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R&S 116924 V(t tififin 49. Vinyl Chloride and The notification made by the B. F. Goodrich Com pany in early 1974 of the occurrence of several Polyvinyl Chloride cases of hepatic angiosarcoma among its polyvinyl chloride (PVC) polymerization workers set off a ififi HENRY FALK rapid chain of events that had a dramatic impact on the field of occupational health. First, vinyl chloride monomer (VCM), the starting material ill in the production of PVC resins, to which tens of thousands of workers had been exposed in recent decades, was transferred from a relatively innocu ous industrial substance to a carcinogen producing a fatal malignancy. Second, epidemiologic data and animal experimental evidence for the carcinogenicity of VCM appeared almost simulta fill neously, providing definitive results that quickly brought about sharply lower occupational stan dards and changed industrial and environmental practices in many countries. Third, because of the |v many consumer uses of VCM and vinyl plastics, concern spread beyond the traditional confines of fr* occupational health to the general public Several excellent articles and conference proceedings discuss tn^multiple facets of disease induced by vinyl chloride [5, 26, 48, 57, 67, 74], `t. i *, This chapter focuses primarily on the epidemiologic findings. and ,>`f\" PVC POLYMERIZATION About 2.5 billion kg/yr of VCM (HjC^CHQ) is produced in the United States, most of it for production of PVC resins. PVC is used primarily in building and construction (particularly PVC pipe, electrical wire and cable, and flooring), home furnishings, recreational products (e.g., rec ords and toys), packaging (e.g., film, sheet, and bottles), apparel, and transportation materials (e.g,, automobile tops, upholstery, and mats), be sides a variety of other products, including medi cal tubing [48], The PVC industry, begun in the United States in the early 1940s, consists of three separate pro cesses. The first step is vinyl chloride monomer production, usually by direct chlorination or oxychlorination of ethylene. This is done in a closed system, although leaks or breaks in the process may lead to transiently high exposure levels. In the United States, ten companies (15 plants) were engaged in this process in 1976; several thousand Trade names are used in this chapter for identification only; this use does not constitute endorsement by the Public Health Service or by the U.S. Department of Health and Human Services, 579 II. Environmental and Occupational Exposures 580 R&S 116925 U.S. workers have been employed in this phase of the industry. The second step is polyvinyl chloride polymerization, in which gaseous VCM (boiling point, --13.5C) is liquefied under pressure in large polymerization reactors or vessels (of ca pacities ranging from several thousand gallons to as much as 35,000 gallons) and chemically reacts to form PVC polymer [26]. The polymerization reaction can be carried out in several different ways--suspension, emulsion, bulk, or solution polymerization--to produce polymer or copolymer particles of differing size and quality [48], In 1976 there were 22 companies (39 plants) that polymerized PVC in the United States; tens of thousands of U.S. workers have been employed in this phase of the industry. The highest exposures to VCM occur in these plants, particularly be cause of the need to open and clean reactor ves sels between reactions, a process that allows resid ual unreacted monomer to escape from the vessel (at one time, workers were lowered into reaction vessels to clean them manually, and undoubtedly they were exposed to peak VCM exposure levels of several thousand ppm--a practice that was phased out in the late 1960s and 1970s after the identification of acroosteolysis in VCM-exposed workers). The third step, PVC compounding and fabricating, involves compounding PVC resins with a variety of substances, such as pigments, plasticizers, fillers, antistatic agents, and stabilizers, and then making them into the various products. Many more fabricating workers are employed than polymerization workers, but VCM exposures have been considerably lower, arising principally from retained unreacted monomer (levels of which have been considerably reduced in recent years). VCM-INDUCED HEALTH EFFECTS Two very uncommon diseases, acroosteolysis (AOL) and hepatic angiosarcoma (IFAD)1, we clearly linked to work in PVC polymerization plants. HAS actually represents the end stage of a hepatic fibrotic precursor lesion (described in detail be low). The earliest references in the literature to liver