Document mpG33jDBovjvyEwxQ4zOZZBRd

R&S 110753 BIO-MEDICAL RESEARCH DOCUMENT DESCRIPTION FORM 63 68 69 ojxojreo 36 Duplicate in all cards: --> I year as-1961- File number [Right justify (Numeric only] Author(s), as Last Name FS (No Punctuation) and coden for journal as JAMA preceeded by one blank space 20 21 C.h. 4 40 41 77 78 Ue Sub-Index Code 60 61 62 11 12 13 Title of Report; end with space-hyphen-hyphen-space. Follow with Index Terms, separated from each other with comma-space. Avoid other punctuation; do not abbreviate. 61 62 21 22 23 24 Source (Journal, Vol., Number, Pages, Date ) 12 IX KN' f (Jo/. 37; m? qj ) ** C <7 i , r- < 61 62 31 32 Brief Summary 12. 10 SUMMARY: 61 62 61 62 63 64 V i 128 HEALTH EFFECTS OF VINYL CHLORIDE L#M*- Carlo H. Tamburro, M.D University of Louisville, School of Medicine, Digestive Diseases and Nutrition Section, 511 South Floyd Street, Room 535, MDR Building, Louisville, Kentucky 40201 INTRODUCTION Vinyl Chloride-Associated Injury in Man Vinyl chloride (CH. CH-C1 sonochloroethylene, 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 toxicity and carcinogenicity has been accumulated in man and in animals. Reports from across the world have Indicated the pre sence of thrombocytopenia, retlculocytosis, and leukopenia among the hematological disorders. Scleroderma type skin lesions, acro-osteolysis of the distal phalanges, and Raynaud's phenomenon have been well de scribed. Abnormalities in pulmonary functional capability and cardiac arrythmias associated with its use as an anesthetic have also been noted. The most widely knowndisorders include hepatic fibrosis, pellosis hepatls, 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 in animals exposed to vinyl chloride. In addition to the liver angiosar comas an1 the brain neuroblastomas, vinyl chloride-exposed rats and mice ha" shown Zymbal gland (sweat gland) carcinomas, nephroblastomas, subeutar...ius angiomas, skin carcinomas, and a variety of adenomas of the breast, pituitary- glands, and other assorted sarcomas 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 reseerch is supported by Contract No. NOl-CN-55212 from the National Cancer Institute, Cancer Control Branch. Texas Reports on Biology and Medicine, Vol, 37, 1973 R&S 110754 Health Effects of Vinyl Cl:lorji!e/T^:.V. urrv 127 UPDATE OF new medical findings related TO chip:-IDE A. Histological Sequences of Injury: The hepatic lesions in the humans and in animals related to prolonged exposure to vinyl chloride have been fairly -..ell characterised. Cr.= of the earliest findings is "activation" or morphological changes in the 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 subcapsular fibrosis with subcapsular bile cucc proliferation, which causes the liver surface to appear "pitted" with snail white scars when viewed at laparotomy or by peritoneoscopy. These lesions are associated with increased portal fibrosis of varying degree mo3t often rounded in shape on the cut surface and only rarely showing short stellate radia tion into the parenchyma. The lobular architecture, in general. Is pre served, 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 be asso ciated with increased deposition of collagen in adjacent sinusoidal spaces. In addition, there is a focal sinusoidal dilatation within the lobular architecture often associated with bl-nuclear hepacocytes, sug gesting active regeneration of the hepacocytes. More recently. Dr. Hans Popper has described focal areas of hepacocycic hyperplasia consisting of two or three cell thick places, not associated with lobular fibrosis and regeneration as seen in alcoholic and viral Injuries. With progres 33 sive exposure to vinyl chloride, there appears to develop increasing So atypla of the sinusoidal lining cells, progressive worsening of the CO focal sinusoidal dilatation (Figure 2), and ultimately, the malignant transformation of the sinusoidal lining cells (Figure 3). At present, it is not clear which of the sinusoidal lining cells (macrophage/Kupffer cell, fibroblast/Ito cell, or the sinusoidal endothelial lining cellfl^ the malignant stem cell which develops angiosarcoma. Most present dl^F strongly suggests chat it is the endothelial lining cell which ultimately becomes malignant and forms the angiosarcoma. Further studies will be needed to verify this thesis. B. Biochemical Detection: Biochemical detection of these lesions has until recently, been mainly by traditional biochemical hepatocellular studies. These have included the alanine and aspartic aminotransferases (SCPT-SCOT), gamma glutamyl transpeptidase (GGTP). alkaline phosphatase, bilirubin (both direct and indirect), and ocher enzymatic studies, such as sorbital dehydrogenase and isocitric dehydrogenase. As illustrated in Figure 6, our preliminary evaluation indicated thac the ability of these traditional biochemical tests to predict the presence of underlying histological hepatocellular damage is at best 80-85% accurate -- the most effective of which is the alanine aminotransferase (SCPT). The gamma glutamyi transpeptidaso is equally as effective but has a 6-8% false positivity; that is, abnor malities of the GGTP levels persist without histological or functional evidence of hepatocellular injury. Although elevations in alkaline phophacase most often reflected the more serious nbr.ormali tv, in almost <4 i i Health Effects of Vinyl Chlcriile/Tamburro 128 one quarter of the individuals, it was found to be normal in the presence of hepatocellular injury. More recently, the introduction of indocyanine green (ICG), an anionic dye similar in its physiological capabilities to Bromsulphaleln (BSP), has increased our ability to identify mild and latent underlying chemical hepatocellular