Document og3q1nYybp91Y6b8VQB9pxxD

712 16 September 1967 ABDOOO19447 Dietary Iron--Davis et al Acro-osteolysis Occurring in Men Engaged in the Polymerization of Vinyl Chloride D KENWIN HARRIS,* mb,bS,W G F ADAMS,f mb, ch b [With Special Plate between Paces 708 and 709] Bnt_msd_J , 1967, 3, 712-714 The polymerization of vinyl chloride has been undertaken in this and other countries for over 20 years without apparent harm to the workers, apart from some accidental exposure to the vapour of vinyl chloride, the anaesthetic effects of which have been well known for years. The process consists, briefly, in submitting a mixture of liquid vinyl chloride and water in the presence of a catalyst to the effects of heat in large pressure vessels known as autoclaves This produces polyvinyl chloride in slurry or latex form which is discharged from the vessel and conveyed elsewhere to be dried into a powder When the auto clave is emptied at this final stage a deposit of white polymer is found on its inner wall. Air is then blown through the open vessel for at least a quarter of an hour, after which an atmo sphere test for vinyl chloride is done inside il If the autoclave is found to be clear of vinyl chloride vapour the cleaner enters it to scrape the wall with a small hand pallet An unusual condition affecting two men employed as autt> clave cleaners in this process was first reported by Cordier it J (1966) After doing this work for several months developed symptoms resembling those of Raynaud's pbenu; menon and later a skin eruption of the hands, and in off case of the forearms, together with general asthenia aflt drowsiness. The most sinking sign, however, was the rad** logical evidence of lysis of some terminal phalanges of hands, and in one case of the feet. Most of these abnormality disappeared and the bones showed signs of healing a year * two after the men had stopped work. ] In view of that article, the hands of 588 men engaged the manufacture of polyvinyl chloride were radiographed ^ * Imperial Chemical Industries Limited, Plastics Division, t Imperial Chemical Industrie* Limited, Mood Division. ABDOOO19448 rl6 September 1967 Acro-osteolysis--Hams and Adams Bunn 'ilDICjLL JOUUiAL 711 /U April 1966 1 150 of them were autoclave cleaners Two cases ^jth x-ray changes in the fingers similar to those described by Cordier et at (1966) were found. Case 1 A 44-year-old man who had worked on die autoclave section of the plant since 1950 had an interesting history in that he was (jjjnosed as a case of scleroderma by a consultant physician and dermatologist in 1957 The diagnosis was made on clinical grounds because of Raynaud's phenomenon) accompanied by puffiness of jbe face and thickening of the skin of the hands, fingers, and left (bteann. The symptoms cannot have been very troublesome, because he had made no complaint, and the condition was noticed by his doctor only when he went to collect a prescription for bis wife On being questioned about his condition during the present jgrestigauon he still made no complaints, and it was only wuh teoccnce that he admitted that his hands often felt unduly cold examination revealed no evidence of the skin condition that had anted m 1957, and the only abnormaliues were (a) pseudo dubbing of all the fingers of both hands , this is not true clubbing, once the angle between the base of the nail and the adjacent skin ns not obliterated , and (6) the hver was palpable on inspiration Radiological Reports --" Hands Periarticular erosions are present to the proximal interphalangeal joints The proximal uiterphalangeal pint of the left little finger is disorganized There are erosions of the terminal phalanges of index and middle fingers of both hands (Special Plate, Fig 1) Feet The fifth proximal phalanges of both feet show erosions on both their distal ends The fifth proximal murphalangeal joint is disorganized on the left (Special Plate, Fig 2) Pelvis There is a widening of the joint space of the iKroiliac joint with cystic marginal sclerosis Chest Normal Skull Normal Cervical spine Normal Teeth Normal SCO Normal " Laboratory tests were earned out, and the only abnormality found vis a persistently raised serum bilirubin The most notable feature was the comparative absence of abnormal findings, apart from those shown on the x-ray film* Laboratory tescs showed nothing abnormal In July, however, he came to see one of us (W G F A) com plaining of fairly persistent pain and frequent attacks of coldness in the fingers, accompanied by pallor On examination at this time there was some tenderness of the finger-tips, more skin nodules were seen to be developing oa the dorsum of his fingers, and some thickening and coarsening of the skm of the face was noted In the course of the next week or two the pains in the fingers and metacarpophalangeal joints increased, and Raynaud's pheno menon was troublesome even in warm weather He was therefore admitted to hospital in August for further investigation The same tests as on the previous occasion were repeated, and once again the results were within normal limits, except m the case of the serum proteins In this test the serum <*2-globulin was 1 mg/100 ml (normal 0 4-0 8 mg) Hyland screening tests for rheumatoid arthritis and lupus erythematosus were normal Serum transaminase was within normal limits The E S R had fallen to 4 mm in one hour (Westergren) Blood pressure was 140/80 Skm biopsy was performed on one of the nodules on the wrist, the histological report being as follows " The full thickness of the dermis is incorporated in an interlacing acellular collagenous nodule, oedematous and partly hyaljuzed, enclosing normal sweat glands and covered by normal epidermis (Fig II) The oedematous interstices contain a fine granular and filamentous material, metachromatic with toluiduie blue, and staining faintly with alcian blue and penodic-acid Schiff, probably breaking up elastic (Fig III) Two small dermal artenes are extremely thick-walled as a result of marked medial hypertrophy and mtimal fibrous Case 2 A 30-vear-old man who had been an autoclave cleaner since 1960, hiving been self-employed as a window-cleaner before that date, recalled no previous senous illness, but had consulted his doctor si 1964 because of shortening of his finger-nails, which he thought to be due to biting them and " lack of calcium " In April 1966 he had no symptoms, but radiologically he showed evidence of acro-osteolysis Pseudoclubbmg of the fingers was found to be present (Fig I) Raised nodules in the skin, described as " Unthomatovs-like " patches, were noted round his wnscs Fre 11 --uase 2. General appearance of thickened dermal collagen-- also showing lymphocytic cuffing of small dermal blood vessel. (H and x 35) Fic 1 --Pseudoclubbmg of the fingers. Radiological Reports--"Hands' Osteolysis is present in the *efts of all the terminal phalanges of the fingers and thumb, wuh ke excepuon of the left ring finger" (Special Plate, Fig 3) faodemaUy it is of interest to note that in most of the x-ray films * these cases seen by us here and m America the ring finger is Effected.) " Sacrum Widening of the joule spaces of Uie sacro*j*c