberately "sniffed" the VCM. s' Chronic Exposure In 1966,* acro-osteolysis (AOL), and in 1973 angiosarcoma of the :1 liver were identified as complications of chronic exposure to VCM (Chap- ^ ter 15). Suciu4 described Raynaud's phenomenon, sclerodermatous skirt C changes, and liver dysfunction in PVC production workers. Experiments with rats exposed to high levels of VCM indicated a high incidence of ' liver, bone, and ceruminous gland tumors. An American epidemiological./ study of PVC production workers revealed an association between an-, giosarcoma of the liver and prolonged exposure to VCM^ Lange* introduced the name vinyl chloridc-mduccd^Base for the systemic disorder that included dysfunction of the liver and lungs, ......vMprnderm'itmis skin chances, and thrbrp-. 194 Grainger, Walker and Ward hocyiopenia in PVC production workers. Specifically, the disorder was characterized by the following. I.IVKR Anaiounrotna of the liver. In 1974, the B. F, Goodrich PVC pro duction plant iq Louisville, Kentucky, voluntarily and admirably revealed that six of its employees who had been exposed to VCM had recently died of angiosarcoma of the liver (ASL).* All six employees had worked as reactor cleaners and had been exposed to high concentrations of VCM. Confirmatory experimental evidence that VCM could induce ASL in animals was soon produced.*1; ASL is a rare histological variety of malignant liver tumor and is variously described as KupiTer cell sarcoma, hemangio-endothelioma, and hemangioblastoma. The essential histological feature is that the liver vascular sinusoids are lined by proliferating tumor cells of endothelial or Kupffer cell origin. There is a dense intra-sinusoidal network of reticulin fibers. '- ASL is almost always the result of exposure to toxic substances such as thorium dioxide (after angiography and other radiodiagnostic proce dures), prolonged arsenic intoxication (therapeutic, vineyard workers) as well as vinyl chloride monomer (VCM reactor cleaners), : *" Within months of the initial Goodrich announcement,^several other patients with VCM-induced ASL were reported in the United States, the United Kingdom, Sweden and Germany. By 1976, as manysis4,7eases of ASL secondary to VCM exposure had been reported; two'of these pa tients were from United Kingdom.*1 Almost all of these patients had worked as reactor cleaners in PVC production plants and had therefore been exposed to the high concentrations of VCM which were prevalent before .the danger was appreciated. It is calculated that the mean period from initial exposure to VCM to the development of ASL is about 17 years. ; *v Clinically, the patients present with features of abdominal tumor, liver failure, ascites, and hemorrhage. Radiology reveals a large liver, often with splenomegaly and ascites. Angiography demonstrates stretch ing of the intrahepatic arteries around tumor masses, abnormal tortuous distorted arteries with rapid filling of hepatic veins (Fig. 11.11). Ul trasound and isotope studies provide confirmatory evidence of.multiple intrahepatic masses. The diagnosis of ASL is made by histological examination on tissue, preferably obtained by laparotomy rather than percutaneous needle biopsy, which may cause severe hemorrhage. The outcome is inevitable fatal. i In VCM-induced ASL there is often a diffuse fibrosis of the portal, perivascular and periductal tracts, of a type rather different to the much 9ieeu s^a V...r. uiiunue monomer-induced Disease Fig. 11-2. Selective coeliac arteriogram showing stretching of intrahepatic arteries by masses, some of which are hypovascular and others which are hypervascular. Abnor mal tumor vessels with premature filling of intrahepatic veins (arrow). This angiosarcoma is not the result of vinyl chloride exposure but is due to an irejection of thorotrast for venog raphy twenty years earlier. may reveal evidence of this with a distorted liver pattern, an enlarged portal vein and splenomegaly.3* It is surprising that as far as is known, no person who has developed ASL has also had skin or bone changes of the type described above as being caused by VCM exposure. It seems that two different mechanisms are involved in VCM-induced liver tumor and in the cutaneous and acroosteolytic manifestations. BONES Acro-osteolysis (AOL) due