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V >': xfr 'id? health effects of vinyl chloride Carlo H. Tamburro, M.D. 128 iU tfpATi University of Louisville* School of Medicine, Digestive Diseases and Nutrition Section, 511 South Floyd Street, Boon 535, MDR Building, Louisville, Kentucky 40201 INTRODUCTION Vinyl Chloride-Associated Injury In Han Vinyl chloride (CH_ CH-C1 onochloroethylene, e gee) has been the basic molecule or monomer of polyvinyl chloride and-its co-polymers and has ( been one of the moat important organic intermediates In the plastics in. dustry for over a quarter of a century. During this tine, evidence fot both chemical toxicity and carcinogenicity has bean accumulated in ^ and in anlmala. Reports from across the vorld have Indicated the pr*. senes of thrombocytopenia, retlculocytosls, and leukopenia among the haoatologleal disorders. Sclaroderma type skin lesions, acro-oateol)aia of tbs distal phalanges, and Raynaud's phenomenon have been veil de scribed. Abnormalities In pulmonary functional capability and cardiac arrythmia* associated with Its use ms an anesthetic have also been not*i,. The most widelykziawndlsorders include hepatic flbtoels, pellosls hepstla, hepatomegaly, splenomegaly, portal hypertension, and hepatic angiosarcoma (1). There Is at present some epidemiological and histo- ' logical data that Large dea^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 in animals exposed to vinyl chloride. In addition to the liver angiosar comas and the brain neuroblastomas, vinyl chloride-exposed rats and mice have shown Zymbal gland (sweat gland) carcinomas, nephroblastotui. subcutaneous angiomas, skin carcinomas, and a variety of adenomas of tb breast, pituitary glands, and other assorted sarcomas of the ovary, pul* nonary, and uterus. A simple summary of cancers by site In vinyl chloride workers In our cohort who had worked more than one year is shorn In Table I. I. Bloc W tradi mi also naspep (attract ml laoc This research is supported by Contract No. NOl-CN-55212 from the National Cancer Institute, Cancer Control Branch. Xexas Reports on Biology and Medicine, Vol. 37. 1978 it"V A. |a*lth Effects of Vinyl Chlorlde/Tamburro l^ o id n ^fcfE OF HEW MEDICAL FINDINGS RELATED TO VINYL CHLORIDE j tHatological Sequences of Injury; ^ hepatic lesions In the humans and in animals related to prolonged .ypoaure to vinyl chloride have bean fairly well characterized. One of 'ZTeatil**1 findings 1* "activation" or morphological changes in tb, Medicine, Digestive Diseases and Street, Boom 535, MDR Building, ,0usoldal lining calls without evidence of hepatocellular toxicity, ^gse sorphological changes In the sinusoidal lining cells are not .rtv associated with an Inflammatory process or evidences of localized ijcTosl*' The more advanced lesions axe associated wlth an Increase in ^capsular fibrosis with subcapsulsr bile duct proliferation, which cams* the liver surface to appear "pitted" with small white scars when yltvtd at laparotomy or by peritoneoscopy. These lesions are associated ittb increased portal fibrosis of varying degree most often rounded In on the cut surface and only rarely showing short stellate rsdle* Man ^ into the parenchyma. The lobular architecture. In general, la prewith the central vein areas being devoid of excessive collagen aroethylena, a gas) ha* bean the b<-(, lorlde and Its co-polymcrs and baa ale intermediates In tbs plastics iB. iry. During this time, evidence fer aulclty haa been accumulated in 3 the world have, indicated the pr*. zytosls, and leukopenia among the a type akin lasions, acro-oateolyii, i'a phenomenon have been well d/ functional capability end cardie 39 an anesthetic have also been net* jde hepatic flhroala, pelloals , portal hypertension,.and hepatic 3ot-soqe epidemiological and biatrrarclnoma bf the -lung end neuroilatsd'vith exposure to vinyl' chi* la ^petition, a* Illustrated In Figure 1, The sinusoidal lining cells pgTeo be helmet shaped, have triangular nuclei and appear to be aeso- /Wtd with increased deposition of collagen in adjacent sinusoidal in addition* there is a focal sinusoidal dilatation within the ^l.f architecture often associated with bi~uuclear hepatocytea, sug^tiog active regeneration of the hepstocytes. More recently, Dr. Bans njpar has described focal areas of hepatocytlc hyperplasia consisting jf ^ or three cell thick plates, not associated with lobular fibrosis ol regeneration as seen in alcoholic and viral lnjurlea. With progres- * exposure to vinyl chloride, there appears to develop increasing ,4|U of the sinusoidal lining cells, progressive worsening of the <4mJ alnusoldal dilatation (Figure 2), and ultimately, the malignant *SMfermation of the sinusoidal lining calls (Figure 3). At prepent, .. if me clear which of. the sinusoidal lining cells (vacrophagsfeupffer I iibroblest/Ito call, or the sinusoidal endothelial lining cell) Is akssllgnant stem call which develops angiosarcoma. Most present data i suggests that it Is the endothelial lining cell which ultimately | juwt Mllgnant and forme the angiosarcoma. Further studies will be ' to verify this thesis. f i^sgbealcal Detection; \ described and shown to develop u In addition to the liver anglosarvinyl chloride-exposed~rats sad gland) carcinomas, nephroblastoma