injury. Indocyanine green can be given in various dose levels for purposes of determining hepatic clearance. At the low dose, 0.5 mg/kg, its predictability is equal to that of the aminotransferases. By increasing the dearat ;.e dose to levels of 2.5 and/or 5.0 mg/kg, one can increase the ability to identify underlying hepatocellular injury to the 98-992! range. A definitive biostatisdeal evaluation of both the specificity and sensitivity of indocyanine green, in comparison 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 workers 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 tests are very sensitive to identifying underlying disease, they have very poor specificity in Identifying the causal agent and, because of this, are suited as screen ing tools rather than diagnostic ones'. C. Various Tumor Types: n /Hepatic angiosarcoma, although appearing to be of a single cell origin, (may be of multiple cell origins. Morphologically it occurs in a cellu lar, cavernous, and solid form. The cavernous and the solid tumor forms xe most effectively detected bv radioisotopic liver scans. In addition, diagnostic angiographic characteristics differentiate angiosarcoma from primary hepatocellular carcinomas, adenomas, cavernous hemangiomas, focal nodular hyperplasia, and macronodulax regeneration of cirrhosis. Whelan et al., have described the characteristic angiography and radio.nuclide changes that are characteristic of hepatic angiosarcoma (3). The tumors exhibit central hypovascularity with puddling and are surrounded by a peripheral stain which peraists late into the venous phase of the angiographic study, Radioisotopically 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 false positive lesion on angiography similar to that seen in angiosarcomas. D. Non-Tumor Vascular Lesions: A second lesion often seen in the non-tumorous portions of tho liver is that of peliosis hepacls; it has been extensively described by Pliskln (4). 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-carcinogenic or pre-angiosarcomatous lesion in vinyl chloride i < I iI I R&S 110756 Health Effects of Vinyl Chleride/Tanburro 129 workers is still under study, E. Radioisotopic Detection: The ability of 99raTc sulfur colloid liver scan to detect anatomical lesions, based on the best medical diagnosis, is supported by the find ings that, of the 19 cases with anatomical lesions, only three were radioisocopically reported as normal. In one of the three reported normal cases, subsequent radioisotopic scans done three months later revealed the underlying abnormalities. What is equally important is that in the 957 "normal" individuals, the scan was reported as abnormal in only 32 cases. These data, therefore. Illustrate an 84* sensitivity (16/19) and a 97% specificity (925/976), with only a 3% false positive rate (32/957). This false positive rate was markedly reduced in sub sequent years when repeated radioisotopic scans could be compared to _. Initial baseline ones. It is our present opinion that the radioisotopic scan, either camera or rectolinear, represents the most effective means of identifying early anatomical lesions with the least degree of false positivity, thus preventing unnecessary diagnostic evaluation. The value and effectiveness of ultrasound versus the radiological isotopic scan as a screening procedure is under study, _____ - 7. Associated Spleen Disorders; An enlargement of the spleen, as determined by radioisotopic scans (greater than 14 cm in longitudinal length) and verified by autopsy or laparotomy in 12 cases, has been seen In 60% of the Individuals with angiosarcoma and 40% of those individuals with the peliosls hepatis lesion. As illustrated in Figure 6 the correlation between spleen size and wedged hepatic vein pressure among vinyl chloride workers illustrated some disparities. At least 10-12% of those individuals with splenomegaly had no evidence of an elevated portal pressure as reflected by wedged hepatic vein pressure. In addition, angiographic studies demonstrated circular lesions in the spleen (llenal peliosis) which had persistent Staining characteristics and were associated with a shortened celiac artery to portal vein circulation time and Increased spleen scan size. The use of 99mTc sulfur colloid clearance by both the liver and spleen gives further suggestive evidence that spleen macrophage cell activity might play a role In the splenomegaly and/or the vascular findings. In the individuals with llenal peliosis, there is a steep rise in the up take of 99mTc sulfur colloid by the spleen after initial recirculation. This may be due to either Increased blood flow and/or increased total number of activated macrophaglc cells. Studies are now under way to further delineate'these lesions. G. Lung Findingsi The medical surveillance program has also illustrated the presence of an unusual lung finding among this cohort of vinyl chloride workers. The abnormality Is characterized by a midzonal lateral pleural thickening, which, on histological examination, thus far has simply illustrated fat and fibrosis. The importance of this finding in approximately 4% of the work force may be non-occupational but regional, i.e., other environmental] pollutants, infections, etc. These lesions do not appear co be (J! R&S 110757 H<-,; iii Kf`errs of Vinyl Giloridu/Tamburro 130 R&S 110758 associated with any pulmonary functional disorders; and their signifi cance and relationship to sticking, tuberculosis, asbestosls, fungal in fection or possible geographic non-occupational environmental pollutants are under study. There is. however. 