joint with cystic marginal sclerosis (Special Plate, Fig 5) C*r Normal " Fig III --Case 2 High-power view of fragmented elastic m upper dermis (Vwfcocff X 270) ABDOOO19449 714 16 September 1967 Aero-osteolysis--Hams and Adams MarwZcqZ. /TovSnJ^ thickening (Fig. IV). The appearances are similar to those desenbea hr Cordier tt al. (1966)." E*ic iv--case L. Higb-pawcs view of artery utuaied deeply wiUun the zone of thickened dermal collagen. (H. and E. X1S0) For a few months after his discharge from hospital he improved, and by the end of 1966 the Raynaud's phenomenon was less marked and the skin nodules were disappearing About this time, however, he began to develop pain in the left knee and toes AT-ray examina tion of the left knee showed a conical erosion on the postenor surface of the patella (Special Plate, Fig 4) By June 1967 he felt reasonably well, though he still complained of pain in the left knee and stiffness of the hands, particularly at the metacarpo phalangeal joints. The skin of the hands and face was practically normal. Comment No treatment was required in Case 1, and the treatment in Case 2 was directed towards relieving the symptoms, since no specific remedy is knows for the condition. Both men were removed from the job of autoclave cleaning as soon as the diagnosis was made, but it is not yet certain how this measure w31 affect the course of the illness It would appear that Case 1 went through the acute stage while still doing his normal job, and the condition has become quiescent m spite of this. Two more possible cases were found in our most recent survey One of these is a 30-year-old autoclave cleaner who has had Raynaud's phenomenon for three years, but in whom no bony changes have been found. The other man is an ex-autoclave-cleaner in whom a suspicious appearance has been noted radiologically in the right thumb, which had, however, been recently subjected to injury Discussion In view of the similarity of the findings in these men to the cases described in the paper of Cordier tt al (1966), it was thought that this condition was almost certainly linked with the men's occupation. Inquiries subsequently made in America and Europe revealed that similar cases had occurred there. In all cases the features appearing most consistently were Raynaud's phenomenon accompanied by osteolysis of the terminal phalanges of the fingers, occurring mainly m auto clave cleaners and not in those engaged in handling the finished product Many raw materials may be used in smirfl quantities a manufacturing the polymer, but the only substance comwij to all cases is probably vinyl chloride. Though every auti is washed with water and has air blown through tt at the of each reaction, small quantities of vinyl chloride may and escape when the vessel lid is opened It is also possible very small pockets of gas may be trapped beneath the polymet adhering to the inner wall, and these can be liberated dunng the subsequent cleaning process. Vinyl chloride, however, htaj been manufactured and handled m this country for over 2Qj years without apparent harm apart from accidental exposing to its well-known anaesthetic action. ^ A point of general interest is the possible relationship qA this condition to the collagen diseases One patient (Case l had, in fact, been diagnosed as a case of scleroderma on clinical grounds 10 years previously The histologist remarked on the superficial similarity of the biopsy taken in Case 2 to sclero derma, but a number of pathologists consider the appearance of the section to be unique Cordier tt al. (1966) mention an unusual skin condition seen m their cases. Suctu et al. (1963)J in a paper describing conditions produced by vinyl chloride* referred to a skin lesion resembling scleroderma, but aero* osteolysis was not mentioned. Finally, at a climcopathological conference at the Roya.ilt. Postgraduate Medical School {BJA 7,, 1966) it was stated thac bony changes were commonly found in the terminal phalanges? in scleroderma It should be made quite clear, however, thf* the many radiologists who have looked at the films of our, cases stated that they had not previously seen this particular* lesion. g It would appear from our own and other cases that this condition is probably a self-limiting disease, which m spitej of bone destruction leaves the patient with little disability- In x-ray films taken a year after the original diagnosis no* further bony changes were noted in Case l In Case 2, how-* ever, there was evidence of partial ossification of the osteolytic bands in the terminal phalanges of both hands * It is our intention to continue annual radiological examine tion of the hands of all men engaged on this work Mechanical methods of cleaning new autoclaves have been introduced, and it is hoped in due course to extend this method to older vessels and thus eliminate the human factor ( Summary f- Two cases of acro-ostcolysis occurring in men engaged in the polymerization of vinyl chlonde are described. The bones affected were the terminal phalanges of the fingers and the sacroiliac j'omts, but in one case the patella and m the otbef the phalanges of the feet were involved The condition was accompanied by Raynaud's phenomenon and skinlesions. ^ It would seem that this condition is probably a self-limiting disease. ` Vft acknowledge with gratitude the help given throughout dj# tnvesugation by Dr Thelwall Jones and other members of* medical staff of the David Lewis Northern Hospital, Liverpool* and by Dr K A Rowley and his colleagues atBlackpoolVictor# Hospital. Jj Rsfsrbncbs M Brit med. J., 1966. 1. 16*2. -5 Cordier, J M., Pievet, C, Lefevre, M. J, and Serna, A. (1966). Med. Tm., 4 3 , Suciu, I, Dretman, I, and Valaskai, M (1963) Mad. tntrrna (But.), **E 967. ABDOOO19450 Dtsch Med Wochenschr 1975 May 2,100(18) 1001-4, 1007 [Acro-osteolysis (acro-osteopathia ulcero-mutilans) in a worker exposed to vapours of synthetics (author's transl)]. [Article in German] Kind R, Hornstein OP. The neuro-cutaneo-osseous syndrome of "sporadic" acrosteolysis (ofBureauBamere), localized to the ends of the feet, has occasionally been seen in workers engaged in the polymerization of vinyl chloride, A case of the disease is descnbed in a 42-year-old worker exposed to different vapours dunng the manufacture of plastic products, but he had never worked with vinyl chloride Outstanding signs were dysproteinaemia, moderate thrombocytopenia, while symptoms of Raynaud's disease as well as scleroderma-like changes in hands and feet (typical of vinyl chloride disease) were absent The onset of the osteolytic and ulcerative process corresponded to prolonged exposure to cold on the job It is, therefore, assumed that there was concealed chronic intoxication with synthetic vapours which, m connection with cold exposure and other individual factors, may have aided in the manifestation of the disease It is possible that under certain conditions synthetics other than vinyl chloride may contribute to the occurrence of sporadic cases of acro-osteolysis PMID 1132314 [PubMed - indexed for MEDLINE] 1 ABDOOO19451 RICHARD LEWIS, MD, MPH VINYL CHLORIDE AND POLYVINYL CHLORIDE From Private