oas, and a variety of adenomas *t * assorted sarcomas of the ovary, P* bmNmtcel detection of these lesions has until recently, been mainly tstdltional biochemical hepatocellular studlea. These have included e abates and aspartic aminotransferases (SGPT-SGOT), gamma glutamyl i wmgsiidsse (GGTP), alkaline phosphatase, bilirubin (both direct and | mMert), and other enzymatic studies, such as sorbitsl dehydrogenase ! a*beecitrlc dehydrogenase. As illustrated In Figure 4. our preliminary In vinyl chloride workers la * year la shown in Table 1. t Indicated that the ability of these traditional biochemical ' age is predict the presence of underlying histological hepatocellular tit at best 80-85X accurate -- the most effective of which Is the * aminotransferase (SGPI). The gamma glutamyl tranepeptldaea is iCt Ho. HOl-CH-55212 from the >ntrol Branch. aa affective but baa a 6-SX false positivityt that Is, abnor> sf the GCTF levels persist without histological or functional at hepatocellular Injury. Although elevatlona in alkaline * Mat often reflected the more serious abnormality, in almost sdlclne, Vol. 37. 1978 Health Effect* of Vinyl Chlorlde/Taaburro ,1th E 128 one quarter of the individuals, It was found to be normal In the preseoc* of hepatocellular injury. More recently, the Introduction of Indocyanine green (ICG), an anlomc dye similar in its physiological capabilities to Bromsulphaleln (BSP), has increased our ability to identify mild and latent underlying cheoic,j hepatocellular injury. Indocyanine green can be given in various dose levels for purposes of determining hepatic clearance. At th^lov do,e 0.5 mg/kg, its predictability is equal to that of the aminotransferase. By increasing the clearance dose to levels of 2.5 and/or 5.0 mg/kg, one* can increase the ability to identify underlying hepatocellular injury t4 the 98-992 range. A definitive blostatistical evaluation of both the specificity and sensitivity of indocyanine green, in cong>arison to the traditional biochemical studies, is now underway. Figure 5 illustrates the correlation found during preliminary studies between liver histology and dye clearance among vinyl chloride worker, with increasing degrees of totel 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 ere very sensitive to Identifying underlying disease, they have very poor specificity in identifying the causal agent and, because of this, art suited as screes* log tools rather then diagnostic ones. C. Various Tumor Types: Hepatic angiosarcoma, although appearing to be of a single cell origin, may be of multiple call origins. Morphologically it occurs in a cellu lar, cavernous, end solid form, Ihe cavernous and tha solid tumor form are most affectively detected by radioisotopic liver scans. In addition, dla'gnostlc angiographic characteristics `differentiate angiosarcoma frbs .primary hepatocellular carcinomas, adenomas, cavernous hemangiomas* focal nodular hyperplasia, and mscronodular regeneration of cirrhosis. Whelan at al., have described the characteristic angiography and radio nuclide changes that are characteristic of hepatic angiosarcoma (3). The tumors exhibit central hypovaecularity with puddling and are surrounded by e peripheral stein which persists late into the venous phase of the angiographic study, ladioisotoplcelly this form of a tuanr presents with e negative peripheral defect which, on occasion, may be missed on the anterior view of e seen but is seen on the lateral or posterior view. As demonstrated by Whelan et al., heeling hepatic in farcts secondary to wedged hepatic venography can creates false positive lesion on angiography similar to that seen in angiosarcomas. D. Non-Timor Vascular Lesions: A second lesion often seen in the non-tumorous portions of the liver 1, that of peliosie hepatis; it has been extensively described by Pliskln (4). These lesions tend to be msoarous. Involving the entire liver an.! have e 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 pra-carcinogenic or pre-angiosarcomatouf lesion in vinyl chloride *c bil uflons, lip tha rtdloi*0 c jtresled iMC , only rt <3Z i**nt ^tisl ,f ident ^itivl lt* o css as o C 9 x o vn \0 if ir ro lg .s e .etlrcular itaialng irtsry t to use (Ives ft light pi to Indi tits of ftis nay amber o farther i, Lung 1m aedl amual tooraal micb, c mi fibt rk fo: | Nllutar 138 lslth Effects of Wnyl Chlorlde/Tamburro J29 URLQS343 ^pfkars Is still under study. vii found to bo normal In Che pretty I I gsdloieotopic Detection: ' Indocyanine green (ICC), an anionic stabilities to Bromsulphalein (BSP), :ify mild and Intent underlying chemiCtj ie green can be given In various dose , hepatic clearance. AC Che low doe, quel to that of the eodnocreseferase*. :o levels of 2.5 and/or 5.0 mg/kg, o^' fy underlying hepatocellular Injury j0 oetatletlcal evaluation of both the ocyanine green, in comparison to the s now underway. on found during preliminary studies earance among vinyl chloride workers luyl chloride exposure. This is of abnormal dye claarencee at both > mg/kg clearance dose among vinyl hough these tests are very sensitive they have very poor specificity In because of this, are suited as scr,,. nee. earing to be of a single cell origin, Morphologically It occurs In a cellj he -cavernous and the solid tumor for* adiOlaotopic llvn^. scans. In #ddlti a tics- differentiate angiosarcoma fr adenomas, cavernous hemangiomas, ^modular regeneration of cirrhosis. chhracSerletic angiography and radio. &tie of hepatic angiosarcoma (3). cularity with puddling and are bich persists late into the venous Sadlolaotoplcally this fora of a i*1 defect which, on occasion, may bt can but la seen on the lateral or f Whelan et, al., healing hepatic !