Document vVQXvBr4Nxq4nVww83KozVE28

VC TAMBURRO, C. - HEALTH EFFECTS OF VINYL CHLORIDE 1978 UCC 041607 1 A A, . 'A.; [r. HEALTH EFFECTS OF VINYL C'lLORIDE Carlo H. Tamburro, M.D. University of Louiavllle, School of Medicine, Digestive Diseases and Nutrition Section, 511 South Floyd Street, Room 535, MDR Building, Louisville, Kentucky 40201 INTRODUCTION Vinvl Chloride-Associated Inlurv In Man Vinyl chloride (CH. > CH-C1 snnochloroethylonc, a gas) has been the basic molecule or monomer of polyvinyl chloride and its co-polymers and has been one of the most Important organic intermediates in the plastics In dustry for over a quarter of a century. During this time, evidence for both chemical toxLcity and carcinogenicity has been accumulated in man and in animals. Reports from across the world have indicated the pre sence Of thrombocytopenia, reticulocytosls, and leukopenia among the hematological disorders. Scleroderma type skin lesions, acro-osteolysls of the distal phalanges, and Raynaud's phenomenon have been well de scribed. Abnormalities in pulmonary functional capability and cardiac arrythmlas associated with its use as'an anesthetic have also beennoted. The most widelyknowndlsorders Include hepatic fibrosis, peliosls hepatis, hepatomegaly, splenomegaly, portal hypertension, and hepatic angiosarcoma (1). There is at present some epidemiological and histo logical data that large clear cell carcinoma of the lung and neuro blastoma of the brain are also associated with exposure to vinyl chlo ride. Vinyl Chloride-Associated Injury In Animals Many of these lesions have also been described and shown to develop is animals exposed to vinyl chloride. In addition to the liver angiosar comas and the brain neuroblastomas, vinyi chloride-exposed rate and mice have shown Zymbal gland (sweat gland) carcinomas, nephroblastomas, subcutaneous angiomas, skin carcinomas, end a variety of adenomas of tht breast, pituitary glands, and other assorted arcomes of the ovary, pul monary, and uterus. A simple summary of cancers by site in vinyL chloride workers in our cohort who had worked more than one year is shown in Table I. This research Is supported by Contract No. NOl-CN-55212 from the National Cancer InstiLute, Cancer Control Branch. -Lpx3j__leports on Biolony and Medicine, Vol . 37 i 978 UPDATE OF fIF.U V \. Histologic . Die hepatic le . exposure to vi the earliest f i.. sinusoidal Unit. Diose morpholoc i usually associ ; necrosis. The ; xiibcapsular fi' : causes the liv'/lowed at Inpar" with increased y shape on the r ; tien into iho "tfivcd, vi'a ; eposition, as tend to be hoi:-' i.ited with ini paces. 11* ad. lobular at'hit. testing act i.ve Popper has desi : of two or three and regenerntii i. -.ive exposure t ii'-pia of the iui nl sinuroic.'' .r.insformatior. it is not clear oil, fibrohlasi malignant . tiongly sugge-t Vromes malign.";' "'cded to vi-rii1 *. Blochem i eg 1 ; *1 chemical deu-traditional l- hi alanine and .' nspep:id isj 11 . roc t) , i a i isocitr.c . 11 u-itio.i ;nd i, '* <t s to pi <-d i i 1 ' v.o is a I h. - - ii ne an i mi t i " 11 ly as t-rfo - ties oi i ho vi i.-nco nl hop -1 h itasc -:osi - ucc 041608 f 126 Health Effect* of Vinyl Chloride?/Tamburro 127 | UPDATE OF NEW MEDICAL FINDINGS PLATED TO VIWYI. CHLORIDE j A. Histological Sequences of Injury: (festive Diseases and 515, MDR Building, a gas) has been the basic ts co-polymers and has fates in the plastics in- thls' time, evidence for been accumulated in man have indicated the pre leukopenia among the lesions, acro-ostcolysls 'n have been well decapability and cardiac etle have also been noted, fibrosis, pcliosis ortenslon, and hepatic lomiological and histo ric lung and ncuroK<osure to vinyl chlo- - The hepatic lesions in the humans and in animals related to prolonged exposure to vinyl chloride have bean fairly well characterized. One of ' the earliest findings if "activation" or morphological changas in Che sinusoidal lining cells without evidence of hepatocellular toxicity. These morphological changes in the sinusoidal lining cells are not usually associated with an inflammatory process or evidences of localized ' necrosis. The more advanced lesions are associated with an increase in I subcapsular fibrosis with subcapsular bile duct proliferation, which causes the liver surface to appear "pitted" with small white scars when viewed at laparotomy or by peritoneoscopy. These lesions are associaced vlth increased portal fibrosis of vsrylng degree moat often rounded In hape on the cut surface and only rarely showing short stellate radia tion into the parenchyma. The lobular architecture, in general, is preatrved, with the central vein areas being devoid of excessive collagen deposition, as illustrated in Figure 1. The sinusoidal lining cells tend to be helmet shaped, have triangular nuclei and appear to ba asse| dated with increased deposition of collagen in adjacent sinusoidal j ipaces. In addition, there is a focal sinusoidal dilatation within the , lobular architecture often associated with bl-nuclear hepatocytes, supf testing active regeneration of the hepatocytes. More recently. Dr. Hans 7 Popper has described focal areas of hepatocytlc hyperplasia consisting ` ef two or three cell thick plates, not associated with lobular fibrosis * and regeneration as seen in alcoholic and viral injuries. With pregrosv five exposure to vinyl chloride, there appears to develop Increasing ; stypla of the sinusoidal lining cells, progressive worsening of the * focal sinusoidal dilatation (Figure 2), and ultimately, the malignant j transformation of the sinusoidal lining cells (Figure 3). At present, i It Is not clear which of the sinusoidal lining ccLls (macrophago/Kupffor 1 cell, flbroblast/Ito cell, or the sinusoidal endothelial lining cell) is tbe malignant stem cell which develops angiosarcoma. Most present data I strongly suggests that it is the endothelial lining cell which ultimately ! becomes malignant and forms the angiosarcoma. Further studies will be j needed to verify this thesis. ind shown to develop in to the liver angiosar`de-exposed rats and nomas, nephroblastomas, 'rlety of adenomas of the -comas of the ovary, pul- r-ride workers in our vn in Table 1. N-55212 from the ! I. Biochemical Detection; i i (lochemical detection of these lesions has until recently, been mainly j by traditional biochemical hepatocellular studies. These have included * the alanine and aspartic aminotransferases (SCPT-SCOT), gamma glutamyl tnnspeptldase (GCTP), alkaline phosphatase, bilirubin (both direct and indirect), and other enzymatic studies, such as sorbital dehydrogenase j-id isocitric dehydrogenase. As illustrated in Figure 4, our preliminary i.