to exposure to VCM was first described by Cordier* in 1966. Industrial AOL has a triad of signs--lytic bone changes, Raynaud's phenomenon and sclerodermatous skin change. The incidence in PVC production workers was approximately 3 percent, and was almost exclusively confined to men who had worked as manual cleaners of autoclaves or reactors.3,7 SKIN CHANGES Sclerodermatous skin changes affect mainly the hands, and vary from R&S 196 Grainger, Walker and Ward :o complete tethering of the skin of both hands, thereby interferingwith nanual dexterity. In severe cases with AOL, the fingers are clubbed and he nails become shortened and curved into a typical watch-glass appear ing trig. 11-3). In one severely affected man, the skin changes involved lie hands, arms, face, trunk and proximal thighs. Histologically* the: skin :hanges,differ from idiopathic scleroderma only in that the skin appeniages are"preserved in the VCM-induced disorder. Direct niicroscopyof he nail folds shows capillary abnormalities similar to those observed in indents with idiopathic scleroderma.11 Blood flow studies confirm that xitli capillary and finger blood flow pre impaired. Sympathectomy has iroved helpful in relieving the Raynaud's phenomenon in some paienis.1,1" LUNG FUNCTION Dyspnea is a common symptom in PVC production workers. Miller1 reported that 80 percent of PVC production workers had restrictive air ways disease after 20 years of exposure. Reduction in lung volume and vital capacity have also been reported. Chest radiographs usually show little abnormality, but reticular and nodular opacities have been reported, and will be further discussed below. Marked defects in lung perfusion were found in production workers at the local factory examined In our study.u In one case, histology of the tung revealed focal thickening of the alveolar wall, and macrophages in the alveolar spaces. The affected indi vidual had'worked on the production of a particularly fine PVC powder with a particle size of 0.5 /im. One other case of PVC-induced pneumoconiosis has been described. disease. Note short terminal segments of Angers and marked .nyl Chloride Monomer-Induced Disease 197 Table 11-1 Symptoms in 37 PVC Production Workers--British Study by Present Authors <A.E.W.) Symptoms Number Affected 1. Excessive fatigue, weariness 2. Coldness of hands 3. Aches in bones or joints 4. Tingling or discomfort of feel 5, Dyspnoea 6. Tingling or discomfort of hands 7. Coldness of feet 8. Muscles aches or pains in limbs 9. Impaired power of hand-grip 10. Loss of libido 11. Pain behind the eyes 22 20 20 17 17 It) If. 15 15 13 3 Percent; 5`>.4 54.0 54.0 45.9 45.9 43.2 43.2 40.5 40.5 35.1 8.1 THROMBOCYTOPENIA This is a well-documented finding in VCD. Veitman11 found that 80 percent of VCD patients had platelet counts between 17,000 x 10s and 14,300 x 10 per liter, and Wegman1* states that 35 percent of PVC workers had abnormal platelet counts. Bone marrow studies reveal no abnormality. ENDOCRINE ABNORMALITIES Hypothyroidism has been reported in VCM-exposcd workers. Suciu found six cases in 168 workers. Sexual impotence is a common complaint in VCM-exposed workers. Low levels of 17 ketosteroids have been reported.*11 MISCELLANEOUS SYMPTOMS Although direct symptomatic enquiries may be suspected of maximizing symptoms, exposed workers continue to suffer many unex plained and persistent symptoms. These are well documented and it is interesting to compare the presenting symptoms in 37 British workers seen personally in 1974 (Table 11-1) with those from a German study published in 1975 (Table 1I-2).1* RADIOLOGICAL ASPECTS '. Acro-ostcolysis induced by VCM is associated with radiological changes which are fascinating, unexpected, probably uni^^ and patho-'. gnomonic. AOL consists of localized zones of bone ncciHrand absorp tion in the hands (and feet), associated with marked coldness and ischaemia of the fingers, which is induced by exposure to cold (Raynahd's MANtMli 198 m 113318 Grainger, Walker and Ward Table 11-2 Initial Symptoms in 70 Patients from PVC Factory--German Study11 Symptoms Number of Patients Percentage 1. Upper abdominal, complaints 2. Tiredness 3. I'reqticnt dizziness ,,, 4. Paraeslhesiae (numbness and tin- gling) in fingers and/or toes 5. Increased perspiration < (i. Sensation of cold in individual > fingers or hands 7. Aiihtnlgia 8. Sexual potency difficulties 9. Pain in the head 10. Pain in the calves 1 42 27 26 22 19 IS 17 13 9 9 60.0 38.6 37.1 31.4 27.1 25.7 24.3 18.6 12.9 12.9 in several different countries in the 1960s." Presumably earlier cases-had occurred, but were not at the time recognized as being related to VCM or PVC. The bone absorption is always remarkably well defined, often con sisting of multiple, clear-cut, deep erosions, as though a bit of bone had been removed by a bone punch. The erosions usually are not outlined by compact bone, but a thin white margin may be seen (Fig. 11-9). The erosions always involve bone surfaces--usually bony prominences, but occasionally articular surfaces. Fragments of bone may be detached, particularly at the tufts of the terminal phalanges, and these detached fragments may undergo further fragmentation and absorption. There is now firm evidence that the healing of bone lesions by new bone formation may occur in the months or years after exposure to VCM has been terminated (Fig. 11-5). There is no periosteal reaction, nor do any localized changes in the overtying skin and subcutaneous tissues appear. The fingers may be clubbed and the nails shortened when the terminal phalanx is affected (Fig. 11-3). The bone lesions are not usually tender or painful. The distribution of the bone lesions is'a highly characteristic feature. The extremities, especially the hands and fingeirs, are most severely involved (hence the name acro-osteolysis). The tufts of the terminal phalanges of the fingers are the most severely affected bone areas. The VCM-induced bone changes of AOL tend to show a remarkable right-left symmetry (Figs. 11-4 through 11-9). Articular bofic erosions occur most frequently in the interplialarigeal and metacarpo-phalangeul joints of the fingers (and toes), but otherjoints, thnv* of thr* snrrr.Uinc mav also he affected bv these charncter- Fig. 11-4. Above left: A.D., 20/11/74. Left middle finger showing transverse band of bone absorption across the mid shaft of the terminal phalanx. Some fragmentation at the base of the sepamted tuft. Marked shortening of the terminal phalanx with clubbing of the soft tissues. Note periosteal cortical absorption on the radial side of middle phalanx (arrow). Erosions at the corner of this bone. Above right: A.D., il/7/77. Left middle finger showing considerable healing. The separated distal fragment has consolidated and now has a triangular proximal end approaching the base of the phalanx. The terminal phalanx remains very short. Note healing of the previously eroded cortex on radial side of the middle phalanx (arrow). Cortication and healing of the previous erosions at the corners of this bone. THE PHALANGES It is probable that Raynaud's ischemic skin changes always precede radiological evidence of bone lesions in ihe fingers. Radiological changes are always more marked and frequent in the distal parts of the terminal phalanges of the fingers. The earliest changes are small, angular, marginal defects in.the terminal phalangeal tufts; these lesions may be simulated by congenital variations in ossification and by previous trauma. There may be small detached fragments of bone related to the defects; these fragments may later be absorbed. As the tuft changes are very liable to observer error, they are not to be relied on unless the sign is unequivocal and there is no history of trauma. Transverse defects in the terminal phalanges are due to circumferen- 200 Grainger, Walker and Ward Vinyl Chloride Monomer-Induced Diseo: R&S 113319 Fig. II-SA. A.D., 2Q/li/74.Left Index, middle and mng fingers showing identical changes with absorption of the middle third of each of the terminal phalanges. (The right fingers showed identical changes.) " ' 4I Fig. II-5B. A.D., 2CV9/76. Same fingers showing consider able he^^ with the proximal surface of the detached tuft bccomii^Knsolidated and growing towards the bases. (The right fingers showed identical healing changes.) Fig. il-6. A.D., 20/11/74. Left elbow showing erosion of the cortex of the olecranon process (arrow). (A similar lesion affected the right olecranon.) so, detach the phalanx's distal portion, which may fragment and/or undergo sclerosis (Figs. 11-4 and 