- venography cancreataa false poUi hat seen in angloaarcoaae. non-tumorous portions of the liver U sen extensively described by Plin* aroua, involving tha entire liwi w a nodules. The stain does partial not ba aeaoclatad with any radfot**' can. Whether these findings r somatous lesion In vinyl chlorld* Qt ability of 99aTc sulfur colloid liver scan to detect anatomical .^iona* baaed on the best medical diagnosis, is supported by the findup that, of the 19 cases with anatomical lesions, only three.ve^e^ rtjloiaotopically reported as normal. In one of the three reported penal cases* subsequent radioisotopic scans done three months later staled the underlying abnormalities. What is equally Important 1b In the 957 "normal" individuals, the scan was reported as abnormal I. only 32 cases. Thpse data, therefore. Illustrate an 842 sensitivity jlt/19) end a 972 specificity (925/976), with only a 32 false positive 0M (32/957). This false positive rate was markedly reduced in subpguent years whan repeated radioisotopic scans could be compered to liltlal baseline ones. It is our present opinion that the radioisotopic 010, either camera or rectollnaar, represents tha most affective means 9l identifying early anatomical lesions with tha least dsgtse of falsa piltivity, thus preventing unnecessary diagnostic evaluation. The *tae and effectiveness of ultrasound versus tha radiological isotopic u a screening procedure Is under study. y, iaoclstsd Splsen Pisordsrs: m mtUtgement of ths spleen, as determined by radioisotopic scans than 14 cm in longitudinal length) and verified by autopsy or ^pirotcmy In 12 cases, has bean seen in 602 of the individuals with f/tteurcema and 402 of thoae Individuals with the pellosle hepatle uiloa. 4s illustrated In Figure 6 the correlation between spleen size d wedged hepatic vein pressure among vinyl chloride workers Illustrated me disparities. At least 10-122 of those Individuals with splenomegaly tfrf oo evidence <?f en elevated portal 'pressure as reflected by wedged vtttlt vein preeeur*.- In addition, angiographic studies demonstrated pircular lesions in the spleen (llenal peliosis) which bed persistent dialog characteristics end were associated with a shortened celiac fury to portal vein circulation time and increased spleen scan size, to ut of 99mTc sulfur colloid clearance by both tha liver and spleen p** further suggestive evidence that spleen macrophage cell activity e*t play a role in tike splenomegaly end/or the vascular findings. In to Individuals with llenal pelloala, there is a steep rise in the upuw of 99mTc sulfur colloid by the spleen efter initial recirculation, hia aay be due to either increased blood flow and/or Increased total *tr of activated macrophaglc cells. Studies are now under way to artWr delineate these lesions. ' leas Finding*: i f h nodical surveillance program has also Illustrated the presence of an ^al lung finding among this cohort of vinyl chloride workers. The i amnellcy ie characterised by a midzonal lateral pleural thickening, ***, oa histological examination, thus far has si^ly Illustrated fat m iUreal*. The Importance of this finding in approximately 42 of the fierce may be non^occupatloaal but regional, l.e., other environmental BMMat*, Infections, etc. These lesions do not appear to be Halch Effects of Vinyl Chloride/Tamburro 130 associated with any pulmonary functional disorders; and their signify, cance and relationship to smoking, tuberculosis, asbeatosls, fungal in, faction or possible geographic nan-occupational environmental Pollutant, are under study. There is, however, preliminary epldsmlological and histological data that strongly suggests sn vinyl chloride industrial Increase workers. in the frequency of Falk and associates lung cancer have been on Study* lng 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, race and sax. Preliminary studies using regional histologically astchadiuo, cancer patiente as controls indicate that the occurrence of this partlc. ulsr call type does not appear to be a geographic phenomena. Analysis Is now underway to determine if there exists a correlation between this particular histological call type and the work exposure history of this cohort population. The correlation, If any, between our pleuralfindi,, and this cellular type of lung cancer has yet to be determined. M rftaboH" ItaboUt* Jfsstio*- he et Is ex Ml HETABOLIC/PATBOGENESIS UPDATE OH VXHYL CHLORIDE Our present knowledge of the metabolism and pathogenic mechanism by which vinyl chloride Induces hepatic lesions may bast be sumarized by Table n. At concentrations of less than 50 ppm, vinyl chloride appears to be metabolised 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: chloroethylene oxide spontaneously rearranges to for# chloroacetaldehyde, which is then-further oxidized to monochloroacetic add or converted to