-aluation indicated that the ability of these traditional biochemical :c*ts to predict the presence of underlying histological hepatocellular image is at best 80-85% accurate -- the most effective of which is the ilanlnc. aminotransferase (SCPT). The gamma gluLamnl crjnspeptidasc is finally as effective but has a 6-8X false positivity; that is, ahnor entitles of the GCTP levels persist without histological or functional cadence of hepatocellular injury. Although elevations in alkaline fiophatase most often reflected the more serious abnormal i ty, in almost Health Effect* of Vinyl Chlcride/Taaburro ia Health Effects one quarter of the Individuals, It we* found to be normal In the presence ` workers is sti of hepatocellular Injury. | Radlolsotf More recently! the introduction of indocyanine green (ICC) , an anionic dye similar in it* physiological capabilities to Bromsulphaleln (BSP), ! The ability o' has increased our ability to identify mild and latent underlying chemical j lesions, basce hepatocellular Injury. Indocyanine green can be given in various dose ; ings that, of levels for purposes of determining hepatic clearance. At the low dose, ; radioisotopic? 0.5 mg/kg, Its predictability is equal to that of the aminotransferase*. ; normal cases, By increasing the clearance dose to levels of 2.5 and/or 5.0 mg/kg, on* revealed the u can increase the ability to identify underlying hepatocellular injury to that in the 9." the 9S-99Z range. A definitive biostatlatlcal evaluation of both the . In only 32 ca-- specificity and sensitivity of Indocyanine green, in comparison to the (16/19) and a traditional biochemical studies, is now underway. rate (32/957) ? sequent years Figure 5 illustrates the correlation found during preliminary studies between liver histology and dye clearance among vinyl chloride worker* with increasing degrees of total vinyl'chloride exposure. This Is further supported by the frequency of abnormal dye clearances at both the low 0.5 mg/kg and the high 5.0 mg/kg clearance dose among vinyl chloride exposed workers (2). Although these taste are very sensitive , initial baseli i scan, either ? of idcntifyl'v } positivity, t' j value and elf' scan as a sc r* to identifying underlying disease, they have very poor specificity in identifying the causel agent and, because of this, are suited a* screen* ) F. Associate' ing tools rather than diagnostic ones. An snlargement Various Tumor Types: (greater than laparotomy in Hepatic angiosarcoma, although appearing to he of a single cell origin, may be of multiple cell origins. Morphologically it occurs in a cellu lar, cavernous, and molld form. The cavernous and the solid tumor font are most effectively detected by radioisotopic liver scans. In addition, diagnostic angiographic charactaristlcs differentiate angiosarcoma from primary hepatocellular carcinomas, adenomas, cavernous hemangiomas, focal nodular hyperplasia, and macronodulnr regeneration of cirrhosis. Whelan et al., have described the characteristic angiography and radio nuclide changes that are characteristic of hepatic angiosarcoeu (3). The tumors exhibit central hypovascularity with puddling and are surrounded by a peripheral stain which persists late into the venous phase of the angiographic study. Radioisotoplcally this form of a tumor presents with a negative peripheral defect which, on occasion, may be missed on the anterior view of a scan but is seen on the lateral or posterior view. As demonstrated by Whelan et al., healing hepatic in farcts secondary to wedged hepatic venography can create a fa] se positive lesion on angiography similar to that seen In angiosarcomas. angiosarcoma lesion. As i! and wedged he; some dispariti had no evidcn< hepatic vein circular lesi staining charartery to por; The use of 99'glves further eight play a the individuu' take of 99mTc This may be d' number of act. further delin. Ken-Tumor Vascular Lesions: A 'second lesion often seen in the non-tumor-vis portions of the liver is th.it of poliosis hopntis; it has boon cMensivelv described by I'llskin (6). These lesions tend to be numerous, involving the entire liver and have a diffuse stain throughout the nodules. The stain does persist into the late venous phase and may not be associated with any radioiso topic abnormalities of the liver scan. Whether these findings represent a pre-enrolnogcnic or pre-angiosarcoma tons lesion in vinyl chloride The medic.. 