5). These transverse defects were seen by Dinman et al.w in 1.2 percent of 5,011 PVC workers (Table 11-3), The loss of a substantial portion of the mid-shaft of the terminal phalanx results in approximation of the detached distal fragment to the base, thereby shortening the distal-segment of the finger (Figs. 11-4 and 5) and accentuating the finger clubbing, which is often a prominent feature (Fig. 11-3). The combined effect of tuft marginal erosions and transverse defects across the shaft may result in complete absorption of the distal portion of the terminal phalanx; this was found in 0.18 percent of Dinman's series (Table 11-3). Tabic 11-3 Prevalence of Radiological Changes in Terminal Phalanges* Characteristic Controls 2,407 (percent) PVC workers 5.011 (percent) Marginal defects Transverse defects Total resorption of distal portion phalanx Shortening Clubbing * From Dinman et nt. 1971." 2.04 7.11 0.25 1,22 * 0.08 0.18 0.46 L26 0.08 ___ at____ . R&S 113320 i2 Grainger, Walker and Ward Vinyl Chloride Monomer-induced Disease 203 Fig. 11-7. A.D., 2(V 11/74. Multiple bone erosions of the left ischial tuberosity. All of these lesions involve cortical bone and the bone surface. (Similar lesions affected the right ischium.) The changes'of AOL are much less marked in the middle and proxmal phalanges. The subperiosteal compact cortical bone along the shaft nay be absorbed, exposing the underlying trabeculae (Fig. 11-4). This :hange is more marked on the radial aspect of the intermediate phalanges, iroducing an appearance similar to the subperiosteal bone resorption of lyperparathyroidism, but the delicate, lace-like trabeculation seen in that Jisease has not been observed in AOL. The fingers are always more severely affected than the toes with egard to both Raynaud ischemic skin changes and bone-destructive esions. Following cessation ofexposure to VCM, the bone defects may begin to heal.1* Small detached fragments become incorporated into larger fragments (Figs. 11-4 and 5); the detached end of the terminal phalanx irows toward its base, often with an arrowhead front (Fig. 11-5) until :ontact is made. The two ends of the bone may then completely fuse, so reconstructing a "new" terminal phalanx. The contours of the new struc Fig. 11-8. A.t).. 20/11/74. Right sacroiliac joint showing deep erosions into (he iliac bone. (Similar lesions were pres ent in the left sacro iliac joint.) ture are, however, quite different from those of the original phalanx. The new structure is shorter, broader, and stumpier, resulting in a perma nently short terminal segment of the finger (with an excess of pulp and soft tissue) and accentuating the finger clubbing (Figs. 11-3 through 11-5). DIFFERENTIAL DIAGNOSIS OF THE BONE CHANGES IN THE FINGERS Scleroderma, whose radiological appearance is most similar to that of VCM-induced disease, is more common in women. Its skin changes differ from those of VCM disease in that ulceration of the tips of the fingers, loss of appendages and soft tissue calcification frequently occur. Esophageal and bowel involvement, with characteristic radiological appearances, are seen in idiopathic scleroderma but have not been reported in the indus trially induced disorder. Hyperparathyroidism may cause radiological phalangeal changes R&S ' ` - \?f 204 Grainger, Walker and Ward Fig. 11-9. A. D., 20/11/74, Deep erosion of central portion of articular surface of the head of the first left metatarsal. (The head of the first right metatarsal had a similar but . smaller articular erosion.) very similar to those caused by VCD, but the large osteoclastoma lesions, vascular calcifications and biochemical changes that occur in hyper parathyroidism are absent in VCD. Ischemic atrophy of the phalanges as seen in diabetes, frost-bite, and ergotism may closely simulate VCM-induced changes; the history and clinical features are decisive. Neuropathic lesions caused by syringomyelia, tabes (usually toes), leprosy, and congenital insensitivity to pain may resemble VCM-induced changes; furthermore, peripheral nerve lesions may produce similar ero sive and destructive changes in ihe extremities. But the associated clinical features and the history will decide. Rare conditions such as familial acro-osteolysis1* (sometimes as sociated wid^osteo-sclerosis