Practice in Occupational Medicine Cleveland, Ohio Reprint requests to: Richard Lewis, MD, MPH Associate Research Professor Division of Occupational Toxicology University of Louisville 512 Hancock Street Room 216 Louisville, KY 40292 Polyvinyl chloride (PVC) is one of the most widely used plastic materials, second in produc tion only to polyethylene. The physical properties of PVC can be readily modified through the addi tion of plasticizers and other additives, leading to diverse applications in construction, tubing, coat ings, and packaging. The PVC industxy has main tained a position of prominence and steady growth for over 50 years--an impressive feat considering that in the mid-1970s the industry was the center of a major occupational health crisis. Today, nearly 25 years after the recognition of the unusual occurrence of hepatic angiosar coma in three workers at a Louisville PVC pro duction plant, vinyl chloride health research continues to provide insights into the causes and mechanisms of occupational cancer. Industrial processes and exposures have changed dramatically in this industry. After origi nating during the 1940s in the United States and Europe, PVC production expanded to other parts of the world. Exposures have varied based on production methods, product composition, emis sion control, and governmental regulations. Like the plastics industry in general, the PVC industry is divided into segments, each characterized by relatively distinct exposures to hazards. Appre ciation of these distinctions, along with the changes in industrial processes and controls over time, is critical to the assessment of the health risks for current and past industry workers. THE POLYVINYL CHLORIDE PRODUCTION PROCESS PVC is produced through the polymeriza tion of vinyl chloride monomer (VCM).4*62*63-91 OCCUPATIONAL MEDICINE: State of the Art Reviews-- Vol. 14, No. 4, October-Deceraber 1999. Philadelphia, Hanley & Belfus, Inc. 719 ABDOOO19452 720 LEWIS VCM production results in limited exposures because the toxicity and volatility of the compounds involved generally has required the use of enclosed systems PVC resin production is the industry segment with the highest potential exposures, partic ularly in the early years when polymerization reactions were incomplete and left significant amounts of monomer unreacted Manual cleaning of reactor vessels was also a characteristic of this segment of the industry PVC compounding involves the addition of plasticizers and other additives to the polymerized resin to alter its phys ical properties. Finally, PVC fabrication involves the production of finished goods through molding and extrusion. While each of these segments is a distinct business, companies often have per formed multiple activities at the same plant site. Monomer and resin operations typ ically were combined, particularly m the early years of the industry, resulting in a direct flow of monomer to the resin operation. Resin producers also may perform compounding, adding certain components to the PVC pnor to shipping to fabrica tors. Finally, fabricators may perform their own compounding operations to produce materials with the unique properties necessary for their finished products. Vinyl Chloride Monomer Production Vinyl chloride is a colorless gas with a faintly sweet odor and low acute toxic ity (Table 1). It was first synthesized in 1835 through the reaction of acetylene and hydrogen chloride.63 This process, involving the use of a mercury catalyst, was the primary method of production when vinyl chloride manufacturing for industrial pur poses began in the 1930s in Germany and the U.S. Production in Japan started in 1946. Since 1960, the primary methods of production have been either direct or oxychlorination of ethylene In these processes, ethylene dichloride is formed followed by cracking to produce vinyl chloride and hydrogen chloride. The finished product is transported as a liquid in pressurized tank cars. By 1976 there were 14 VCM production facilities m the U.S. with an annual production of over 3 billion Kilograms (kg).63-91 At the same time, production in Western Europe and Japan was 3.9 and 1.3 billion kg, respectively. Vinyl chloride TABLE 1. Characteristics of Vinyl Chloride Monomer CAS Number Synonyms Description Odor threshold Molecular weight Boiling point Specific gravity Vapor pressure (20 C) Explosive limits Conversion 75-01-4 Chloroethylene, chloroethcne, ethylene monochlonde Colorless gas with sweet, mild odor Approx. 3000 ppm 62.50 -13 9C(7F) 2.15 2530 mm 4-20% by volume 1 ppm equals 2 6 mg/m' CAS * Chemical abstract service, ppm = parts per million ABD00019453 Vinyl Chloride and Polyvinyl Chloride 721 currently is used almost exclusively m the production of PVC resins. Pnor to 1974, VCM saw limited use as a anesthetic, refrigerant, aerosol propellant, and intermedi ate m sulfonamide production.24 63 n Exposure control in vinyl chloride monomer plants always has been critical Chlonne and hydrochloric acid are potent respiratory irritants requiring strict mater ial containment procedures. Ethylene dichloride is also highly toxic. The finished product is highly flammable and is transferred directly from storage vessels to pres surized railcars Thus, the toxicity of intermediates, volatility of the product, and bulk handling and transfer methods all served to limit worker exposure in monomer production. In addition to low levels of exposure to fugitive emissions, VCM pro duction workers may be exposed to low concentrations of VCM when connecting and disconnecting hoses, obtaining samples, or conducting quality control analyses. While exposures are better controlled in this segment of the industry today, expo sures likely were quite limited historically, as well. Polyvinyl Chloride Resin Production Commercial synthesis of PVC resins began in 1933. Production was acceler ated in the U.S., Japan, and Germany during World War II.91 The primary method of production is suspension polymerization. Production occurs in large, stainless steel reactor vessels (termed "polys"). Using a batch process, vinyl chloride is mixed with water, a suspending agent (polyvinyl alcohol or cellulosics), and a surfactant. With addition of a catalyst (usually organic peroxide) and heat, an additional polymeriza tion reaction is initiated, after which the reaction becomes exothermic. Through cooling and agitation, PVC particles of varying sizes are suspended in the colloid as the reaction proceeds. After the reaction is completed, the unreacted VCM is re moved and recovered. The PVC slurry is centrifuged, dried, and screened, forming a powdered resin. This material may be bagged and shipped or further processed. Emulsion polymerization is similar, however, an additional emulsifying agent in which the polymer is soluble is used, resulting in a smaller particle size. Dispersion resins formed in this manner may have particle sizes ranging from 0.1 to 1 micron. Two additional methods include bulk polymerization (which does not use other liquids) and solution polymerization (using an organic solvent). By the mid-1970s there were 38 PVC production facilities in the U.S. operated