1 : unusual lung ' abnormal i ty i' which, on his- md fibrosis, w, rk force m." pollutants, i 128 Italth Effaces of Vinyl Chlorlde/Tamburro 129 | writers Is still under study, to ba normal In the presence lnr green (ICG), an anionic m tu, Bromsulphalein (BSP), ml latent underlying chemical in be given in various dose Iterance. At the low dose, iat of the aminotransferases, if 2.5 and/or 5.0 mg/kg, one :lng hepatocellular Injury to il evaluation of both the :reen, in comparison to the rvay. iurlng preliminary studies -ong vinyl chloride workers Ide exposure. This Is il dye clearances at both trance dose among vinyl o tests are very sensitive very poor specificity in this, are suited as screen* j I. Radioisotopic Detection: : The ability of 99Tc sulfur colloid liver scan to detect anatomical 1 lesions, based on the best medical diagnosis, is supported by the find; Ings that, of the 19 cases with anatomical lesions, only three were > radlolsotopically reported as normal. In one of the three reported f sormal cases, subsequent radioisotopic scans done three months later ; (tvealed the underlying abnormalities. What is equally Important is j that In the 957 "normal" individuals, the scan was reported as abnormal * tn only 32 casas. These data, therefore, illuatrate an 84Z sensitivity j (16/19) and a 97Z specificity (925/976), with only a 3Z false positive ( rate (32/957). This falsa positiva rate was markedly reduced in subj itquent years when repeated radioisotopic scans could be compared to i Initial baseline ones. It Is our present opinion that the radioisotopic | scan, either camera or rectolinear, represents the most effective means J af Identifying early anatomical lesions with the least degree of false ^ foiltivlty, thus preventing unneceasary diagnostic evaluation. The ^ nlue and effectiveness of ultrasound versus' the radiological isotopic lean as a screening procedure is under study. f. Associated Spleen Disorders; f la enlargement of the spleen, as determined by radioisotopic scans 't of a single cell origin, ally it occurs in a celluis and the solid cumor forrs c liver scans. In addition, rentiate angiosarcoma from cavernous hemangiomas, .generation of cirrhosis, lie angiography and radioistic angiosarcoma (3). :h puddling and are is late Into the venous ically this form of a luei't ich, on occasion, may be seen on the lateral or al.. healing hepatic incan create a false positive angiosarcomas. f (greater than 14 cm in longitudinal length) and verified by autopsy or laparotomy in 12 cases, has been seen in 60Z of the individuals with -. angiosarcoma and 40Z of those individuals with the peliosis hepetis t Union. As illustrated in Figure 6 the correlation between spleen size and wedged hepatic vein pressure among vinyl chloride workers illustrated i none disparities. At least 10-12Z of those individuals with splenomegaly | kad no evidence of an elevated portal pressure as reflected by wedged hepttic vein pressure. In addition, angiographic studies demonstrated * circular lesions In the spleen (lienel peliosis) which had persistent staining characteristics and were associated with a shortened celiac ' artery to portal vein circulation time and increased spleen scan size. ; Ih* use of 99raTc sulfur colloid clearance by both the liver and spleen gives further suggestive evidence that apleen macrophage cell activity * eight play a role in the splenomegaly and/or the vascular findings. In _ ih* individuals with llenal peliosis, there is a steep rise In the upj take of 99mTc aulfur colloid by the spleen after initial recirculation. This may be due to either increaied blood flow and/or increased total | mnber of activated macrophegic cells. Studies are now under way to further delineate these leelona. C. lung Findings: -.rtiens of the liver la c'.v described by iMiskln - Ini the entire liver and Tie stain does persist tinted with any radioiso- r these findings represent lrn in vinyl chloride I The medical surveillance program has also illustrated the presence or on unusual lung finding among this cohort of vinyl chloride workers. The . knormality is characterized by a mid zonal lateral pleural thickening, idileh, on hlstolcglcal examination, thus far has simply illustrated fat ; Wd fibrosis. The importance of this finding in approximately 4Z of the rk force may be non-occupational but regional, i.e., other environmental pollutants. Infections, etc. These lesions do not appear to be r (! ;; \* f , ; f \r I A . Wr it . 41 Health Effacta of Vinyl Chlorido/Tamburro IX `hsalth Effects of associated with any pulmonary Functional disorders; and their signifi cance and relationship to smoking, tuberculosis,, asbestosis, fungal in fection or possible geographic non-occupational environmental pollutant* are under study. There is, however, preliminary epidemiological and histological data that strongly suggests an increase in the frequency of lung cancer among vinyl chloride industrial workers. Falk and associates have been study ing the incidence of large clear cell carcinoma occurring among vinyl chloride polymerization workers, which appears to be higher than one would expect to find in the general population matched for age, rece, and sex. Preliminary studies using regional histologically matched lung cancer patients as controls lndicata that the occurrence of this partic ular cell type does not appear to ba a geographic phenomena. Analysis is now undtrway to determina if there exists a correlation between this particular histological cell type and the work exposure history of this cohort population. Tha correlation, if any, between our pleural finding* and this cellular type of lung cancer has yet to be determined. .i METAB0L1C/PATH0CF.KES7S UPDATE OK VINYL CHL0R1 l)Ji Our present knowledge .of the metabolism and pathogenic mechanism by which vinyl chloride induces hepatic lesions may best be sunmarized by TableII. At concentrations of less than 50 ppm, vinyl chloride appears to be metabolized by the alcohol dehydrogenase system. At levels in the range of 200 ppm, oxidation appears to occur by the peroxidase - catalase system. With higher levels, the mixed function oxidase system appears to be the major route of oxidation of vinyl chloride into its metabolic intermediates: chloroethyiene oxide spontaneously rearranges to form chloroacetaldehyde, which it then further oxidized to monochloroecetlc acid or converted to chloroethanol. Honochlornacetlc acid is not seen in urine samples at low doses and may be only formed with higher ex posures of vinyl chloride. Chloroethanol and cliloroacetaldehyde are most likely detoxified via the glutathione-cvstelne conjugation system. This system, however, is saturable; and at higher levels, vinyl ehlorid* is excreted via the lungs unchanged (5). Elmore e aU, utilizing a modified Ames system and pure synthesized vinyl