disease or findings suggestive of AOL in VCM-exposed workers date from 1949 and have been summarized [40, 57, 67]. The liver findings in these early reports were described as "hepatitislike changes," hepatomegaly, and abnormalities on liver function tests. Detailed descriptions of AOL appeared in 1966 and 1967, and during the early 1970s the characteristic liver disease and its patho genesis were described by Lange et al. and by Marsteiler et al. in Germany as well as by Creech and co-workers and Popper and Thomas in the United States. Acroosteolysis. In 1967 Harris and Adams de scribed two cases of AOL in Britain [32]. The main findings included symptoms of Raynaud's phenomenon, osteolysis in the terminal phalanges of some of the fingers, and thickening of the skin or raised nodules on the hands and forearm. One case included puffiness of the face and was ini tially interpreted as scleroderma. The lytic lesions of the terminal phalanges of the fingers led to an appearance of pseudoclubbing; additional findings suggestive of a systemic effect included lytic le sions of the phalanges of the feet, cortical erosion in the patella, and widening and marginal sclerosis of the sacroiliac joint. In 1967 Wilson et al, described 31 cases of AOL (less than 3 percent of the polymerization workers) in a U.S. company [78], They observed the same primary triad of Raynaud's phenome non, scleroderma-like lesions on hands and fore arms, and lytic lesions of the terminal phalanges of the fingers; systemic manifestations, such as ra diographic abnormalities in the feet, were not seen. AOL was subdivided into a mild stage (loss of cortex of one or more tufts of the distal pha langes), an advanced stage (more severe lytic de struction, with complete loss of the tuft and a por tion of the shaft of the distal phalanx), and a healing stage (fragmentation of the tuft or shaft and subsequent bony or fibrous union) (Figs. 1 and 2). AOL was observed to occur primarily in workers who cleaned reactors, leading to restric tion of manual activity of some workers, although the process also spontaneously improved in others. An epidemiologic study of 5,011 U.S. employ ees reported in 1971 identified 25 definite and 16 possible cases of AOL [16]. Of the 25 patients, 24 had Raynaud's phenomenon, and all 25 pa tients had cleaned reactors at some point, leading to the conclusion that manual cleaning of reactors was important in causation [13]. Recent reports have continued to point to some systemic changes in skin, bones, and sacroiliac joint [17, 25, 30, 37, 45]. Vascular changes in the digital arteries of the hand associated with AOL, including narrowing of the lumen and partial or total occlusion, have been demonstrated.by arteri ography [38]. In immunologic studies of workers with vinyl chloride disease, some of whom had evidence of Raynaud's phenomenon or AOL, FIGURE 49-1. Hand x-ray of long-term polyvinyl chloride polymerization worker with marked acroosteoiysis, November 1964. (Courtesy of Dr. John Creech, B. F. Goodrich Company, Louisville, Ken tucky. ) Ward et al. identified a number of abnormalities, including evidence of circulating immune com plexes and their deposition in vessels [70]. The hypothesis that these immunologic changes may be related to the pathogenesis of AOL and to other aspects of VCM-induced disease needs fur ther study. A puzzling aspect is that AOL was not de scribed in detail until the 1960s. Unlike HAS, which has a prolonged latency period of approxi mately 20 years, AOL can have a very short la tency period of 1 to 2 years and thus should have occurred in the 1940s and 1950s. Either the disase was missed during those years or it did not Jccur because of unidentified factors that are yet to be explained. (One author suggested that AOL first occurred after the introduction of vinyl chlo ride-vinyl acetate copolymers [48]. Unfortunately, such exposure information is lacking in virtually all published reports of AOL). Liver Disease. In studies carried out during the 1960s in Rumania, Sudu et al. described hepato megaly in vinyl chloride workers (reversible in some after cessation of VCM exposure), which was often associated with abnormalities of liver function tests [60]. The spectrum of VCM-induced liver disease began to emerge from studies of PVC polymerization workers in Germany, starting in 1972. Lange et al. described workers with he patic fibrosis, splenomegaly, and thrombocytope nia--all suggestive of portal hypertension--in the absence of significant hepatic parenchymal dam age [38]. In a subsequent report, 81 percent of 70 w-orkers studied were noted to have