by 21 companies.63 Annual U.S. capacity was approximately 2 billion kg in 1976, accounting for one-third of the world production. Western Europe production in 1976 was approximately 3.7 billion kg, with another 1 billion kg produced in Japan.91 There was substantial growth in production between 1950 and 1970, aver aging over 10% per year. After slowing in the 1970s and early 1980s, annual pro duction worldwide has continued to increase by 5-6% per year (Fig. 1). Historically, PVC production operations have resulted in the highest levels of worker exposure. In the 1940s and 1950s, VCM was considered to be relatively non toxic.23 62100 The inherent challenges of handling large volumes of a volaule gas m large-scale production were evidenced in the early years by plant explosions caused by spontaneous combustion of VCM (when concentrations exceeded 20,000-40,000 parts per million [ppm]). VCM's volatility, high odor threshold, and minimal irritant effects all likely contributed to high levels of exposure. Sources of emissions included leakage during transport or storage, charging of reactor vessels, and sampling. In addition, the poly merized PVC absorbed VCM, and the reaction slowed considerably when the con version approached 95%. Thus, the PVC resin contained significant amounts of ABDOOO19454 722 LEWIS North American PVC Production FIGURE 1. North American polyvinyl chloride production, 1940-1998. residual VCM. The trapped VCM was released primarily during the drying process, with lower amounts emitted during compounding and processing. One problem in the early years of PVC production was the accumulation of residual material on the inside of large reactor vessels (autoclaves or "polys"). Operators or helpers would enter these reactors to manually clean them. If the reac tor had not been properly exhausted, anesthetic levels of VCM could be present, causing inebriation or unconsciousness. Pockets of VCM gas also were encountered during the manual scraping of resins from reactor walls.24 Peak exposures during re actor cleaning may have routinely exceeded several thousand ppm.4*62*95 In addition, reactor cleaners may have been exposed to residual catalysts, solvents, or comonomers (e.g., vinylidiene chloride, vinyl acetate).19 Today, exposures during re actor cleaning have been eliminated by exhaust venting with VCM recapture, air testing prior to vessel entry, and the use of respiratory protection. Estimates of historical exposures suggest that VCM concentrations in PVC pro duction operations may have ranged from S00 to over 1000 ppm prior to I960.419-62'63-93-120 Peak exposures may have been much higher. In 1961 the American Conference of Governmental Industrial Hygienists (ACGIH) recommended a threshold limit value of 500 ppm based primarily on prevention of neurologic and anesthetic effects. Levels continued to drop to 100-300 ppm by the early 1970s. In 1974, after the recognition of an association between exposure and hepatic angiosar coma, the Occupational Safety and Health Administration (OSHA) set the permissi ble exposure limit for vinyl chloride at 1 ppm as a time-weighted average. Similar standards limiung both short-term and peak exposures to VCM were adopted in the mid-1970s around the world. Modem production processes maintain strict exposure control, often using continuous monitoring systems. Polyvinyl Chloride Compounding and Fabrication PVC resin may be shipped as pellets, powders, or liquid latex. All PVC under goes some form of compounding to modify its properties prior to being formed into a final product. Rigid PVC is comprised of 85-90% resin, while flexible PVC contains 40-60% resin. The compounding of the resin consists of the addition of plasticizers. ABDOOO19455 Vinyl Chloride and Polyvinyl Chloride Bottles and packaging Wire i 723 Ripe and conduit 42% Windows and doors 4% FIGURE 2. End uses of polyvinyl chloride resin. impact modifiers, stabilizers, fillers, colorants, flame retardants, and biocides. Com pounding may be performed by the resin manufacturer, the fabrication plant, or by specialty compounding companies. The compounding process consists of reheating and melting the resin, then adding additional materials during mixing. The compounded PVC resin may be sent directly to the molding process or be cooled and reformed into a secondary resin for later process ing. The majority of PVC is processed using extrusion, calendering, or injection molding (see Lewis' chapter "Health Issues in Plastics Production and Processing"). PVC is one of the most versatile plastic materials due to its blending capability with a wide range of additives (Fig. 2). The majority of PVC is used in construction primarily as pipe and conduit and as siding. These are formed by extrusion. Calendering and coating processes are used for flooring and textiles. Injection mold ing is used to produce bottles, containers, and fittings. Worker exposure to VCM always has been limited in compounding and fabrica tion. A survey by the National Institute of Occupational Safety and Health (NIOSH) in 1975 reported levels of 0.85 ppm for calender personnel, 0.16 ppm for compound ing, and 0.1 ppm for extrusion." Other hazards of fabrication include potential expo sure to asbestos, used as a filler in floor tiles and other materials in past years (generally pre-1970). Lead stabilizers also have been used in PVC production, al though the elevated exposure levels of lead toxicity are rare in the industry. Molding processes involving the heating of plastic and occasional overheating of PVC materi als may generate hydrochloric acid and other respiratory irritants. Apart from the chemical hazards of PVC fabrication, trimming of parts can result in both lacerations and upper extremity problems, particularly with rigid, durable formulations. RECOGNITION of industry hazards Acro-osteolysis The first reports of an unusual occupational condition affecting PVC production workers came out of France, England, Japan, and the U.S. in the early 1960s.*1*7109IW149 ABDOOO19456 724 LEWIS This condition was characterized by pain and clubbing of the fingers and Raynaud's phenomenon Termed acro-osteolysis, it was observed exclusively in workers who entered reactors for cleaning and used hand scrapers. Diagnostic criteria varied in clinical case reports, but generally was based on a combination of symptoms of pain or numbness of the fingers and x-ray evidence of erosion of the distal tufts of the phalanges. The condition was self-limited and usually resolved after removal from work. Clinical evaluation of the majority of these individuals failed to reveal evi dence of systemic poisoning or hepatotoxicity.30'06'49 Alteration in manual cleaning methods eliminated the condition.19 '09 While often listed as an effect of VCM exposure, acro-osteolysis is more ap propriately ascribed to PVC production. Several aspects of this condition were un usual. While PVC production began in the early 1940s, acro-osteolysis was not seen until 20 years later. The cases occurred in persons working for as little as 1 month in reactor cleaning. While it is possible that the condition could have been missed in