chloride intermediate* have shown that vinyl chlorldt, chloroethanol and chloroacetic add art not mutagenic in their biological systems (6). This strongly supports the hypothesis that vinyl chlorldt monomer is neither heps to toxic nor carcinogenic until it has been metabolized to its intermediate forms by the liver and/or other tissues. However, chloroacetaldehyde and chloroethylene oxide were definitely found to be piutagenlc, producing recom bination DNA defects in bactsria. These findings present difficulty in explain in.', why the hepatoryte, as the primary metabolic site for vinyl chloride, docs not undergo any significant evidence of hepatotoxicitv nor ra'ignant transformation. The adjacent sinusoidal lining cells must either metabolize th vinyl chloride in a similar manner but have a less iffectjvc detoxification of the-metabolite or receive from the hepatoc-, te the Intermediate sietnbolites, such as chloroethanol, which it mnv then convert to chloroacetaldehydo without being able to detoxify or further oxidize this mutagen. Although the hepotocyte is the prinary site for vinyl chloride octabolism, its r net aboil tes may > formation. Primary hepatocel exposure re vinyI port this concept animals exposed ttuurs. Mlcrosom. NADPH cytochrome Tlutathione and r rsrkcrs were also biochemical studi ini.no transferase. trnase, total prt 137 hours of exp.. Irial or the mirt was nn increase . .ant decrease In faII.wed with no Hies.' bi-'clteml. a ' discernible rh.-in- This decrease in exposure are verin rapidly Hovel demonstrated a ... *n increase in ' fullowed by an i pyrophosphate .it production of A' M the terminal leant changes i. up to 250 hours Itloride expose: hepatocellular ; in adaptation c for purposes of nlignant tram, sivcd or de i o> i i "Idal lining malile to detoxi i,-vcloping 0NA i -indies hav" f,. irlous sinus, i ; .' ii Ley to ini' -.Hiate meL , . ! , `x'nstr.ite.. nn . . :. s versus ' i r iher ver if t.1 a tivity (b is*-.! *.. the hep.ito. rm t m Hftf5 I .* r Vi*T t \ IT** ''it? -* * * t. 1 Ns*i d ^-.5 -r . Isn vK-; ucc 041612 130 | Italth Effects of Vinyl Chlorlde/Tanburro 131 >rs; ind their signifi, asbettosis, fungal in' environmental pollutants i setabolism, its capacity to detoxify the vinyl chloride intermediate I sttabolites may be the major reason it does not undergo malignant trans| formation. ind histological data ncy of lung cancer among 'delates have been studyoccurring among vinyl o be higher than one -suited for age, race, Itologlcally matched lung currenee of this partic le phenomena. Analysis orrelation between this -xposure history of this *veen our pleural findings - be determined. mgenic mechanism by which be summarized bylihlcll. loridc appears to In At levels in the range Toxldase - catalase oxidase system appears ride into its metabolic ;ly rearranges to form ed to monochloroacotlc cetic acid is not teen need with higher a>loroaeotaldchyde .ue inp conjugation system, r levels, vinyl chloride et l., util izinr, a 1 chloride intermediates, <d chloroacetlc acid art Ibis strongly supports i tiicr hepatotoxic nor r intermediate forms by i-etaldehyde and chloroentc, producing rccoci- j Primary hepatocellular biochemical alterationa observed during prolonged I tzposure to vinyl chloride in Che ret may add further evidence to supi port this concept. Subcellular enzymes and metabolites were studied in taloals exposed to 10-20,000 ppm of vinyl chloride ranging from 14-137 i hours. Microsomal, mitochondrial, and cytosol enzymes, including p450, SADFH cytochrome reductase and mixed function oxidase, were studied, t Glutathione and glutathione reductase as oxidative and detoxification | tarkers were also determined, in addition to the conventional clinical I biochemical studies, which included aspartate (SGOT) and alanine (SGPT) ' lalnotransferase, alkaline phosphatase, bilirubin, lactic acid dahydro| ftnase, total protein, albumin, cholesterol and triglycerides. After j 137 hours of exposure, no significant changes occurred in the mitochon] drlal or the microsomal enzymes nor in the glutathione content. There | vm an Increase in the glutathione reducta<o at 30 hours and a slgnifij tint decrease in glucose-6-phosphataae (C-6-P3 after 71 hours of exposure, I followed with an increase in glucose-6-phosphate dehydrogenase (G-f-PD). * These biochemical findings occurred without evidence of histologically j discernible changes in the conventional biochemical studies. | This decrease in G-6-I* and increase in G-6-PD after "simulated" chronic exposure are very similar changes to those found by Weber and Lee (7) - in rapidly developing primary hepatocellular tumora. Their studies loeanstrated a decrease in gluconeogeneais with a reduction in G-6-P and ; n Increase in G-6-PD and transaldolase. These biochemical changes were { followed by an increase in purine biosynthesis (increased phosphorlbosy 1- ;~rophosphate aminotransferase - PRPP) and eventually an increase in the production of ATP and GTP, leading to increased nucleic acid synthesis. it the termination of our experiment (at 37 hours), there were no signif icant changes in PRPP; but studies are now underway exposing animals to , tp to 250 hours to determine if the hepatic enzyme biochemistry in vinyl 1 chloride exposure is similar to that seen in rapidly dividing primary hepatocellular tumors. It may well be that these findings may represent ar, adaptation of the hepatocyte, with increasing nucleic acid synthesis t;r purposes of repair, and may make these cells more susceptible to v.llgnant transformation if the carcinogenic agent Is unable to be re, wed or detoxified with sufficient efficiency. In contrast, the sinut'ldal lining cells may well be able to oxidize these metabolites but i -able to detoxify them effectively and therefore be more susceptible to developing DNA injury. the hor.itorvt''. m ' uudt rzo an1 it t r^-.' forr it i. .. -ctabnl i zo Llie \ i .'.