thrombocyto penia, 67 percent had increased Bromsulphalein (BSP) retention, and 57 percent had splenomeg aly; 14 percent had increased serum enzyme lev els, indicating hepatic damage [66]. Pathology studies demonstrated activation of hepatic sinu soidal cells and hepatic (particularly perisinusoidal) fibrosis, with lesser changes in hepatocytcs II. Environmental and Occupational Exposures 582 r *> f[ * O f* R&S 116927 FIGURE 49-2. Follow-up hand x-ray of same worker as in Figure 49-1 almost 10 years after cessation of polymerization work, April 1974. (Courtesy of Dr. John Creech, B. F. Goodrich Company, Louisville, Kentucky.) [27]; fibrosis of the liver capsule was clearly vi sualized at laparoscopy [46]. In 1974 Creech and Johnson first reported hepatic angiosarcoma following VCM exposure when theyr described three cases among PVC poly merization workers at the B. F. Goodrich plant in Louisville, Kentucky [14]. Subsequent detailed studies at that plant identified additional cases of HAS and cases of nonmalignant hepatic disease, consisting primarily of hepatic fibrosis, portal hy pertension, and splenomegaly [20], Study of pa thology specimens from VCM-exposed workers at various stages of liver disease and of serial biop sies in a number of workers who ultimately de veloped HAS enabled Popper et al. to establish the morphologic progression and pathogenesis of HAS, which are similar to those seen in idiopathic HAS and HAS resulting from other causative agents [54, 55, 64]. The earliest findings in the precursor stage are areas of combined hyperplasia of hepatocytes and sinusoidal cells associated with an excess of reticulin and with sinusoidal dilation. The latter changes can progress to hepatic fibrosis, portal hyperten sion [6], and occasionally peliosis hepatis; the hy perplastic sinusoidal ceils become increasingly atypical and eventually undergo malignant trans formation in the development of HAS (Figs. 3 and 4). Hepatocellular injury is not a feature of the early stages of this sequence, although it does appear in the later stages. Therefore, the hepatic disease caused by VCM is quite distinct from that caused by most previously identified hepatotoxins [53]. An increased frequenq' of abnormalities of standard liver function tests, particularly in VCMexposed workers with clinical findings compatible with VCM-related hepatic disease, has been re ported in a number of studies [40, 60, 66]. As can be seen from the above discussion, however, liver function abnormalities are a relatively late finding, and a number of cross-sectional studies of actively employed PVC polymerization workers f `.f C_ r fc FIGI plasi cells. 100> SchO' York have 79]. mg : tests indue pie a repea As a funct ommt Th velop staces noted tectin tests : nogra R&S 116928 1_^r'rV;,,3H P St*"*'1 >%.. -, #< 49. Vinyl Chloride and Polyvinyl Chloride 583 MS |i!iS [ i <, t < - ``"f'T i i||iS|f MS * iihjrtif umm Sill FIGURE 49-3. Circumscribed nodule, showing hyper plasia and hypertrophy of hepatocytes and sinusoidal cells, in a vinyl chloride worker. Hematoxylin eosin, 100X- (Courtesy of Dr. Hans Popper, Mount Sinai School of Medicine of the Citv University of New York.) FIGURE 49-4. Trabecular angiosarcoma in a vinyl chloride worker. Note cords of hyperplastic hepato cytes, sometimes surrounding bile plugs. These cords are surrounded by layers of angiosarcoma cells. The sinusoidal spaces are dilated. Hematoxylin eosin, 60X. (Courtesy of Dt. Hans Popper, Mount Sinai School of Medicine of the City University of New have not detected increased abnormalities [72, York.) 79]. Nevertheless, when incorporated into ongo ing medical surveillance, standard liver function 77]. The degree of reversibility of the hepatic tests have been valuable in identifying VCM- fibrotic precursor lesion has not been determined induced hepatic disease, particularly when multi [4], but withdrawal from exposure is prudent, in ple abnormalities or prolonged abnormalities on the hope of preventing progression. Survival after repeated examination have been observed [42]. HAS is diagnosed has been estimated to average As a result, periodic screening with standard liver only several months. Dannaher et al. recently re function tests has been included in NIOSH rec ported on the use of chemotherapy in cases of ommendations and U.S. regulations [65]. VCM-associated HAS to improve the duration There is a generally perceived need for the de and quality' of survival [15]. velopment of reliable screening tests for the early stages of VCM-induced hepatic disease, Tamburro Tilis et al, reported a chronic et al. utilized hepatic clearance of