chloroethanol. Monochloroacetic add is not seen In urine samples at low doses and may be only formed with higher ex posures of vinyl chloride. Chloroethanol and chloroacetaldehyde are most likely detoxified via the glutathione-cysteine' conjugation, system. This system, however, is saturable; end at.higher levels, vinyl chloride Is excreted via the lungs unchanged (5). * Elmore nt al. utilizing a modified Ames system end pure synthesized vinyl chloride intermediate*, have shown that vinyl chloride, chloroethanol and chloroacetlc add are not mutagenic In their biological systems (6). This strongly supports the hypothesis that vinyl chloride monomer is neither hepetotoxlc nor carcinogenic until it has been metabolized to Its intermediate forms by the liver and/or other tissues. However, chloroacetaldehyde and chloroethylane oxide were definitely found to be mutagenic, producing recom bination SNA defects In bacteria. decree --ure ar Idly C trate 33 lease O ed by VI sspha cion term :hang 150 h. ^da ex Wfatocellu adapter: tar purpose: Uprnot t: md or dai 1 mldal Unit ; mall* to d< tattloplog I These findings present difficulty In explaining why the hepatocyte, as the primary metabolic aite for vinyl chloride, does not undergo any significant evidence of hepatotoxlclcy nor malignant transformation. The adjacent sinusoidal lining cells must either metabolize the vinyl chloride in a similar manner but have a leaa affectiva detoxification of tha metabolite or receive from the hepatocyte the intermediate meta bolites, such as chloroethanol, which It may then convert to chloroacetaldehyda without being able to detoxify or further oxidize this mutagen. Although the hepatocyte la the primary site for vinyl chloride htatits have mrious aim *Uty to t tadiite nets torn tra ted 9IM versus fgthtr veri . mtlvity (ba ? tha bapat URL 65345 Taaburro 130 gialch Effects of Vinyl Chlorlde/Tamburro 131 ctlonal disorders; and their signify , tuberculosis, aabeatoaie, fungal in_ n-occupational environmental pollutant, .^holism, its capacity to detoxify the vinyl chloride intermediate -c*bolitee may be the major reason it does not undergo malignant trans- hepatocellular biochemical alterations observed during prolonged Idemlologlcal and histological data gfposora to vinyl chloride in the rat may add further evidence to sup- i In the frequency Of lung cancer aaotu Falk and associates have been study. :all carcinoma occurring among vinyl finatlshisexcpoosnecdeptto. 1S0u-2bc0,e0l0lu0 lapprmenozfymviensyelncdhmloeritdaeborliatensginwgerefrosmtud14ie-1d37in * rf. Microsomal, mitochondrial, and cytosol enzymes, including p450, ditch appears to be higher than one yjiM cytochrome c. reductase and mixed function oxidase, were studied. il population matched for age, race, ig regional hletologlcally matched lm,. -j.thioce and glutathione reductaee as oxidative and detoxification ^ters were also determined, in addition to the conventional clinical ite that the occurrence of this partly, ba a geographic phenomena.' Analyst wqfheaical studiea, which included aspartate (SCOT) and alanine (SGFT) -jaotransftrase, alkaline pboaphataaa, bilirubin, lactic add dehydro- ara exists a correlation between chi* and tdic work exposure history of thi* total protein, albumin, cholesterol and triglycerides. After Tjjhoura of exposure, no significant changes occurred in the mitochon- >n, if any, between our pleuralfiodj^, : or the microsomal enzymes nor in the glutathione content. There icer ha* yet to be determined. * 4,4 tn Increase in the glutathione reductase at 30 hours and a elgnlfldecrease in ilucose-6-phosphstase (C-b-P) after 71 hours.of exposure, 'IOTl CHLORIDE flawed with an increase ln glucose-6-phoaphete dehydrogenase (G-6-PD). ; ^ biochemical findings occurred without evidence of histologically oilam and pathogenic oechanisa byvhl< | g/ismlbl* changes in the conventional biochemical studies. ions say best be eumarlzed by Table if. { ppm* vinyl chloride appears to be 5 decrease In G-6-P and increase in G-6-PD after "simulated" chronic genase system. At levels In the ra&jp ccur by the peroxidase - catalase lxed function oxidase system appear* ^^Mvrs are very similar changes to those found by Weber and Lea (7) tepidly developing primary hepatocellular tumors. Their studies 1 00u crated a decrease in gluconeogcneele with e reduction In G-6-P and of vinyl chloride into its meteboU, 4e spontaneously' rearranges to for* further oxidised to monochloToacetlc . Kosochloroecetic acid is not trrr . tscreass in G-6-PD and transaldolase. These biochemical changes were .lleverf by n increase in purine biosynthesis (increased phoephoribpsyl; ,**i*phat aminotransferase - PRFP) end eventually an increase in the Auction of AT? end CTP, leading to increased nucleic acid 'synthesis. may be only forme^vith higher x- ethanoi and chloroacetaldahyde arc P m Urination of our experiment (at 37 hours), there were no signif- tathione-cyatains conjugation ayste* ,m( changes ln ?KP?; but stales are now underway exposing animals to stand t higher levels, vinyl cMorim . m m 250 hours to determine if die hepatic eosym* biochemistry in vinyl Klmore at si., utilising a awtlds exposure is similar to that seen in rapidly dividing primary mbealsed vinyl chloride intermediate ` "Batscallular