`l t i vc iic t o :< t f if it i "ii `.'n" intermedia tv ; elf* p rentert to chlort-- tirrhcr oxidize lln:: -ice for vinyl ciilerii!.1 '..idles hive begun in our laboratory to isolate bepatocytes and the .rleu* sinusoidal lining cells and deter-.inc the individual cell types' 'illty-c.' both oxidize vinyl chloride, as well as detoxify its intcr".M.ite metabolites. These studies, only recent lv begun, have already tiaenstraied unusual differences between the enzyme activity of hepatoutea versus mesenchymal cells. Our preliminary studies, which require -'erther verification, failed to demonstrate mixed function oxidase tllvity (based on micromoles per minute per million cells) in contrast *.u the hepatocytes. Further purification of the mesenchymal cells and Health Effects of Vinyl Chloride/Tamburro 13 Zenith Effects of * i verification of their cellular type oust be doni- before any definitive ulmals and in hu conclusions can be drawn from these preliminary- observations. They do, i however, suggest that metabolic differences of the various cell types I The ii^ottance of may play an important role in the ability of cells to oxidize and/or chloride is furti, detoxify potential carcinogens. **, et al., (9>' indi ievelop a four-fi- ;J Pathogenesis via Human Case Studiesi :ra*t, the adult The co-factor role of such agents as alcohol in the pathogenesis of vinyl . tevlew of Prospec chloride carcinogenesis may be suggested by a naturally paired tvo-cas* | It is highly unli' study. Case A - Employee began to work in vinyl chloride polymerization plant in 1947 as a chemical operator. He worked In the polymerization process for 18 years, and estimated exposure during this time ranges fror 50-10,000 ppm of vinyl chloride. He had a history of extensive alcohol consumption and was discharged from employment because of this in 1968. In 1962 he had the first clinical abnormalities related to liver injury, and these were identified histologically as being alcohol Induced in 1964. Ills alcohol consumption was greater than 512 cc per day. Case I - This individual was also employed in the same polymerization plant and began working at the same time and at the same Jobs and from 1947 until Case A was discharged 18 years lster. Case B continued to work in poly merization plant process for an additional ten years at expoaure ranges of 50-10,000 ppm. ; the chemical cart 1 experiments or hr characterizing tl . tan help direct However, me tabo 1 < further studied metabolites arc formation, the it I illustrated in a scan* of prevent { ; Although vinyl c! In 1974 during the medical surveillance program's initial phase. Case 1 was Identified as having persistent biochemical abnormalities which were clinically and histologically shown to be due to vinyl chloride injury and a developing cellular type of angiosarcoma. His alcohol consumption had been less than 50 cc par day. He did, however, have a history of malaria during his military servics prior to vinyl chloride expoaurs and was transiently HB^Ag positive in 1974. | almost identical i tlon of animal mi rather than the tlnue to gather : to determine the sent the effect! grama, which arc , In time of cris! Histologically, Case B was verified as having angiosarcoma. During the same year. Case A was shown to have evidences of both alcoholic injury with cirrhosis and the characteristic lesions of vinyl chloride Injury, including subcapsular fibrosis with bile duct proliferation, peliosls system has been , in collaboration lery Workers Uni l International A- hepatis, sinusoidal cell activation, focal sinusoidal dilatation and This prospectiv. areas of rounded portal fibrosis. Histologically, the hcpstocytes showed dustrial environ atypical change consistent with hepatocellular carcinoma and the sinu carcinogenic: soidal lining cell changes characteristic of angiosarcomatous tissue. not yet studied In these two case studies, in which the duration and degree of exposure was as Identical as one could expect in human biological system, we have Individuals developing tumors of two different cell types. It is sug gested from these findings that alcohol played a significant mle in tH carcinogenic: or materials suly carcinogenic known to be can hepatocyte's inability to detoxify the vinyl chloride metaboliros, ti i:-.-by causing DNA injury and ultimately leading to the development ol primary hepatocellular carcinoma. be basic cpid. ..itegorLes is I arcinogen. Pi Some recent animal studies by Dr. Martha Rad ike and her group (8) in Cincinnati have shown a four-fold Increase in hepatic tumors among alcohol-fed rats exposed to vinyl chloride in contrast to those exposed to vinyl chloride alone. The role of secondary or co-factors in the development of chemic.it carcinogenesis needs much furLlicr study, both in ur record mlnir being recorded reasons and wou This basic data history, and n a record of pn 132 ] Italth Effects of Vinyl Chlorlde/Tamburro 133 before any definitive observations. They do, :he various cell types Us to oxidize and/or the pathogenesis of vinyl !rurally paired two-case l chloride polymerization 1 In the polymerization ring this time ranges fros -ry of extensive alcohol `ecause of this in 1968. related to liver injury, % alcohol induced in 512 cc per day. Case B polymerization plant and jobs and from 1947 until itlnued to work in poly ears at exposure ranges 'a Initial phase. Cose B abnormalities which were vinyl chloride injury His alcohol consumption nr, have a history of 'vl chloride exposure and closarcoma. During the both alcoholic injury vinyl chloride injury, I Iteration, peliosls idal dilatation and the hepatocytes showed ireinoma and the sinuiosarcomntous tissue. and degree of exposure logical system, we have II types. It is Rurslgniflcant role In the ride nernbolltes, t'tere1 ,' Jevelcr-ent o: tiJ her group (81 in tic tumors among tr.v=t to those exposed r co-factors in Che further study, hoth in 1 | ttlmals and in human obsarvacions. ( The importance of tha hepatocyte's ability to adequately metabolize vinyl chloride is