indocyanine decrease in pulmonary function in PVC polymer en as a sensitive indicator of liver function and ization workers exposed to VCM and PVC dust ed the value of radioisotopic liver scans in de [39]. Gamble et al. found no evidence of a chronic tecting early anatomic lesions [62, 76]. Other decrease, but they' did demonstrate acute loss of tests under evaluation include gray-scale ultraso pulmonary function during the course of a single nography and hi vivo capillary microscopy [44, workshift [25]. A recent report from England de- jig m R&S 116929 II. Environmental and Occupational Exposures 584 scribes some deterioration of lung function, slight abnormalities of the chest radiograph, and com plaints of slight dyspnea associated -with exposure to PVC dust [58]. Cases of pneumoconiosis induced by PVC resin also have been reported, and a report from Italy described 20 cases of PVC pneumoconiosis in. workers exposed to PVC dust [2, 47]. By ultrastructural evaluation of lung biopsy material, Arnaud et al. demonstrated PVC particles in pul monary macrophages and giant cells [2]. The respective roles of retained VCM, PVC dust, and PVC additives such as plasticizers in the develop ment of these pulmonary changes need to be clari fied. An increased risk of lung cancer in PVC poly merization workers has also been reported (see below). Since 1975 there have been a number of reports of increased frequencies of chromosomal aberra tions in cytogenetic studies of peripheral lympho cytes from VCM-exposed workers. Subsequent negative reports have presented apparently con flicting results and difficulties in reconciling these findings, although the various methodologies, par ticularly with regard to level of VCM exposure and choice of control groups, have not always been comparable [23, 52], It has been suggested that positive results are related primarily to the elevated VCM exposures occurring before 1973; two re ports have demonstrated the disappearance of cyto genetic abnormalities in groups of workers fol lowed periodically since 1975 [1, 31]. In any event, it is uncertain how to interpret these cyto genetic findings in terms of health risk to individ ual workers. Also, potential confounding factors in the industrial setting demand consideration in greater detail. As part of a cross-sectional medical screening of PVC polymerization workers, Infante et al. noted increased reporting of fetal loss by wives of VCMexposed workers [35], A number of methodologic issues have been raised concerning that report, and, clearly, data on spontaneous abortions ob tained directly from the workers' wives would have been preferable. High rates of congenital anom alies of the central nervous system have been re ported in communities with PVC polymerization plants [33]; subsequent case control studies have not been able to confirm that the excess defects are related to VCM exposure [18]. Nevertheless, an ever-expanding literature on the mutagenic effects of VCM in microbial and mammalian test systems raises concern about possible genetic or reproduc tive effects, although teratogenicity (production of major congenital anomalies) has not been iden tified in animal systems [67]. OTHER EFFECTS A number of other findings, including hyperten sive changes and symptoms such as headaches and fatigue (possibly related to the anesthetic effect of high dose exposures), have been reported [38, 40, 60, 72]. EPIDEMIOLOGY OF HEPATIC ANGIOSARCOMA Two reports from NIOSH, in 1975 and 1978, summarized the worldwide distribution of known VCM-related cases of HAS [41, 59]. The great majority of such cases have occurred in PVC poly, merization workers; 64 such cases had been identi fied to NIOSH as of October 1977. At that time 23 cases had been identified in the United States 10 in Canada, 9 in the Federal Republic of Ger many, 8 in France, and the remainder from Bel gium, Czechoslovakia, Great Britain, Italy, Japan, Norway, Sweden, and Yugoslavia. For those 64 cases, the latency period (i.e., the time from first exposure to diagnosis) ranged from 9 to 38 years, with a median of 21 years; the length of exposure ranged from 4 to 31 years, with a median of 18 years; and the age at diagnosis ranged from 37 to 71 years, with a median of 49 years. The ma jority of cases were diagnosed after 1973. The most recent tabulation of cases worldwide documents 98 cases of VCM-related HAS, pre dominantly in PVC polymerization workers (per sonal communication, John Stafford, ICI Petro chemicals and Plastics Division, Welwyn Garden City, England). The years of peak occurrence were 1975 through 1978 (9-11 cases per year), al though