earlier years, a more likely explanation is that it was related to some combination of vinyl chloride and other exposures. PVC production methods varied, and many fa cilities produced copolymers of VCM with vinyl acetate, vinylidiene chloride, and other materials.'9 The attack rate was low, reported at 10-15 cases per thousand workers.29 109 149 In a survey of U.S. operations only 7 of 32 plants reported any cases (defined as Raynaud's phenomenon and x-ray findings).29 The ultimate cause and significance of acro-osteolysis likely will remain un certain. There have been no new outbreaks reported since the early 1970s. Early re ports of abnormalities in collagen metabolism and immune complex formation remain intriguing, but have not been further evaluated.63'140 What is more notable is that the identification of a new occupational disease focused research on this indus try, but failed to identify the ultimate risk: the development of a rare occupational cancer. Hepatic Angiosarcoma The recognition of the association between hepatic angiosarcoma and work in PVC production is one of the classic sentinel health events in occupational medi cine history. Hepatic angiosarcoma is exceedingly rare, with an estimated annual in cidence of approximately one case per 100 million population.6*47*2 In 1971 a patient of Dr. John Creech, a Louisville surgeon, died of this condition. Creech, who also served as the facility physician at the B.F. Goodrich PVC production plant in Louisville, became aware of a second case in a plant worker in 1973. Knowing the rarity of the condition, Creech and Dr. Maurice Johnson (medical director for B.F. Goodrich) reviewed facility medical records and identified two other cases of he patic angiosarcoma in plant workers. Noting that all four workers had been involved in PVC production for 14-27 years, the angiosarcoma cluster was reported in both medical literature and lay press."-22 This report was immediately followed by reports of additional cases around the world.87 Based on the angiosarcoma experience, OSHA implemented an emergency temporary standard, lowering occupational VCM exposure to 50 ppm. This standard was followed by a final rule in 1975, which established a permissible exposure limit of 1 ppm and a short-term exposure limit (15 minutes) of 5 ppm. The OSHA Vinyl Chloride Regulation (29 CFR 1910.1017) also required annual medical examina tions and biochemical testing of liver function, with semiannual examinations for persons who had worked for over 10 years in the PVC industry (see Medical Sur veillance, page 734). ABDOOO19457 Vinyl Chloride and Polyvinyl Chloride 725 TABLE 2. Distribution of Vinyl Chloride-Exposed Workers Who Developed Hepatic Angiosarcoma, by Year of Hire* Year of Hire No ofVC*Exposed Workers With HA % of VC-Exposed Workers North America Western Europe Other Pnorto 1945 1945-49 1950-54 1955-59 1960-64 1965-69 1970 and later TOTALS 22 25 35 42 31 16 1 172 * Cases reported through 1993 VC n vinyl chloride, HA hepatic angiosarcoma 13% 15% 20% 24% 18% 9% 1% 100% 15 7 0 16 9 0 9 21 5 10 29 3 5 26 0 1 13 2 0 10 56 106 9 Shortly after the discovery of the association between VCM exposure and he patic angiosarcoma, several case registries were established.43'"6 The Worldwide Register of Cases of Angiosarcoma of the Liver (ASL Register) established in Europe in 1975 is still maintained today by physicians affiliated with the Association of Plastic Manufacturers of Europe. By 1993, the ASL Register had recorded 173 cases from 14 countries.32 The majority of the cases have come from North America and Western Europe. The majority of persons who developed hepatic angiosarcoma were hired in the early years of the industry, with nearly half hired prior to 1955 (Table 2). The North American cases appear to have been hired earlier than those reported from Western Europe. As of 1993, there was only one case reported with a year of hire after 1970. This case is also unusual in that it represents the rare occurrence of angiosarcoma in a fabrication worker involved in bag extrusion, not PVC production. To date there have been 21 cases of hepatic angiosarcoma in workers from the original Louisville plant (Fig 3), more than any other manufacturing facility. What is most striking is the continuing occurrence in the retiree population. Rather than indi cating a risk to workers entering the industry in later years, however, the Louisville ex perience demonstrates that persons who entered the industry in the pre-1960 years remain at nsk for the rest of their lives. While the latency period for patients diagnosed prior to 1975 is 12-28 years, those diagnosed subsequently have shown a latency of 27-47 years. This suggests that exposures in the early years of the industry resulted in some form of damage that is a permanent precursor to malignant degeneration.1*^6*-129 Another notable aspect of this disease is that the risk of developing hepatic an giosarcoma was not evenly distributed among PVC production operations.32-4' Of the 33 VC/PVC plants that were in operation in the U.S. prior to 1965, only 14 (42%) have reported cases (Table 3). There appears to be a strong clustering of cases, with a few facilities accounting for the majority. In North America, four plants (including the original Louisville plant) account for over 80% of the reported cases. A similar, although less pronounced, clustering is seen in Europe. At present, the basis of this Finding is unknown. It may be related to absolute VCM exposure levels, hut it also could be due to combined exposures for cofactors. PVC production may have involved addition of various catalysts and modifiers. In addition, facilities may have produced PVC copolymers with vinylidiene chloride, vinyl acetate, or other materials.19-3661 One observation at Louisville was the possible association of ABDOOO19458 ABDOOO19459 Vinyl Chloride and Polyvinyl Chloride 727 TABLE 3. Clustenng of Angiosarcoma Cases North America Western Europe VC/PVC Plants Operating Pre*1970 48 44 Plants Reporung Angiosarcoma Cases 14 (29%) 23 (52%) No of Plants No of Cases No of Plants No, of Cases Plants Reporting > 10 Cases Plants Reporting 3-10Cases Planus Reporting 1-2 Cases Total Angiosarcoma Cases 3 40 (70%) 4 57 (54%) 6(tl%) 7 32 (30%) 10 11 (19%) 12 17 (16%) 57 (100%) 106(100%) angiosarcoma with diethyl maleate, a chemical that depletes hepatic glutathione.18-36 The clustenng phenomenon and risk based on year of hire both suggest that factors in addition to VCM exposure intensity may be important in the pathophysiology of this condition. Clinical Aspects of Hepatic Angiosarcoma The clinical presentation of hepatic angiosarcoma has been variable and nonspecific.9-27-36 44-59-73'73-84 Right upper quadrant pain is common, and cases may be di agnosed during a workup for gall bladder disease. Fatigue, nausea, and weight loss are reported frequently, as might be expected with a rapidly progressive hepatic ma lignancy. This disease should be suspected in persons who have worked in PVC pro duction prior to 1970, particularly those who performed reactor cleaning. In addition to VCM exposure, other risk factors for the development