tumors. It may well be that these findings may represent Loroethanol end cbloroecetic acid *u m adaptation of the bepstocyte, with Increasing nucleic acid synthesis systems (6) . this strongly support* 1 w fwfwu of repair, and may mak these cells mors susceptible to monomer Is neither hepstotoxic ncr ibolixed to its intermediate font b* ncever, chloroscetsldehyd* and chU- ) transformation if the carcinogenic agent is unable to be remi or detoxified with sufficient efficiency. In contrast, the sinu ate*! lifting cells may veil be able to oxidize these aetalboll tea but id to he mutagenic, producing ratfv emit to detoxify them effectively end therefore be more susceptible to _ mmieottif DBA injury. , ,'f* ** - . Ln explaining why the hepatocy t#, ** *< have begun in our laboratory to isolate hepetocytes and the '1 chloride, does not undergo am ' *** sinusoidal lining celle and determine the individual cell types' ity nor malignant trana format toe 1 ***** to both oxidise vinyl chloride, as well as detoxify its inter- a must either metabolise the via* satebolltea. These studies, only recently begun, have already iva a leas effective detoxificeti** : *maMiid unusual differences between the enzyme activity of hepato- he hepatocyte the intermediate *** *** vitewe mesenchymal cells. Our preliminary studies, which require ch It may then convert to chlore W failed to demonstrate mixed function oxidase detoxify ot further oxidise tht* **7 (based on micromoles per minute per million cells) in contrast a the primary site for vinyl ebl"* ** bepatocytes. Further purification of the meseabhyaal celle and '.'i-V-f] [' V,' W -f.K \k': Health Effects of Vinyl Chloride/Tamburro 135 iltb 6 verification of their cellular type must be done before any definitive concluelone can be drawn from these preliminary observations. They <j0 however* suggest that metabolic differences of the various cell type* * may play an Important role in the ability of cells to oxidise and/or detoxify potential carcinogens. ,1s*1* Pathogenesis via Human Case Studies: The co-factor role of such agents as alcohol in the pathpgeuesia of vim chloride carcinogenesis may be suggested by a naturally paired tvo-ca,* study. Case A - Employee began to work In vinyl chloride polymerlzatio plant in 1947 aa a chemical operator. He worked In the polymerization " process for IB years, and estimated exposure during this time ranges fr 50-10,000 ppm of vinyl chloride. He had a history of extensive alcohol9* consumption and was discharged from employment because of this in I9(g In 1962 he had the first clinical abnormalities related to liver injury end these were identified histologically as being alcohol Induced in 7t 1964. His alcohol consumption was greater than 512 cc per day. Case | - This individual was also employed la the same polymerisation plant began working at the earns time and at the same jobs and from 1947 unti] Casa A was discharged 18 years later. Casa B continued to work In p*]y, merixation plant process for an additional ten years at exposure rang*/ of 50-10,000 ppm. In 1974 during the medical surveillance program's initial phase. Case | was identified as having persistent biochemical abnormalities which wer 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. Ha did, however, have a history of malaria during hla military service prior to vinyl chloride exposure sttd was transiently HB^Ag positive in 1974. Histologically, Casa B was verified aa having angiosarcoma. During the same year. Case A was ehowo^to have evidences of both alcoholic injury with cirrhosis and the characteristic lesions of vinyl chloride Injury, including subcapsular fibrosis with bile duct proliferation, peliosle hepatie, sinusoidal call activation, focal sinusoidal dilatation and areas of rounded portal fibrosis. Histologically, the hepatocytea thou*; atypical change consistent with hepatocellular carcinoma and the sinu soidal lining call changes characteristic of angiosarcomatous tissue. In these two cose studies, In which the duration and degree of exposure wee es identical aa one could expect in human biological system, ve haw Individuals developing tumors of two different cell types. It is sug gested from these.findings that alcohol played a significant role In th* hepatocyte's inability to detoxify the vinyl chloride metabolites,the by causing DHA Injury and ultimately leading to the development of primary hepatocellular carcinoma. Soma recent animal studies by Dr. Martha kadike and her group (6) la Cincinnati have shown a four-fold increase In hepatic tumors among alcohol-fed rata exposed to vinyl chloride in contrast to those exposed to vinyl chloride alone. The role of secondary or co-factors in the development of chemical carcinogenesis needs much further atudy, both hie pro* (trial Mtcleoge me yet i wreinogt er eeterl ty carclr move to he basic mtsgcrlc mrclaoge I record ! misg rac i Nasoas a Ids bail Meter?, record URL 05347 li. mburro -T % i33 gfalth Effects of Vinyl Chloride/Tamburro jgg amt ba done before any definitive : prellalnery observations. They do, ferences of the various cell types iblllty of cells to oxidise end/or ^iasld and In human observations. p, ia^ortance of the hepatocyte's ability to adequately metabolize vinyl >l0ylde la further Illustrated by