of the Albers-Schonberg type) and idiopathic a^Asteolysis may produce changes in the phalanges very similar to those of VCM-induced AOL; however, there may be a family history, whereas there is no history of VCM exposure in the other condi- Vlnyl Chloride Monomer-Induced Disease 205 Severe psoriatic arthropathy and sarcoidosis may produce bone le sions having a slight resemblance to AOL, but the clinical features are quite different. It cannot be too strongly emphasized that exposure to VCM is the key factor in confirming a diagnosis of VCD. Almost every patient diagnosed to have AOL due to VCM exposure has worked as a reactor or autoclave cleaner; It is the manual scraping and cleaning of the reactor's inner watts that subjects the workers to levels of exposure sufficient to induce bone necrosis. OTHER BONE LESIONS Phalangeal lesions have been emphasized here because of their invar iable predominance, but bone lesions may occur in other locations. They are always present on corticated bone surfaces--either articular or nonarticular--and appear as punched-oul, clear-cut, small areas of bone destruction, sometimes bordered by a thin white margin. The lesions occur predominantly on bony prominences or pressure points, such as the olecranon process (Fig. 11-6), os-calcis ischial tuberosities (Fig. 11-7), or the angle of the mandible. Neither periosteal reactions nor overlying local skin changes (other than the scleroderma of VCD) are present, and the lesions are painless, requiring a skeletal radiological survey for their detection and enumeration. The bone erosions have a very strong pre dilection to be symmetrical both in site and in size on the two sides of the body (Figs. 11-4 through 11-9). One of our own patients'7 was a 35-year-old male who had worked in PVC production (including reactor cleaning) for five-and-a-half years. He continued cleaning and scraping reactors for several months after AOL symptoms had developed. He appears to have the most severe and exten sive bone and skin changes ever recorded in AOL due to VCD, with severe destructive changes in the phalanges (Figs. 11-4 and 11-5), ulnar styloids, olecranon processes (Fig. 11-6), medial and lateral humeral epicondyles, outer ends of the clavicles, upper ends of the humeri, hal luces, cuneiforms, malleoli, os calces, lower poles of the patellae, greater trochanters, ischial tuberosities (Fig. 11-7), sacroiliac joints (Fig. 11-8),7 and angles and vertical rami of the mandibles. Most of the radiographs in this chapter are of this patient. If should be added that considerable healing of the phalangeal lesions occurred a few years after exposure to VCM was terminated (Figs. 11-4 and 5). ARTICULAR LESIONS The sacroiliac joints appear to be particularly prone to the bone changes of VCD. Dodson et al." reported four sacroiliac cases; several ?i)i; R&S 113322 Grainger, Walked a rid Ward fif - ; olliers hnve also been recorded. The lesions are Ihe usual clean-cut erosions, sometimes corticated, usually multiple, extending deeply from the articular surface into the adjacent bone, particularly of the ilium, but also of the sacrum (Fig. 11-8). The appearances are quite different from those of ankylosing spondylitis in which the erosive changes are much less well defined, shallower, and accompanied by changes in the sur rounding bone; ankylosing spondylitis eventually heals with bone an kylosis. It will be interesting to follow uji patients with VCD changes in the sacroiliac joints in older to determine the end stage. Articular erosions may also occur in several otherjoints, particularly tho't: of the hands, aims, feet and legs (Fig. M-9). The bone lesions consist of well-defined articular erosions; there is no surrounding os teoporosis, no joint effusion and no para-articular swelling (Fig. 11-9). VASCULAR CHANGES IN THE HAND ,, ' ,, yft Four of our more severely affected VCD patients had retrograde radial arterial catheterization and hand arteriography (RGG). Each showed occlusion of some of the digital arteries (Figs. 11-10 and 1*1); the occluded segments were both tong and short. Digital arterial occlusions were by no means invariable! in fingers severely afTecied by Raynaud's phenomenon or AOL. There was an increase in the number of small vessels in the vascular tufts