of hepatic angiosarcoma include exposure to Thorotrast (thorium dioxide, a radiocontrast agent used in the 1930s and 1940s),*0-63 arsenic (both Fowler's solution and arsenical pesticides),38 an abolic steroids,39 and dioxin.90 Clinical signs include hepatosplenomegaly and right upper quadrant tender ness. Jaundice and ascites may be present in advanced cases. Laboratory evaluation usually reveals minimal elevations of GGPT, alkaline phosphatase, bilirubin, and transaminases in relation to the extent of disease.21-3*39*60,73*871261127 Many of the initial cases diagnosed in the 1970s presented with more significant evidence of liver dis ease, including portal hypertension and esophageal varices.10-84*17-103 These have been uncommon in the cases diagnosed in later years and may reflect differences in expo sure intensity and underlying histopathology. More recently there have been reports of a marked increase in von Willebrand factor in persons with hepatic angiosar coma, a significant observation based on the endothelial origin of the tumor.48 Filling defects may be evident on liver spleen scans and blood-filled cystic le sions on ultrasound or by arteriography.1301*3147 CT scans and nuclear magnetic res onance imaging are useful in establishing a diagnosis.4573146 Imaging studies should be pursued prior to needle biopsy due to the risk of hemorrhage with this multifocal lesion. Open biopsy often is necessary to establish the histologic diagnosis. Hepatic angiosarcoma is a tumor arising in the endothelial cells of liver sinusoids.,'-J6-,,w i< 128114 \u histologic diagnosis of hepatic angiosarcoma may be difficult. The tumor is usually multicentric at the time of presentation, with numerous areas of normal liver tissue replaced by hemorrhage and necrosis. There is envelop ment of hepatic cords by neoplastic sinusoidal lining cells with irregular nuclei and elongated cytoplasm (Fig. 4). The sinusoidal spaces are dilated, and in early lesions ABDOOO1946CJ FIGURE 4. Hepatic angiosarcoma (courtesy of C. Tamburro, M.D.). there is reactive fibrosis. Hepatocytes are initially spared, but later show reactive hy pertrophy. Ultimately, large regions of the liver are replaced by cystic hemorrhagic spaces. The tumor cells stain positively for factor VHI-related antigen on immunoflu orescence103--further support for the endothelial origin of the malignancy.46 The early cases also were characterized by subcapsular fibrosis, with rice like lesions apparent on gross examination.64 87*134 Microscopically, there was pro liferation of atypical sinusoidal lining cells and periportal fibrosis (Fig. 5). These FIGURE 5. Perisinusoidal fibrosis in areas of liver not infiltrated by hepatic angiosarcoma (courtesy of C. Tamburro, M D.). ABDOOO19461 Vinyl Chloride and Polyvinyl Chloride 729 lesions also have been observed m persons without angiosarcoma.*2* Whether these represent precursor lesions or are a necessary factor in malignant degenera tion is unknown The localization of the liver injury to the sinusoidal region accounts for many of the clinical characteristics of this disease. The diffuse fibrosis involving the sinu soidal spaces causes liver enlargement, blockage of flow through the portal vein, and portal hypertension. Within the liver parenchyma, however, there is only limited damage to the hepatocytes. Thus, cases present primarily with gastrointestinal bleed ing or liver and spleen enlargement, not signs of liver failure. The lack of direct in volvement of the liver cells explains why routine liver enzyme testing has not been useful in detecting either fibrosis or angiosarcoma until the condition is far ad vanced. While the malignancy may metastasize, local spread, hemorrhage, and he patic compromise are the primary causes of death.73-* Prognosis has been poor. Most patients die less than a year after diagnosis, many within weeks to months of presentation. One patient from the Louisville plant was apparently cured after wedge resection. A second patient survived for 6 years after receiving several cycles of chemotherapy (doxorubicin and cyclophos phamide).13 Recunence after resection and liver transplantation also has been re ported.94 At present, resection of an early lesion confined to a single lobe of the liver appears to be the only treatment with a reasonable chance of extended survival or cure. Because of the rarity of the condition and sporadic nature of occurrence, clini cal treatment protocols have not been adequately developed or studied. Molecular Mechanisms of Carcinogenicity The basis for the development of hepatic angiosarcoma in PVC production workers is unclear. One possibility is that when VCM exposures are very high, metabolic pathways of detoxification in hepatocytes are overwhelmed, resulting in presentation of reactive metabolites to adjacent sinusoidal cells.'2* At lower levels of exposure, vinyl chloride is metabolized by alcohol dehydrogenase to monochloroacetic acid, which is then excreted in the urine.119 At higher exposure levels, vinyl chloride is metabolized by the cytochrome P450 system to the electrophilic metabolites chloroethylene oxide (CEO) and chloroacetaldehyde (CAA).,UI29 These reactive compounds are detoxified through interaction with glutathione to form thiodoglycolic acid (Fig. 6). Impaired detoxification due to excessive expo sure or depletion of glutathione results in the reactive metabolites covalently bind ing to macromolecules, including bases on nucleic acids. At the molecular level, a combination of high peak exposures or exposures to other substances (such as to vinyl acetate, vinylidiene chloride, or diethyl maleate) may explain the clustering phenomenon described previously. Studies of workers with current and past exposure to vinyl chloride have iden tified increased rates of nonspecific genetic alterations, including chromosomal aberrations, micronuclei, and sister chromatid exchange frequencies.50-31-95 The re active vinyl chloride metabolites CEO and CAA have been shown to form DNA adducts in both animal studies and in vitro systems.42-55121 The etheno adducts are persistent and may result in point mutations in cellular oncogenenes and tumor sup pressor genes. Workers with hepatic angiosarcoma have been shown to have A:T to T.A missense mutations of the p53 tumor suppressor gene that can be detected through measurement of antibodies in serum.61"2136 Exposed workers also have been shown to have point mutations of the c-Ki-ros oncogene, detected through measurement of an abnormal p21 protein.13-28 49X1 This is caused by a GOAT transition ABDOOO19462 730 LEWIS vinyl chloride H\ /H NC=C H-^ '''Cl alcohol dahydroganasa H\ Cytochrome P450 * /H monochloroecetic add I excreted n x--C I ^ 01 spontaneous II CH2CI O chloroethylene oxide V^ ^ chioroecetaldehyde scavenged by eutfhydryl groups/glutathtone covalent binding to macromolecules FIGURE 6. Metabolism of vinyl chloride. in the second nucleotide of codon 13 (Fig. 7). While these findings hold promise in understanding the underlying cellular pathophysiology of this chemically-induced malignancy, it is still uncertain whether these are markers of exposure, susceptibil ity, or disease. vinyl chloride ntitMtruttt F1ffiSiP7i\ 1.N6 -ethenodeoxyadenosine pttgaiw codon 179 codon 249 codon 255 p53 protoin arginine to tryptophan FIGURE 7, Proposed mechanism of vinyl chloride-induced p53 mutation resulting in abnormal p53 protein. ABDOOO19463 Vinyl Chloride and Polyvinyl Chloride 731 Respiratory Disease Several investigations have suggested that exposure to PVC dust may cause a decrease in lung capacity, airway obstruction, and chest x-ray changes, and crossshift drops in lung volumes.