further Illustrated by the preliminary repocts of Dr. Maltoni J *t al., (9), indicating that newborn rata exposed to vinyl chloride 2 develop a four-fold increase in primary hepatocellular cancer. In cons tratt, the'adult rat of the same species develops anglosercomas. i ' ieview of Prospective Hedicsl Surveillance System: It is highly unlikely that any singular approach to the understanding of the chemical carclnogenasls (i.e., chemical structure studies, animal txptrlments or human epidemiological studies) will completely succeed in i characterizing the pathogenic sequence. Structural studies of chemicals can help direct attention to those agents which my be more carcinogenic, however, metabolic activation of chemicals also needs to be done and further studied in Ames-type bacterial systems to dstermlne whether the astabolltes ere the potential mutagen/carcinogens. Even with this in formation, the methods by which these agents produce' cancer must he Illustrated in animals so that we may devalop earlier and more effective Mans of prevention and screening of our industrial workers. , Although vinyl chloride hss demonstrated both in animals and humans | ilsost identical histological and morphological changes, this llliistra* tlon of animal model extrapolation to humans is by far the exception rather than the rule. It is, therefore, equally important that one con tinue to gather accurate epidemiological data in a prospective fashion, " to determine the human variation from animal studies as well as to docu- *nt the effectiveness of our prevention methods and surveillance pror ;ram, which are often instituted on the basis of limited knowledge and i la time of crisis. To this point, a prospective medical surveillance I tvitem has been designed and initiated by the University of Louisville la collaboration with the B. F. Goodrich Company and its unions (Dlstilj lary Workers Union, International Brotharhood of Eltctrlcal Workers, f International Association of Machinist Workers, and Pipefitters Union). i f This prospective prototype system is based on the classification of in- lustrial environments into three categories (10). Type A or possible .-arcinogsnlc: This would include those industries utilizing materials sot yet studied for their carcinogenic potential. Type B or probably ; carcinogenic: This would include those induacries utilizing a material 1 or nattrials suspected to be potentially carcinogenic. Type C or actual ly carcinogenic: This would Include all industries utilizing a material * inovn to be cancer-producing either in animals or man, "-t basic ecider.icl riical data required fre- -.srlo-.-i Inc ".trial ::icrie$ is based up;-, the possible, probable -t aetcal pri-'.cncc- of a nreinegen. Those Type A Industrial environment*, would need to collect t record minimal epidemiological data, almost 90* of which is already 'ting recorded or collected by most industries for other socio-economic reason* and would require only minimum outlay of cost and personnel time, ibis basic data would include an employee work history, a job exposure Mitory, and a medical illness history composed of three parts. First, t record of previous medical illnesses based on pre-employment historv Health Effects of Vinyl Chlo-ride/Tanburro 134 ' Health Effeces and examination. Second, a t.cord of all medi'-al Illnesses and hospi talisation during employment. In most cases, with certain modifications. this can be obtained by way of third party insurance payments. Third, j company/plant-based mortality record based on the diagnosis at time of death for each worker. Almost all of this information is presently recorded and kept in various forms by chemical industries (for business purposes), the medical care systems or as part of vital statistics. : At the second level, Type B, a periodic medical history and physical examination should be required; and, in addition, rank order monitoring should be performed for each job occupation where Individual chemical monitoring Is available. Where possible, area monitoring data should be utilized for these rank orderings, and preferably, when scientifically available, individual monitoring would be substituted for the rank order system. Updating of job classifications and job exposure indices based on rank order determinations has already been done In actual Industrial environ ments at a cost of approximately SlO/porson for (lie Initial updating,' The cost of maintenance of such records is estimated to be less than $]/ person/year employed. In Type C industries, those environments actually using carcinogens, regular history and physical examination will be required and performed with increasing frequency as the duration of employment Increases. In dividual monitoring should be used to determine the actual exposure. Where this is not yet scientifically developed, efforts should be made to design usable monitors for this purpose. In Type C Industrial en- * vironments, collaborative and cooperative efforts among the industrial ' conmunity, the labor force, and the scientific community are essential in order to allow an accurate, ongoing systematic collection and analysl of the epidemiological information. These data will help resolve the problems of safe exposure levels, frequency of screening needed, effec tiveness of screening, and the identification and effect of co-factors upon individuals exposed to actual carcinogens, INDUSTRIAL HEALTH EDUCATION In order to accomplish this, expansion of educational programs within these industries is needed and must be continually Improved and updated. Any industry working with possible carcinogens should have educational programs directed not only at their employees, but also their families, the managerial personnel, and union represun totlves. In those environ ments where probably carcinogens are involved, educational programs are needed for industrial medical personnel and para-medical personnel. This is especially important in those industries