the reporting may not be complete for_the most recent years. The patient with the most re cent date of first exposure began work in 1966. Cases of HAS have been reported in individuals exposed to lesser concentrations of VCM than PVC polymerization workers--for example, PVC fabricating workers or individuals residing near PVC plants [3, 9, 19, 4l]--but, because of the relatively large numbers of individuals potentially exposec ologic s tions, I: initially and rela number associate periods of VO any shir In ns States ( (1963--: cally co: merizati States; ; o^fcp Studies c tumors, to VCM hort moi zation v malignar 49, 50, t ties in c included (so that studies h cancer o of death; and later culty in VCM, F merizatic in the pre An int jority of weiler er cancer [" onstrated marily in subtype ( or c^uc to H sure^J was seen plant, wi rather the cancer an Therefore of the al 49. Vinyl Chloride and Polyvinyl Chloride 585 exposed at these lower levels, additional epidemi to distinguish between exposures to VCM and ologic studies are needed to evaluate these associa tions, In a study of Thorotrast-induced HAS, the PVC in the analyses, to discover whether the trends of excess cancer risk noted above continue initially reported cases had high-dose exposures and are confirmed. and relatively short latency periods, while a larger number of cases that appeared later had exposures associated with lower doses but prolonged latency periods [22], Thus it is important to follow trends of VCM-related cases of HAS in the future for any shifts in epidemiologic patterns. In nationwide reviews of HAS in the United States (1964-1974) and the United Kingdom EXPERIMENTAL STUDIES In 1971 Viola et al. first demonstrated the carcino genicity of VCM in rats exposed to 30,000 ppm for 12 months [69]- Hepatocarcinogenicity, par ticularly HAS, was reported later in a series of experiments by Maltoni [43] and reproduced in (1963-1977), from 6 to 7 percent of pathologi cally confirmed cases occurred among PVC poly merization workers (12 of 168 in the United other laboratories [67], VCM has been reported to produce HAS at doses as low as 25 ppm in rats, and a variety of tumors, including Zymbal gland States; 2 of 33 in the United Kingdom) [3, 21]. carcinomas, nephroblastomas, nonhepatic angio sarcomas, and skin, brain, lung, and mammary tu mors, have been produced in multiple species (in OCCUPATIONAL MORTALITY STUDIES cluding rats, mice, and hamsters) [43]. Hepato Studies on animals have identified a multiplicity of cellular carcinomas also have been observed after >, in addition to HAS, following exposure exposure of newborns to VCM. Maltoni's data CM (see below). As a result, a series of co suggest an increase in mammary tumors at doses rnoraliry studies, primarily of PVC polymeri as low as one ppm [43]. zation workers, have evaluated the risk for all It appears that a metabolite of vinyl chloride, malignant neoplasms in these groups [10, 12, 24, rather than VCM itself, is the ultimate carcino 49, 50, 61, 63, 75], Some of the primary difficul genic substance. In bacterial and other test systems, ties in conducting and interpreting these studies the mutagenicity of VCM is greatly increased by included the relative youth of the PVC industry the addition of a metabolizing system (e.g., rat (so that most of the workers in the various cohort studies have not passed through the age of peak cancer occurrence), the relatively small numbers of deaths among workers with prolonged exposure and latency in some of the studies, and the diffi culty in precisely quantifying past exposure to liver microsomes), and an evaluation of animal carcinogenicity data suggested a closer link of HAS formation with amount of VCM metabolized than with VCM exposure concentration [7, 28]. Al though a number of mutagenic metabolites are formed, the reactive epoxide (chloroethylene ox VCM, PVC, and other chemicals used in the poly ide) formed during the oxidative metabolism of merization processes, such as other monomers used the VCM double bond appears of greatest concern. in the production of copolymers. The short-lived active metabolites are formed in An increased risk of HAS was seen in the ma the hepatocytes but are carcinogenic in the adjacent jority of studies [12, 24, 49, 61, 63, 75]. Wax- sinusoidal cells, which, unlike the hepatocytes, weiier et al. noted an increased risk of respiratory appear to have limited ability for detoxification cancer [74], Detailed follow-up investigation dem [51, 56]. The reactive mctabolite(s) are thought onstrated that the excess lung cancer risk was pri to initiate the carcinogenic process