*'"-71'*1-92'94'115 PVC dust exposure may occur in drying, mixing, and bagging operations. Particle size varies depending on the polymeriza tion method and form of the final product. Dispersion resin particles are very fine and fall into the respiratory (< 1 micron) range. Suspension polymerization produces resin particles that are slightly larger, but this process still may result in exposure to respirable dust. In addition to exposure to PVC, compounding operations can in volve exposure to plasticizers and other additives. In pre-1975 production opera tions, workers also may have experienced relatively high levels of exposure to VCM. Finally, PVC operations may result in over-heating of the resin, releasing hydrochlo ric acid or other respiratory irritants. Initial animal studies had considered PVC dust to be inert Subsequent studies of relatively high exposure levels have demonstrated some evidence of a mild fibrotic process with granuloma formation.1 There are several case reports describing evidence of pulmonary fibrosis in persons who have been exposed to PVC. Pneumoconiosis was described in a 53-year-old man with 23 years of exposure to PVC dust.3 Biopsy revealed diffuse areas of fibrosis with small focal lesions. Lung function was only mildly reduced, and there was no evidence of impairment in gasexchange. Several epidemiologic studies have been conducted on workers exposed to PVC dust. The findings in the positive studies in many respects parallel the case report described above. When detected, chest x-ray evidence of pulmonary fibrosis has been subtle."-94-'15 While the incidence is low, die abnormalities seem to occur in persons with longer exposure histories. Changes in lung function have been slight and generally not associated with respiratory impairment Several cross-sectional studies have failed to find any evidence of respiratory disease in workers exposed to VCM or PVC dust.17*52-96-97 Overall, the risk of respiratory disease in workers ex posed to PVC dust appears to be low, particularly in current compounding opera tions. Interpretation of historical reports requires consideration of exposures to additives or thermal degradation products, in addition to PVC dust Other Health Effects Reported in PVC Production There are several other historical reports of findings in PVC production work ers. In 1949, a Russian study reported evidence of hepatitis, anemia, and gastritis in PVC compounders exposed to chlorinated naphthalenes used as plasticizers.87 Since the chlorinated naphthalenes are potent hepatotoxins, the relationship of this early study to the general VCM/PVC experience is uncertain. Several early reports from Germany and Eastern Europe described a condition termed "vinyl chloride disease."120-137 This was characterized by hepatosplenomegaly, thrombocytopenia, musculoskeletal symptoms, and a variety of other find ings. The exact cause of this syndrome is also uncertain. In some of these studies, exposure levels were such that narcosis from over-exposure to vinyl chloride was common. In addition, potential exposure to other materials, such as ethylene dichtoride, vinylidiene chloride, and other chlorinated solvents, may have contributed to the findings. Several anecdotal reports have associated vinyl chloride exposure with sclero derma and other connective tissue diseases.99119 Central and peripheral nervous system effects were reported in workers with high levels of exposure.71*97-*01 ABDOOO19464 732 LEWIS Angiosarcomas of other tissues, including the finger and mandible, have been re ported.-6 UH Vinyl chloride is an animal teratogen.67 Early reports of possible birth defects in communities surrounding PVC plants were not substantiated in later studies.107117 EXPERIMENTAL STUDIES Animal studies conducted in the 1930s identified that exposures at 200,000-400,000 ppm were lethal.'00 Hyperemia of lungs, liver, and kidneys were seen on necropsy. Followup studies in 1961 on multiple species with exposures at 50-500 ppm daily for several months revealed only subtle findings of increased liver weight and granu lar degeneration,76^ Based on these studies, the recommended exposure level of 500 ppm for vinyl chloride was based primarily on prevention of central nervous system narcosis.107 Experiments on the toxicity of vinyl chloride were renewed in the late 1960s following the identification of acro-osteolysis in workers, an unusual degeneration of bones in the hands. In a 1971 study,131 rats were exposed to 30,000 ppm for 4 hours per day for 12 months in an attempt to reproduce acro-osteolysis. In addition to demonstrating alterations in hepatocytes and centrilobular necrosis, tumors were identified in lung and bone tissue. Subsequent investigations have demonstrated dose-related excesses of hepatic angiosarcoma in rats at 30,000-50,000 ppm.85,86 The experiments also showed an excess of zymbal gland tumors, along with ex cesses of neuroblastomas and nephroblastomas. EPIDEMIOLOGIC INVESTIGATIONS OF THE POLYVINYL CHLORIDE INDUSTRY Immediately after the recognition of the association between vinyl chloride ex posure and hepatic angiosarcoma, several epidemiologic investigations were under taken. A large cohort of over 10,000 workers from 17 U.S. facilities were assembled in 1974, and mortality has been evaluated in four sequential studies.3-20-124150 Several other large cohort mortality studies have been reported from Europe and around the world (Table 4).I347-70,721IU13,33*,43 The most consistent Ending has been the excess of digestive system cancers, due to marked increase in mortality from hepatic angiosarcoma. While the exact rates for hepatic angiosarcoma are not available, the magnitude of the excess is stag gering when compared with other occupational cancers. From die plant population in Louisville (2500 workers) there have been 23 cases of hepatic angiosarcoma over the past 35 years. The expected rate is 1 per 100 million per year. Thus, the esti mated standard mortality rate for this population exceeds 25.000!637 Because of the rarity of hepatic angiosarcoma, many mortality studies have used "best evidence** to distinguish cases horn those of primary liver cancer. In the most recent update of the U.S. cohort, 17 of 47 deaths (36%) classified as liver cancer on the death certificate were found to actually be cases of hepatic angiosar coma.2 In the European study, 16 of 17 cases in which tissue was available were found to be angiosarcomas based on histologic review.111 This diagnostic uncertainty has confounded efforts to determine whether vinyl chloride exposure also presents a risk of primary liver cancer.12-31 After removal of