where Federal occupa tional iaws require or an industry desires to institute n surveillance program. Finally, in those industrial envi r aiments where an actual carcinogen is in use, educational endeavors rust be expanded beyond the industrial environment. These should include the local medical com munity (in order to help them better understand the medical surveillance service being rendered in relationship to the private physician's role in the care of the employees), the local community (relative to its potential danger), the business community, and the industrial community ' not involved i> understand the standing on tlu sunltles can 1. nomic difficul As evidence of systems In an compliance rat' high voluntary concern of the and labor in lc become clear iroxpertise and a communities' bi economic rclati on an ongoing, of medical ? r 11 ferenee with t'. bent screening is needed in au ability and th and will requie collaborative < ty. and the m i and geographic supporting, wii ileavoring to In effective meanRonicity. SUMMARY Vinyl chloride hern used .is ,n i.ircinogcnic c.i onvert it fro-., vitli prolonged . .loses hody cel ulignant trnns Injury. These |ury occurs. V the same p.ittei fence of pre-r,,. ells in di ' a ]ury to . rg.i rain and Ivi'pn I nves Lig.-I! 01 . a r I y del it or,' ,pco lit" v, l i c ,,i.'ii. ' MOV- . v* ' ill- JSii # A 134 e<Ue*l illnesses and hoapl**ith cartain modiflcacioni, JtiMSrince payments. Third, a * M the diagnosis at time of Ufonutlen is presently -<<1 industries (for business wt ef vital statistics. wfcil history and physical I'.lbn, rank order monitoring a there individual chemical |Mt aonitoring data should "*?erebly, when scientifically instituted for the rank order 'Mere indicts based on rank to actual industrial environ* fet the Initial updating. H tluted to be less than $3/ otsslly using carcinogens, i be required and rerformed A esploymenc increases. In- . **4; the actual exposure. vd, efforts should he made Is Type C industrial en'f*t among the industrial .lit covMinity are essential HStlt collection and analysis ms will help resolve the <f screening needed, effecfc:r and effect of co-factors :^4tlooal programs within .rjilly improved and updated. ?< should have educational *, but also their families, ::ives. In those environ- educational programs are Tira-medlcr. 1 person*'..] . "ft where Fed err.! :i:| a- irstitutc a -lii'-.L ' i inner * "amts vlv. re in i. i.i 1 * -t he expanded ho' .-iui Lhc * '.he local medic .1 . omi*.j the medical surveillance -private physician ' . rote ---ulty (relative n* its ad the industrial cui'Hiintiv health Effects of Vinyl Chlor tde/Tanburro 135 i i sot Involved in similar use of carcinogens, so that they may better wderatend the health and safety of these employees. The lack of under standing on the pert of the non-involved business and industrial comi. aunitlea can lead to unnecessary socio-economic stigmatization or eco ! nomic difficulties. is evidence of the potential effectiveness of such medical surveillance systems in an.actual carcinogenic environment. Table III illustrates the tOBpliance rates for medical screening over the past three years. This high voluntary compliance on the pert of the employees illustrates the concern of the employees and the cooperative effectiveness of management and labor in identifying and correcting industrial problems. It has l become clear, in our past four years, that industry's need for scientific expertise and assistance must be coupled with the medical and scientific \ comunitles' better understanding of the work environment and its socio economic relationship. The conducting of medical surveillance programs on an ongoing, long-term basis require* adaptation of our present method* of medical ecreenlng so as not to cause unnecessary and excessive inter ference with the Industrial function and at the same time deliver the best screening surveillance system at the lowest cost. Much more work lx needed in adapting such systems and demonstrating their implement- I eblllty and their cost effectiveness. This Is not a short-term endeavor and will require well thought out planning and a marked increase in the collaborative effort among industry, the labor force, the local comnitnIn ty, and the scientific conmiunities (local or regional ones). Regional ind geographic cancer centers can play a major role in assisting and supporting, with scientific expertise, their local industries in en deavoring to better Identify potential carcinogens and develop the most effective means of preventing both acute toxicity and long-term carcino i genicity. <f SPC1ARY Vinyl chloride Is a basic chemical for plastics manufacturing and has been used as an anesthetic agent. Vinyl chloride's previously unknown carcinogenic capability appears to be related to the body's ability to convert it from a non-toxic or minimally toxic chemical to a toxic and, with prolonged exposure, cancer-forming agent. Early exposure inenimals causes body cells to make adaptive changes which may prepare them for malignant transformation and appear to precede evidence of morphological Injury. These findings appesr to occur before a low-grade chemical in jury occurs. Vinyl chloride chemical injury in man appears to follow the same pnttern. Present clinical data in humans now demonstrate evi dence of pre-cancer injury and cancer transformation of various types of cells in different organs of the hody. Manifestations or pre-canccrmis Injury to organs other than the liver (such is the lung, heart, spleen, brain and lymph.11 ii system) may also he occurring and require furrher invest i gal ion. Earlv detection of these pre-eancerous chemical injuries requires a prosper t i vo (ingoing system of surveillance .mil the development of diag nostic metlieds whi.li can identify specific causa L agents In the presence of n- " siiei 11 i injury. Such a systematic approach lias been developed and in .'p.u nion. Its initial aeli i c.. men l s appear to l>o the I 'k fc > t$V Health Effects of Vinyl Chloride/Tamburro |\ 1J( 1 Health Effad ] foundation for future auccaaa In controlling the health effeett of In dustrial chealcal*. REFERENCES 1. Sellkoff, I.J., Hatnond, E.C., Eds: Toxicity of vinyl chloride polyvinyl chloride. Ann. NY Acad. Scl. 246:1-337, 1975. 