by covalent marily in the large-cell undifferentiated histologic bonding to hepatic macromolecules, including subtype (not previously related to either smoking DNA [71]. or chemical exposure) and was related most closely The evidence for the carcinogenicity of vinyl to PVC dust exposure rather than to VCM expo chloride has raised considerable concern about the sure [74], An increased risk of respiratory cancer safety of a number of structurally related halogen- was seen also by Buffier et al. at a VCM production ated hydrocarbons [11]. Studies on animals indi mt, where exposure would have been to VCM cate the probable hepatocarcinogenicity of vinyli- her than to PVC resin [10]. Increases in brain cancer and lymphatic tumors have been noted [75]. Therefore, it is imperative to continue follow-up dene chloride [68] and vinyl bromide [8], and epidemiologic studies on humans (although of questionable quality) have raised concern about of the already identified and studied cohorts and the carcinogenicity of chloroprcne [36]. Reviewing II. Environmental and Occupational Exposures 586 the available data on the carcinogenicity of se lected halogenated hydrocarbons. Infante and Marlow have stressed the paucity of available epi demiologic data to evaluate this question in hu mans, in spite of the demonstrated animal carcino genicity for a number of these compounds [34]. OCCUPATIONAL STANDARDS In the United States, the Occupational Safety and Health Administration (OSHA) requires that a worker's exposure to VCM not exceed one ppm (8-hour time-weighted average). The ceiling con centration limit for 15 minutes or less is 5 ppm [65]. In general, European VCM exposure stan dards, except those of the Scandinavian countries, are set somewhat higher than in the United States [29, 67], REFERENCES 1. Anderson, D,, Richardson, C. R., Weight, T. M., et aL Chromosomal analyses in vinyl chloride exposed workers: Results from analysis 18 and 42 months after an initial sampling. Mutat. Res. 79:151, 1980. 2. Arnaud, A., Pommier DeSanti, P., Garbe, L., et al. Polyvinyl chloride pneumoconiosis. Thorax 33:19, 19^8. 3. Baxter, P. J., Anthony, P. P., MacSween, R. N, M., et al. Angiosarcoma of the liver: An nual occurrence and aetiology in Great Britain. Br. J. Ind. Med. 37:213, 1980. 4. Berk, P. D., Martin, J. F., and Waggoner, J. G. Persistence of vinyl chloride-induced liver injury after cessation of exposure. Ann. N.Y. Acad. Sci. 246:70, 1975. 3. Berk, P, D., Martin, J. F., Young, R. S., et al. Vinyl chloride-associated liver disease. Ann, Intern. Med. 84:717, 1976. 6. Blendis, L. M,, Smith, P. M., Lawrie, B. W., et al. 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M., Taylor, K. J. W., et al. Monitoring liver disorders in vinyl chloride monomer workers using greyscale ultrasonography. Br. J. Ind. Med. 33:132, 1976. 78. Wilson, R. H., McCormick, W. E., Tatum, C. F., et aL Occupational acroosteolysis. J.A.M.A. 201: 577, 1967. 79. Wyatt, R. H,, Kotchen, J. M., Hochstrasser, D. L, et al. An epidemiologic study of blood screening tests and illness histones among chemi cal workers involved in the manufacture of poly vinyl chloride. Ann. N.Y. Acad. Sci. 246:80, 1975. Environmental and Occupational Medicine EDITOR William N. Rom, M.D., M.P.H. Associate Professor, Division of Respiratory, Critical Care and Occupational (Pulmonary) Medicine. Department of Internal Medicine; Chief. Division of Occupational and Environmental Health. Department of Family and Community Medicine; Director, Rocky Mountain Center for Occupational and Environmental Health. University of Utah School of Medicine, Salt Lake City, Utah ASSISTANT EDITORS Atiilio D. Renzetti, Jr., M.D. Professor and Chief, Division of Respiratory. Critical Care and Occupational (Pulmonary) Medicine, Department of Internal Medicine. University of Utah School of Medicine, Salt Lake City, Utah Jeffrey S. Lee, M.P.H., Ph.D. Assistant Professor, Division of Occupational and Environmental Health, Department of Family and Community Medicine; Director, Industrial Hygiene, Rocky Mountain Center for Occupational and Environmental Health, Uni~ versity of Utah School of Medicine, Salt Lake City, Utah Victor E. Archer, M.D. Clinical Professor, Division of Occupational and Environmental Health, Department of Family and Community Medicine, Rocky Mountain Center for Occupational and Environmental Health, University of Utah'School of Medicine, Salt Lake City, Utah Foreword by Irving J. Selikoff, M.D. Director. Environmental Sciences Laboratory, Mount Sinai School of Medicine of the City University of New York, New York Little, Brown and Company, Boston Iff}-