of the pulps at the fingertips. The cause of this change is not known; while it could represent an attempt to produce collateral circulation, it may alternatively result from stasis ofblood flow in the fingertips--an effect ofshortening and bone destruction. Similar hyperemia of the terminal pulp's vascular rctc has been reported in hypertrophic pulmonary osteoarthropathy. ** (Club bing of the fingers is a feature ofboth AOL due to VCM and hypertrophic pulmonary osteo-arthropathy.) PULMONARY RADIOLOGICAL CHANGES Dyspnea was a frequent presenting symptom in our series (Table M-l). Radiology of the chest was normal in this group, but Selikoff ct al.,0> 11 reported that the chest radiographs of 13.3 percent bf 985 PVC polymerization workers showed linear, nodaktrSr reticular changes. Ven tilation and perfusion isotope scans have shown occasional lung perfusion defects in our group.* Lung function tests have been difficult: to interpret partly because of the high incidence of tobacco smoking, blit six bf our patients showed impaired carbon monoxide diffusion defects. Vinyl Chloride Monomer-Induced Disease 207.* Fig. 11-10. A.D., 1975. Arteriography of left hand showing occlusion of the ulnar digital artery of the thumb, and the radial digital artery of the index finger. THE PATHOGENESIS AND IMMUNOLOGY OF VINYL CHLORIDE DISEASE The multisystem clinical features of VCD strongly suggest that a circulatory factor is involved in its pathogenesis. The histological finding of perivascular inflammatory infiltrate and the end-stage narrowing of dermal vessels with subintimnl fibrosis are also suggestive of a circulating, complex disorder.** The accumulated clinical, histological and im munological evidence suggest that VCD is a complex-mediated disease, with thrombocytopenia and splenomegaly being secondary features that follow complement activation and a persisting immune response. Evidence is presented here to suggest that a metabolite of VCM (probably chlorethylcnc epoxide) binds to IgG, promoting aggregation of lgG molecules.'Exposure to cold precipitates these complexes; the com plexes in turn stimulate complement activation, causing platelet aggrega tion and fibrinogen conversion to fibrin. Both of these processes occlude capillaries and other small vessels. Raynaud's phenomenon, as well as the 208 Grainger, Walker and Ward Fig. 11-11. V., 1975. Arteriography of right hand showing patchy occlusion of the ulnar digital artery of the index finger. Note dense arterial rete in the pulp of the terminal segments of all the fingers except the index. dermal osseous and other clinical manifestations, are explainable with this smalt vessel occlusion hypothesis. Metabolism of Vinyl Chloride Monomer Animal studies in the metabolism and excretion of VCM have shown that VCM may be eliminated in three principal Ways: (1) expiration by the lungs of unchanged VCM, (2) expiration ofCO* derived as a metabolite of VCM, and (3) urinary excretion of the metabotites of VCM. c The major urinary metabolites are thio-diglycolic acid, S (2-chlorethyl) cysteine, N-acetyl S (2-chlorethyl) cysteine, and urea. Inter mediate or alternative metabolites of VCM include monochloracettc acid, 2-chloroethanol, 2-chloroacetaldehyde, and chlorethylene epoxide." It app^K that the proportion of VCM that is metabolized is greater when the pal is exposed to a small dose. Saturation of the major or primary metabolic pathway results in redirection through alternative and I Vinyl Chloride Monomer-Induced Disease R&S 113323 209 potentially toxic metabolic pathways.*4 The cyclic chlorethylene epoxide is a highly unstable alkylating agent with a very short biological half-life but a high potential biological activity. Il has a market! affinity fur free sulphydril pool in rats. This affinity for sulphydril radicals allows the chlorethylene epoxide to cross-link between and to aggregate molecules of IgO and other plasma proteins in vivo. The metabolite IgU complexes and aggregates are readily precipitated on cooling. Immunological Abnormalities The major immunological abnormalities in VCD include hyperimmunoglobulinemia with a polyclonal increase in lg(i, cryoglob ulinemia, cryofibrinogencmia, and in vivo aclivalioti ol complement via the classic activation pathway.