2. Tamburro, C.H.: The hepatic role in carcinogenesis and Its early detection -- the vinyl chloride modal, Tale Journal of Medicine and Biology (In preen). 3. Whelan, J.C., Creech, J.L., Tamburro, C.H.: Angiographic and radio nuclide characteristics of hepatic angiosarcoma found in vinyl chloride workers. Radiology 118:549-577, 1976. 4. Pliskln, K.: Fellosls hepatis. Radiology 114:29-30. 1975. 5. Hefner, R.E., Jr., Watensbe, P.G. Cehrlng, P.J,: Preliminary studies of the fate of inhaled vinyl chloride monomer in rats. Ann. KT Acad. Sd. 246:135-148, 1975. 6. Elmore, J.D., Wong, J.L., laumbach, A.p., et al: Vinyl chloride mutagenicity via the metabolites chlorooxiranc and chlorscetaldehyde monomer hydrate. Blochem, Blophye. Acta 442:405-419. 1976. 7. Weber, C., Lea, M.A.: The molecular correlation concept. In Methods In Cancer Research. Edited by N. H. Busch. NT, Academic Press Inc, 2:523-578, 1967. 8. Radiks, M.: Personal communication. 9. Maltonl, C.: Recant findings on the carcinogenicity of chlorinated olefins, conference on Comparative Matabollam and Toxicity of Vinyl Chloride-related Compounds. National Institute of Environmental Health Sciences, NIH, May 2-4, 1977. 10. Greenberg, R. A., Tamburro, C.H., and Eupchclla, C.E.; A prospec tive medical surveillance program for tha detactlon and prevention of industrially ralated cancar. Prevention and Detection of Cancer, Vol. II., Ed: H.E. Nleburgs, Marcel Oekker, Inc., New York (In press, February, 1978). CANCERS BY COHORT WOPr WORK PERIOf Jt, iu >. V v.tT UCC 041618 V 136 t Health Effects of Vinyl Chlorida/Tastburro nk htalth effects of ln- TABLE I 137 'elclty of vinyl chloride M-J37, 1975. ittlMtenesis and its early * Journal of Medicine and *1.1 Angiographic and radio"a found in vinyl chloride rn*s29-30, 1975. l*li P.J.: Preliminary -Assonoser in rats. Ann. NY t al: Vinyl chloride ie sad chloracetaldehyde ::t#5-*19, 1976. 'fslltion concept. In Ivsch. NY, Academic Press 'faotsniclty of chlorinated snd Tonicity of Vinyl of Environmental Health tensile, C.E.: A prospec* ;ilon and prevention of detection of Cancer, Vol. . *su York (In presa. j - ' i CANCERS BY SITE IN POLYVINYL CHLORIDE PRODUCTION PLANT COHORT WORKING MORE THAN 1 YEAR WHO DIED DURING THEIR WORK PERIOD OR AFTER RETIREMENT. SITE LUNG LIVER BRAIN COLON PANCREAS THYROID PROSTATE eye UNKNOWN NUMBER 28 10 5 A 2 1 1 1 1 H e a lth E ffe c t* o f V in y l C h lo rid e /T e .b u rro - "*aiaiarar^ ^BlM*iliAj5ffidfc* 'J-'i*:-;',TP'L?".Tzrd " '** f -'- - -*!&'- '(/,*:r>f V--` '' * .' =*" ' V' - *-' '!'"'; -i*' ,, 'l . _ -t t'f >_ TABLE II PROPOSED VINYL CHLORIDE METABOLISM PATHWAY IN THE RAT 1. Cl-CH-CH2------ -fl-rn.-ru._nu _. ALCOHOL ^ dehydrogenase ^ CH2 c^ " C^CI,rCHr"tl"_^br* cich2-cho CICHj-COOH HI. C1-C11-CH. OXIDASE C1~C\7CH2----- --CH2-CH0----- .CKH2-C00H TABLE III COMPLIANtl. ill qt|2 PEOPLE EMPLOYED COHTINUOUSLY AT TYPE C PLANT (JUNE 1, 1975 to MAY 31, 1977) s'K**, 11:. l j Z '-^-UlT-UlL -LiOi2"l-*j*-'" 8 TABLE IM COMPLIANCE OF 992 PEOPLE EMPLOYED CONTINUOUSLY AT TYPE C PLANT (JUNE 1, 1975 to MAY 31, 1977) Laboratory tests Liver-spleen scans History and physicals 1st 897, 732. 582 00 tj*l YEARS 2nd 862 76" 3rd** 8 81% - 69% NONE OF* 3 YEARS 3% 7% 12% O r*i < 9 *< O o * THIS IS PERCENTAGE OF EMPLOYEES WHO HAVE NOT PARTICIPATED IN ANY OF THE THREE SCREENING COMPONENTS DURING ANY OF THE YEARS. ** THE DECREASE IN THE 3rd YEAR OCCURRED MAINLY AMONG NON-PRODUCT ION WORKERS, ESPECIALLY THOSE IN ADMINISTRATIVE JOBS. g cjSfea, CX 03^ Ki r$ ucc 041822 140 :?rr*v>-. \ *. V " '*?* <v*.< .-jw; vVV, V \ - lW>V U. * ... t** .^sc-*S; A*,* ; ; .* * Wu* .* *.' * ' i * **| r ' JtK Vj. * *d portal fibrosis with .story cells mainly mono- Figure 2. Focal sinusoidal dilatation is soon with activated sinusoidal calls (arrows). Lobular architecture otherwise well preserved with normal appearing hepatocyte with some increased nunher of bt-nuelenr hvpotocytes. (Low power x 100) ucc 041624 1 142 j 143 ( I figure 4. Frequency of biochemical abnormalities being present and correctly Indicating the presence of significant histological ahnor- t i aallrles (SOFT * alanine aminotransferase: c<;t gamma glutamyl I transport idnse; AIK PROS Alkaline t'hi'st'h it .i :c; SHUT * aspartic l aminotransferase; ICD isocltrlc dehydrogenase and ICO * Indocyanine green clraranee). ,hnne w'uh malicn.int ''Oldai cells Into .''inn- %* M% 4R*4 S3/. Tiy. CANCER 7. WTTM A 44 ilNQWKAI. ><0% FAT ICO A PORTAL A 1 R FIBROSIS AA Q <*/. FAT 5 MINIMAL 3> FOROSIS X A AA A AA A 44 4 1 MINOR CHANCES AA A AAA A AA A 444 A I I NORMAL LIVER AA A AA A AA A A 0-O.t UM.9 1.0*2.9 3.0-3.9 AO-SJO J AVERAGE VC EXPOSURE MDEX Figure 5. Correlation between liver hlstelej;v and indoevanine dye clearance (0.5 a: and 5.0 mg dose) abnormalities in vinyl chloride workers with inere is 1np vinyl chloride oy: sure a* determined bv avera"e exposure inde:. Ju l . where: Jn^ me her of months at exposure . le v) E; *= _ i~iire rated on a rank order ``ale (re,i,i 1 to 6 (l-lowvst; h> i, lie e l : SnL ' total Tenths services at VCI : I ent i , CONTROL STAT | Susan Wyatt ( j U.S. Enviro' i North Carol , In her wort 1 Ms. Wyatt p' , for the atn I at the time j ERA regard!* Still not f ! a private ir Hence, the I ceedings. T > tat ion. i J ABSTRACT ENLARGED NORMAL SPLEEN SIZE Figure 6. The correlation between spleen site and wedged hepatic vein pressure in vinyl chloride workers. t The Enviro- ; chloride as and promulr the author1 21, 1976. r Fund (EOF) review of c I moved to di j ment agree' to the sta I proposed or numerous c> The main ilated unde of the Ac t i level whic: ) an ample such hazar to determi: ide and it ' termined : standards leve 1 ach. Texas Ren-