the preliminary reporta of Dr.Maltoni tsl<* (9) * indicating that newborn rats exposed to vinyl chloride ^jop e four-fold Increase in primary hepatocellular cancer. In con- >s alcohol in the pathogenesis of viny] ,estad by a naturally paired tvo-case work In vinyl chloride polymerization r. Be worked In the polymerization l exposure during this time ranges Le bed a history of extensive alcohol i employment becauae of thla In 196&, ibnormalltlea related tp liver Injury, cally as being alcohol Induced In ' greater than 512 cc per day. Case l In the same polymerization plant 7r* at the same jobs end from 1947 until r. Case B continued to work la p0jy. litlonel ten yeers et exposure range* tit, the adult rat of the same spades develops angiosarcomas-. --,, of Prospective Medical Surveillance System: a is highly unlikely that any singular approach to the understanding of ^chemical carcinogenesis (l.e., cbemicsl structure studies, animal ^perlments or human epidemiological studies) will completely succeed In marsctarlxlng the pathogenic sequence. Structural studies of chemicals j>*lp direct attention to those agents which may be more carcinogenic. pttvtr, metabolic activation of chemicals also needs to be done end terther studied In Bass-type bacterial systems to detsrmins whether the |rtAbolites ere the potential mutegen/cerclnogene. Even with this In (tfHcion, the methods by which these agents produce cancer muet be ; lil--cratad in animals so that we may develop earlier and mora effective i 00^ of prevention end screening of our industrial workers. I mfeoufh vinyl chloride has demonstrated both In animals and humans . ones program's Initial phase. Case Identical histological ami morphological changes, thla llluacra- . biochemical abnormalities which vt, i to be due to vinyl chloride Injury inglosarcoma. His alcohol conauaptUn (le did, however, have e history of . dfs of animal model extrapolation to humane Is by far the exception J than the rule. It is, therefore, equally Important that one con- <tr to gather accurete epidemiological data In a prospective fashion, ! m gturnlns the human variation from animal studies as well as to docu- . .prior to vinyl chloride exposure *m ( gn tbe effectiveneae of our prevention methods and surveillance pro- 974. i gmti which are often instituted on the basis of limited knowledge end , m ties of crisis. Tq this point, a prospective medical surveillance lee.-having anginaIreoaa. During Uv. : evidences of both alcoholic Injury :1c lesions of vinyl chloride Injury. jniM.hss been designed end Initiated by the University of Louisville w collaboration with the B. ?, Goodrich Company and Its unions (Distil- an Workers Unloo, International Brotherhood of Electrical Workers, in^Llm^uct proliferation, peliosi* j wematlonal Association of Machinist Workers, end Pipefitters Union). iW focal elnueoidal dilatation sod Histologically, the hepatocytee ttaaw atocellular carcinoma and the sis^rlstlc of angloaarcometous tissue. | %t* prospective prototype system is based on the claeeification of ln- I mrlal environments Into three categories (10). Type A or possible I sNlwgenlc: This would include those Industries utilising materials f w* pet studied for their carcinogenic potential. Type B or probably i the duration and degree of expos*** wKteofenlc: Thla would Include those Industries utilising a material t in human biological systca, * estetlals suspected to be potentially carcinogenic. Type C oractual- o different cell types. It is *- f * eMtinogenic: Thla would Include all industries utilizing a material ohol played e significant role is ^ f ewes to be cancer-producing either In animals or man. the vinyl chloride metabolite*, tlw* Be bosk epidemiological date required from the various industrial y leading to die development of (eateries Is based upon the possible, probable or actual presence of a ' sSsiaafan. Those Type A industrial environments would need to collect [erthe Kadike end her group (B) Is r * tesetd minimal epidemiological data, almost 902 of which la already ncrease in hepatic tumors among ^ Mg recorded or collected by moet industries for other socio-economic hlorlde In contrast to those sapsmd * ^mm sad would require only minimum outlay of cost and personnel time. of secondary or co-factors in tbs h teolc data would include an employee work history, a job exposure sis needs much further-study, ka*> and e medical illness history composed of three parte. First, of previous medical illnesses based on pre-employment history '<<-! J Health Effects of Vinyl Chlorlde/Taaburro ptlth Efl 134 and examination. Second, a record of all medical Illnesses and hoepitalleation during employment. In most cases, with certain modifications this can be obtained by way of third party Insurance payments. Third ' company/plant-based mortality record baaed 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 systesis 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 la available. Where possible, area monitoring data should be utilized for these rank orderings, end preferably, when scientifically available, individual monitoring would bs 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 st s cost of approximately $10/person for the initial updating. The coat of maintenance of such