the hepatic angiosarcoma cases, slight excesses of liver cancer remain in some of the cohort studies. Several case re ports have identified primary liver cancer in conjunction with histologic evidence of vinyl chloride-induced fibrosis in heavily exposed workers.35,110 Morbidity from liver disease also may be increased, although confounding by hepatitis B and alcohol ABDOOO19465 Vinyl Chloride and Polyvinyl Chloride srn oo oe Sss *Swi rN*> ^" r^- r--SO3(r^S~ n3P* co *'r> m^ n eOsoS Qsc&oC o 8. I eC 2 cro I wf** X 2 2 M* r<sM fi KK 22 22 (O CO S2 2 fn> fO wC-lf3S mcs m oco ^ v> ts * -* rn S * 2 CO m i in 5 9>i}\- ur>-> ^M~ d^_$ 2523 CO CO CO SO p*: co is *n SSg'g 2 * I oc I fS I II I i i wo r r* *"i.J25 2t2O?':^992P> 2O&' 8* aSS iHpi 5< jS fl t" in a -- I u> N. p! * * 733 ABDOOO19466 734 LEWIS may be important.3*'*129 At present, however, it appears that if vinyl chloride does cause primary liver cancer, the attnbutable risk is small. A possible brain cancer excess in vinyl chloride-exposed workers has been reported in several studies, and this association often is listed in reviews of the sub ject. A recent investigation has revealed that the brain cancer excesses reported in U.S. vinyl chloride studies have been related to a cluster at a single facility 77.w.i4t.u2.,5i Detailed exposure evaluation at that facility by multiple investigators, however, has failed to reveal any relationship between the brain cancers and vinyl chlonde exposure. In two other studies reporting an increase in brain cancer, one featured only two cases and inadequate latency (1 year),'5*3' and the other had no cases of hepatic angiosarcoma.113 Vinyl chloride exposure and PVC production do not appear to place workers at risk for other cancers.7-31 The large cohort studies have consistently failed to demon strate any risk of lung cancer. One study found an excess of suggested that this was associated with PVC dust exposure, but a second study using different methods found no relationship.I4M51 One Italian study of PVC fabricators reported an excess mortality from lung cancer.116 A Swedish study also reported excess lung cancer morbidity in PVC fabricators, although the population also was exposed to asbestos (used as a filler in floor tile).57 There are reports of possible relationships between vinyl chloride exposure and other cancers, including lymphosarcoma2-131 and malignant melanoma.117 Given the large number of studies conducted and the number of cancers evaluated, these iso lated reports of associations should be interpreted cautiously. MEDICAL SURVEILLANCE In the U.S., OSHA requires annual medical surveillance for all workers ex posed to vinyl chloride monomer in excess of 0.5 ppm as a time-weighted average (without regard to use of respiratory protection). This is required semi-annually for all persons employed in vinyl chloride or polyvinyl chloride manufacturing for over 10 years (Thble 5). The medical surveillance experience at the Louisville facility is typical of what has been seen in the industry in general. After the recognition of the angiosarcoma case, a medical screening program was initiated at the Louisville plant that included biochemical testing, ultrasonography, arteriography, and liver biopsies.21 Evaluation of over 1000 workers led to approximately 100 liver biopsies and resulted in the identification of two additional cases of hepatic angiosarcoma (Fig. 8). TABLE 5. Required Medical Surveillance Under the OSHA Vinyl Chloride Standard* Type of Exposure Frequency Examination Content VCM exposure 8 hr TWA in excess of 05 ppm Annual Employed in VCM or PVC Semi-annual production for over 10 years Medical history pertaining to liver disease (alcohol, blood transfusions, hepatitis, medications) Physical examination of lungs, liver, kidneys, and skin Blood tests: bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase Optional: Lung function, chest x-ray, urinalysis, additional blood work, liver scans __ * 29 CFR 1910.1017 TWA * time-weighted average ABDOOO19467 Vinyl Chloride and Polyvinyl Chloride Ch.mlrtry panel 1,187 workers Abnormal 41 Borderline 315 Repeat chemistry panel 315 735 Liver-spleen scan 116 Abnormal 75 Arteriography/Blopsy 7 2 CASES OF HEPATIC ANGIOSARCOMA FIGURE & Results of mass screening of PVC production workers in 1975 after the initial discovery of hepatic angiosarcoma. (From Creech J, Makk L: Liver disease among vinyl chloride production workers. Ann NY Acad Sci 246-88-94,1975; with permission.) After two years, the program was altered to be in compliance with the OSHA testing requirements. However, the program has failed to detect any of the subse quent cases of hepatic angiosarcoma. This is related in part to the lade of sensitivity and specificity of liver enzyme testing.126127 Persons with significant tumor burdens may only have minimal enzyme elevations. At the same time, borderline elevations are common in persons due to alcohol use, medications, and other, nonspecific fac tors. Another problem has been the occurrence of disease in retirees who no longer participate in the program. For the most part, cases present as described previously, with abdonunal pain, weight loss, and fatigue. Other methods may be more valuable in detecting disease and/or risk. Both bile acids and clearance studies have been associated with evidence of chemically-in duced liver toxicity.80118 These findings correspond to the periportal fibrosis seen on biopsies. What is uncertain is whether fibrosis represents a precursor lesion for tumor development and whether it is persistent or reversible. Other investigators have reported elevation of von Willebrand factor (factor VIII) in persons with he patic angiosarcoma.49 The levels correlated with tumor progression and may be valu able in both early diagnosis and tracking tumor progression. In general, workers with low levels of exposure to vinyl chloride show no abnormalities on diagnostic testing.121 SUMMARY Polyvinyl chloride remains an important plastic resin. Exposures to vinyl chlo ride monomer, and possibly other materials, during the early years of production led ABDOOO19468 736 LEWIS to the development of hepatic angiosarcoma in workers at facilities throughout the world. Several other syndromes, including acro-osteolysis, were associated with PVC production, but less clearly with vinyl chloride. Continuing research on the cel lular mechanisms of this well-established occupational carcinogen may provide valuable insight into the pathogenesis of this disease in general. Continuing study of PVC production workers also may help to establish a threshold for the development of this rare malignancy. REFERENCES 1. Agarwal DK, Kiw JL, Srivista SP, Seth PK` Some biochemical and histopathological changes in duced by polyvinyl chloride dust in rat lung. Environ Research 16:333-341,1978. 2. Amaud A, Plommier DeSanti P, Garbe L, et al. Polyvinyl chloride pneumoconiosis. Thorax 33.19-25,1978. 3. Applied Epidemiology, Inc: Epidemiologic study of men employed in the vinyl chloride industry between 1942 and 1972.1 Re-analysis of mortality through December 31,1982. II. 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