** There is also evidence to suggest mild T-cell depression with a reduction in the circulating T-cell population and a reactive increase in the circulating B-cell population. Immunofluorescent examinations of skin and lung biopsies have demonstrated the depo sition of IgG with associated complements C3 and fibrin in relation to the histological lesions described in small blood vessels. Hypothetical Mechanisms In the Immunological Pathogenesis of Vinyl Chloride Disease The association of known immunological abnormalities and metabolic data relating to VCD permits the formulation of a hypothetical model for the pathogenesis that will explain the diverse features of this multi-system illness. An alternative metabolite of VCM--probably chlorethylene epoxide--binds to IgG, producing a structural conformational change that promotes aggregation of the IgG molecule. (The aggregated molecules or structurally anomalous monomers may also become antigenic, but this is probably of minor significance.) The IgG aggregates remain soluble, but they are cryoprecipitable and may initiate complement activation. Pre cipitation of the IgG aggregate by cold causes complement activation that results in platelet aggregation (with consequent apparent throm bocytopenia), and conversion of fibrinogen to fibrin with polymerization. Occlusion of small vessels results, from both of these mechanisms. Occlu sions of the'skin capillaries may cause the anomalies observed by Maricq;** the resulting ischemia will stimulate new collagen biosyn thesis." Occlusion of small "end" vessels in cortical bone may result in* the characteristic lytic lesions, while occlusion of dermal vessels may result in sclerodermatous changes. The final phase in this hypothetical mechanism is sSBbrpetuating, R&S 113324 210 Grainger, Walker and Ward -1ft which explains why the disease appears to progress for many months after . removal from VCM exposure. t, Jr - FXmtJMivNTAL EVIDENCE - ---yj*'' Eighty-eight workers from a local VCM polymerization plant were studied by one of us (A.E.W.). They were divided into three groups on clinical evaluation (Table 11-4): 9 patients with definite VCD, 44 patients with possible VCD, and 35 asymptomatic patients. Immunochemical and immunological investigations showed a grada tion of abnormalities throughout'the three groups: polyclonal increases in IgG, cryoglobulinemia, in vivo complement conversion, and a cell- mediated immune defect (Table 11-4). ., The cryoglobulin was a mixed cryoglobulin comprising IgG,: C3, and fibrinogen. ,r. The rheumatoid factor as assessed'*by latex agglutination "was uni versally negative, but hemagglutination showed low titer po&iUve results in eight of the nine persons in Group 1, and ten of the 44 in Group 11, indicating the presence of aggregated IgG in the serunTofthe more severely affected individuals. Direct immunofluorescent examination of skin and muscle biopsies from Group I individuals showed close correlation betwecfi'lhe' presence of cryoglobulin and that of IgG, C3, and fibrin both within ther lumen of small vessels and adherent to the vascular endothelium. ' ? ` ,r Ultracentrifugal analysis. IgG preparations from Group I patients appeared visually less stable than those from Group III and from healthy volunteers. Sedimentation velocity analysis indicates the presence of high molecular complexes exceeding 19S, but these complexes are produced in vitro due to the instability of IgG prepared from VCD patieritfe (Group 1). Some preparations give lower than normal values for IgG; for these, the normal S20W concentration dependence of the sedimentation coefficient Table 11-4 Immunological Abnormalities in Vinyl Chloride-Induced Disease (VCD) and VCM-Exposed Workers Clinical Group " PACIA assay In vivo i positive Number Cryoglobulin C) conversion (MAO or RF) 1 VCD II possible V(D III VCM exposed 9 8(90%) 6(66%) 5(55%) 44 15 (33%) 19 (44%) - *12 (27%) 35 0 0 0 Vinyl Chloride Monomer-Induced Disease 211 is reversed. The molecular disintegration after initial dimerization17 and. the reversed concentration dependence of the S value constitute further evidence of the structural anomaly within the lg<i molecule. Interaction with Protein A indicates a chemically induced IgG struc tural anomaly. Addition of Protein A to purified igli bom