records Is estimated to be less than $3/ person/yaar employed. In Type C Industries, those environments actually using carcinogens, regular history and physical examination will be required and performed with Increasing frequency es the duration of employment Increases, in dividual monitoring should be used to determine the actual exposure. Where this is not yat scientifically devalopsd, efforts should be Mde to design usable monitors for this purpose. In Type C industrial en vironments, collaborative and cooperative efforts among the industrial coasuaity, the labor force, and the aclantlflc community arc sssentlal In order to allow an accurate, ongoing systematic collection and-analyai, of the epidemiological Information. These deta will help resolve the problems, of safe exposure levels, frequency of screening needed, effec tiveness of screening, and the identification end effect of co-factors upon Individuals exposed to actual carcinogens. INDUSTRIAL WVST.TH EDUCATION In order to accomplish this, expansion of educational programs within these Industries Is needed end 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, end union representatives. In chose environ ments where probably carcinogens are Involved, educational programs are needed for Industrial medical personnel end para-medical personnel. This la sspsclally Important In those Industries where Federal occupstlonal laws require or an industry desires to Institute a surveillance program. Finally, in those Industrial environments where an actual carcinogen Is In use, educational endeavors must be expended beyond thr industrial environment. These should include the local medical com munity (In order to help them better understand the medical survelllatv service being rendered In relationship to the private physician's role In the care of the employees), the local conmunity (relative to its potential danger), the business community, end the industrial community invol' jderstanc ,landing < amities c gjmlc dlfi p evident ; tfitea* {0aplianct , fcigh volut joncem ol pd labor Itcome el } upertise ! pnunltlc * paoomlc t ,0 an ongc ${medics] ferenee wi pet scree le needed *lllty *r mi will 1 [labors t O. aw* 0JI ogre '-of CO i 1 < i r cm. .. - it Uh prole taaaes hoc mllgnent ujury. 1 ; firy occur f Sw aaoe p i fence of r \ mUa In c lajury to Wain and lemtlgat toly dete Imapecti\ tic met ,f Son-apt *' If nov tti I^lth Effects of Vinyl Chlorlde/Taaburro 135 URL 05349 S': - ft *A '* otA^Lwedicel lllneeees and hospiTQStftcayss, with^artaio modification, '4 Insurance payment*. Third, d bqafij on the diagnosis t time 0f ofthi* Information Is presently involved In eimilar use of carcinogens, so that they may better *p4erstsnd the health end safety of these employees. The lack of under standing on the part of the non-involved business and industrial comlalcied can lead to unnecessary socio-economic Stigmatization or ecoic difficult!*. by chemical Industrie* (for busin*,, or^ee yart of vleel statlatlc*. u evidence of the potential effectiveness of such medical surveillance *Lte *n actual carcinogenic environment, Table III illustrates^ftie odlc medical history and physical , in addition* rank order monitoring cupation where individual chemical* eible, eree monitoring date should * and preferably* when scientific,]], uld he substituted for the rank ore*, ^liante rates for medical screening over Che past three years. This |i|h voluntary compliance on the part of the employees illustrates the ^ecarn of the employees and the cooperative effectiveness of management . labor in identifying and correcting Industrlel problems. it has ieoae clear in our peat four years, that Industry's need for scientific partis* and asaiatxnca must be coupled with the medical and scientific jg^mitlsa1 batter Understanding of. the work environment end Its socio-tiaaic relationship. Tha conducting of medical surveillance programs - job exposure indices based on rani en done in actual industrial envlrg*. O/person for tha initial updating, orda if eatlmatad to he lees than It as ongoing, long-tar* basis requires adaptation of our present methods . iriical screening so as not to cause unnecessary and excessive interUfjica with the industrial function end at the seme time deliver the oat screening surveillance system at the lowest cost. Much more work vd*d in adapting such systems and demonstrating their implement- nenta actually using carcinogens, atlom will be required and perform ratlOh>of employment locreesea. uco determine the actual exposux*. ^developed, afforte ahould be >urposm* In Type C industrial arativ^efforte among the Industry aciaudflc coamualty ate eeetniu. mUtty and their coat effectiveness. This is not a short-term endeavor ml vil* require well thought out planning and a marked increase in the *lUbot*tlve effort among industry, the labor force, the local communl- ad the scientific communities (local of regional onas). Regional gaegraphlc cancer centers can play a major sole in assisting and ' jfMuleg, vltb scientific expertise, their local Industries in *nj a*nrt"t to better identify potential carcinogens end develop the moat. * maeas of preventing both acute toxicity and long-term carcino- gMelCf* Log systematic collection .and iwIm. Theae data will help resoly* tw> me . aqueney of acreenipg needed, rll*.ification and effect of co-f*cl*> arclhogena, *mi chloride la.a baelc chemical for plaatlca manufacturing and has . i an anesthetic agent. Vinyl chloride's previously unknown eieetenie capability appears to be related to the body's ability to ^eeri It from a non-toxic or minimally toxic chemical to a toxic and, am *v*longed exposure, cancer-forming agent. Early exposure in animals on of educational programs ) uu be continually improved and * to* arclnogens should have educdMft employees, but also their faailiae representatives. In cheat oe*t* Involved, educational program tfp v : nel and para-medical peraoemri e Industries where Federal er*aa aairea to institute a ivmUliei f %. horfv cells to make adaptive changes which may prepare them for it transformation and appear to precede evidence of morphological These findings appear to occur before e low-grade chemical inSM eerer*. Vinyl chloride chemical Injury in man appears to follow gkgam pattern. Present clinical date In humane now demonstrate eviEBto pro-cenear injury and cancer transformation of various types of la different organa of the body. Manifestations of pre-canceTOus iMg to organs other then the liver (such as the lung, heart, spleen, lyaphatlc eyetern) may also be occurring end require further al environment* where en erlaal icieit. deevora must he expanded h|Ni d include the local medical V** understand the medical awedil itien of these pre-cancerous chemical injuries requires a I** "Wing system of surveillance and the development of dlag- Ip to the private phyaiciaa't M tttototoe which can identify specific causal agents In the presence >cal coamunity (relative W Ml ,(Uv Injury. Such a systematic approach has been developed jnity* and the industrial <" le operation. Its initial achievements appear to be the Health Effect* of Vinyl Chloride/Taaburro Health 136 foundation for future success In controlling the health effects of dustrial chemicals. REFERENCES 1. Sellkoff, I.J., Hanmond, E.C., Eds: Toxicity of vinyl chloride polyvinyl chloride. Ann. NY Acad. Scl. 246:1-337. 197S. 2. Tamburro, C.H.: The hepatic role In carcinogenesis and-lts early detection -- the vinyl chloride model, Yale Journal of Medlclne~and Biology (In press). 3. Whelan, J.G., Creech, J.L., Tamburro, C.H.: Angiographic and radio* nuclide characteristics of hepatic angiosarcoma found In vinyl chloride workers. Radiology 118:549-377. 1976. ? 4. Pllakin, M.: Peliosis hepatis. Radiology 114:29-30. 1975. 5. Hefner, R.E., Jr., Vatanabe, P.G. Gehrlng, P.J.: Preliminary studies of the face of Inhaled vinyl chloride monomer in rats. Ann hy Acad. Sci. 246:135-148. 1975. 6. Elmors, J.D., Wong, J.L., Lawbach, A.D., et al: Vinyl chloride mutagenicity vis the metabolites chlorooxirane and chloracataldehyde monomer hydrate. Biochem. Blophys. Acts 442:405-419. 1976. 7. Weber, G., Laa, H.A.: The molecular correlation concept. In Methods in Cancer Research. Edited by N. H. Busch. NY, Academic Press Inc, 2:523-578, 1967. 8. Radike, M.: Personal communication. 9. Maitool, C.: Recent findings on the carcinogenicity of chlorinated olefins. Conference on Co^arative Metabollem end Toxicity of Vinyl Chloride-related Compounds. National Institute of Environmental Health Sciences, NIB, May 2-4, 1977. 10. Greenberg, R. A., Tamburro, C.H., and Kupchalla, C.E.: A prospec tive medical surveillance program for the detection and prevention of industrially related cancer. Prevention and Detection of Cancer, Vol. II., Ed: H.E. Mleburga, Marcel Dekker, Inc., New York (In press, February, 1978). CANCE COHOR WORK c 33 O cn CJ cn o aburso 136 < ^ itrolliag the health effect# of in- Health Effectg of Vinyl Chloride/Tamburro TABLE I 137 d#: Toxicity of vinyl chloride ci. 246:1-337, 1975. e In tardnogeneaie end It# early 1, Tele Journal of Medicine and urro, C.H.: Angiographic and radio. 1 ngloaarcoma found in vinyl chloride I Radiology 114:29-30, 1975. G. Gehrlng, P.J.: Preliminary chloride monomer in rate. Ann. ky ch, A.D., et el: Vinyl chloride orooxfrane and chloracetaldehyde Vcta 442:405-419, 1976. alar correlation concept. In >y H. H. Buech. NX, Academic Preaa ^ i the cazclnogeniclty of chlorinated itaboliam and Toxicity of Vinyl l Inetitute of Environmental Health fi * and Kupchella, C.E.; A prospec-vthe.detectlon' and prevention of .ion'end Detection of Cancer, Vol. ;r, Inc., New York (In preea, ff ! j t ; wwttKS 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 URL 05351 H ealth E ffe c t* o f V in y l C h lo rid e /T a b u rro TABLE II PROPOSED VINYL CHLORIDE METABOLISM PATHWAY IN THE RAT I. Cl-CH=CHo------ Cl-CHo-CHo-OH c t ALCOHOL * Cl-CHo-CHO-- DEHYDROGENASE z CICHo-COOH z n. ci-ch2-ch2-oh h2o2 CATALASE cich2-ch2ooh-- cich2-cho III. Cl-CH=CHo--------oxidase ^ a_Cf^--^Cl-Cty-CHO--C1CH2-C00H 2SES0 IdO ` TABLE 111 COMPLIANCE OF 992 PEOPLE EMPLOYED CONTINUOUSLY AT TYPE C PLANT (JUNE 1, 1975 to MAY 31, 1977) ^onrun2-U<1 cAfALASE CICH2-CH200H----- ClCHrCHO in. ci-ch=ch2 OXIDASE Cl-CH^^CHj--^Cl-CH2-CHO--C1CH2-C00H TABU III COMPLIANCE OF 992 PEOPLE EMPLOYED CONTINUOUSLY AT TYPE C PUNT (JUNE 1a 1975 to MAY 31, 1977) YEARS NONE OF* 1st 2nd 3rd** 3 YEARS 89% 86% 84% 73% 85% 81% 58% 76% 69% 3% 7% 12% ` I^lEifNP6E^0T^TfD^^YAE^ r^V^I.PART1C1PATED ANY 0F TME TMEE 3< o a- 1 CL H)