VCD patients resulted in immediate precipitation of a heavy complex, (his feature was not observed with normal IgG or IgG from asymptomatic VCM-exposcd workers (Group III). In a gel-phase technique, stable Protein A:IgG complexes have only been seen in either Melinite or possible) VCD patients, or in rheumatoid arthritis. The stmcfmnl anomaly of IgG in rheumatoid patients is well documented111 and the finding oI'similar results in VCD patients is further evidence of it chemically induced IgG structural anomaly. The PACIA assay for circulating complexesi0 depends on the pres ence of immune complexes or immunoglobulin aggregates in the test sample that inhibit agglutination of IgG-coated latex particles by an ngglutinator substance. The agglutinators currently employed are murine agglutinator (MAG) and rheumatoid factor (RF). The presence of sig nificant quantities of circulating complexes in 50 percent of Group I and Group II workers with MAG suggests that the majority of complexes in VCD are greater than 20-22 S, although positive results with the RF agglutinator show that 11-55 S complexes are also present. Conclusions of Experimental Evidence Ultracentrifugal analysis and PACIA assay give direct evidence of the presence of circulating complexes in VCD. This confirms the indirect evidence obtained from cryoprecipitation and in vivo complement activa tion. Further direct evidence is provided by immunofluorescent micros copy. Evidence for the molecular anomaly in IgG is provided by the Protein A interaction and by sedimentation velocity analysis. It has not yet been proven that the metabolite:IgG complex is antigenic, but the presence of aggregated IgG is sufficient to activate complement by the classic activation pathway, thereby triggering the final recycling stage in the pathogenesis of vinyl chloride-induced disease. Summary of Immunological Studies It is postulated by us that the pathogenesis of vinyl chloride-induced disease is the occlusion of small blood vessels in skin, bone and other tissues by aggregation of platelets, and the conversion of fibrinogen to 212 Grainger, Walker and Ward .r fibrin (which encourages thrombosis). It is suggested that these vesseloccluding processes are initiated by the precipitation (particularly by cold) ofimmunoglobin (IgG) aggregates that have resulted fromstructural clr.tngcs induced in the IgG molecule by a metabolite of vinyl chloride monomer. This metabolite may well be chlorethylene epoxide. ETIOLOGY OF VINYL CHLORIDE-INDUCED DISEASE At the present time, it is not known how VCM produces such a wide range of abnormalities <n so many body systems--both in humans and in animals. One possibility is that of a direct toxic effect on the tissues by VCM or one of its metabolites. Another possibility is that the tissue damage is secondary to vascular and/or immunological change. Most probably a combination of these (and possibly other unknown) factors is responsible for the many and varied pathological changes. The immunological changes described above strongly favor the hypothesis that an immunological chain of reactions may be the cause of small vessel damage and occlusion, ultimately resulting in ischemic tissue changes. . VCM enters the body by direct inhalation of gas and When small particles of PVC (carrying VCM) are inhaled. Inhaled particles of PVC \ may, tliemsclves, exert a toxic reaction. y r"' jq i| It is very interesting that no PVC polymerization workef lias been y/W reported to be suffering from both AOL and angiosarcoma of liver. This " suggests that VCM may initiate more than one type of toxic reaction, or that there is considerable individual variation in organ susceptibility to toxic levels of VCM. As angiosarcoma ofthe liver usually develops after a long latent period (15-20 years), some workers with AOL due to VCM may subsequently develop liver tumors. CONCLUSION Since 1974, the levels of exposure to VCM in PVC production plants have been reduced to five parts per million. No further cases of VCMinduced disease should appear if these new standards are maintained. It II is, however, quite possible that highly exposed workers employed in the industry before 1974 will develop angiosarcoma of the liver at a later date. 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