6rellminary)t-pidealologlcal and ^ilstologicalj data, that strongly suggests an Increase In the trcqucncy ot lung canceramong vinvl 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, race, and sex. Preliminary studies using regional histologically matched lung cancer patients as controls indicate that the occurrence of this partic ular cell type does not appear to be a geographic phenomena. Analysis is now underway to determine if there exists a correlation between this particular histological cell type and the work exposure history of this cohort population. The correlation, if any, between our pleural findingsJ and this cellular type of lung cancer has yet to be determined. METABOLIC/PATHOCENESIS UPDATE ON VINYL CHLORIDE Our present knowledge of the metabolism and pathogenic mechanism by which vinyl chloride Induces hepatic lesions may best be summarized by Tablell. 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: chloroethylene oxide spontaneously rearranges to form chloroacetaldehyde, which is then further oxidized to monochloroacetic acid or converted to chloroethanol. Monochloroacetic acid 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; and at higher levels, vinyl chloride is excreted via the lungs unchanged (5). Elmore et al., utilizing a modified Ames system and pure synthesized vinyl chloride intermediates, have shown that vinyl chloride, chloroethanol and chloroacetlc acid-are not mutagenic in their .biological systems (6). This strongly supports the hypothesis that vinyl chloride monomer is neither hepatotoxic nor carcinogenic until it has been metabolized to its Intermediate forms by the liver and/or other tissues. However, chloroacetaldehyde and chloro ethylene oxide were definitely found to be mutagenic, producing recom bination DNA defects in bacteria. These findings present difficulty in explaining why the hepatocyte, as the primary metabolic site for vinyl chloride, does noc undergo any significant evidence of hepatotoxicity nor malignant transformation. The adjacent sinusoidal lining cells must either metabolize the vinyl chloride in a similar manner but have a less effective detoxification of the metabolite or receive from the hepatocyte the Intermediate meta bolites, such as chloroethanol, which it may then convert to chloroacetaldchyde without being able to detoxify or further oxidize this mutagen. Although the hepatocyte Is the primary site for vinyl chloride Health Effects o f Vinyl Chloride/Tar-.burro 13 i 6 S i-0 W metabolism, its capacity to detoxify the vinyl chloride intermediate: metabolites may be the major reason it does not undergo malignant trans formation. Primary hepatocellular biochemical alterations observed during prolonged exposure to vinyl chloride in the rat may add further evidence to sup33 port this concept. Subcellular enzymes and metabolites were studied in 99 animals exposed to 10-20,000 ppm of vinyl chloride ranging from 14-137 hours. Microsomal, mitochondrial, and cytosol enzymes, including p450, NADPH cytochrome c_ reductase and mixed function oxidase, were studied. Clucathione and glutathione reductase as oxidative and detoxification markers were also determined, in addition to the conventional clinical biochemical studies, which included aspartate (SCOT) and alanine (SOFT) aminotransferase, alkaline phosphatase, bilirubin, lactic acid dehydro genase, total protein, albumin, cholesterol and triglycerides. After 137 hours of exposure, no significant changes occurred in the mitochon drial or the microsomal enzymes nor in the glutathione content. There was an Increase in the glutathione reductase at 30 hours and a signifi cant decrease in glucose-6-phosphatase (G-6-P) after 71 hours of exposure, followed with an Increase in glucose-6-phosphate dehydrogenase (G-6-PD). These biochemical findings occurred without evidence of histologically discernible changes in the conventional biochemical studies. This decrease in G-6-P 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 tumors. Their studies demonstrated a decrease In gluconeogenesis with a reduction in G-6-P and an increase in G-6-PD and transaldolase. These biochemical changes were followed by an increase in purine biosynthesis (increased phosphorlbosylpyrophosphate aminotransferase - FRPP) and eventually an increase in the production of ATP and GTP, leading to increased nucleic acid synthesis. At the termination of our experiment (at 37 hours), there were no signif icant changes in PRPP; but studies are now underway exposing animals to up to 250 hours to determine If the hepatic enzyme biochemistry in vinyl chloride exposure Is similar to that seen in rapidly dividing primary hepatocellular tumors. It may well be that these findings may represent an adaptation of the hepatocyte, with increasing nucleic acid synthesis for purposes of repair, and may make these cells more susceptible to malignant transformation If the carcinogenic agent is unable to be re moved or detoxified with sufficient efficiency. In contrast, the sinu soidal lining cells may well be able to oxidize these metabolites but unable to detoxify them effectively and therefore be more susceptible to developing DNA injury. Studies have begun in our laboratory to isolate hepatocytcs and the various sinusoidal lining cells and determine the individual cell types' ability to both oxidize vinyl chloride, as well as detoxify its inter mediate metabolites. These studies, only recently begun, have already demonstrated unusual differences between the enzyme activity of hopatocytes versus mesenchymal cells. Our preliminary studies, which require further verification, failed to demons crate mixed function oxidase activity (based on micromoles per minute per million cells) in contrast to the hepatocytes. Further purification of the mesenchymal cclJs and Hc.ilt.Ii Effects of Vinyl Cliloride/Tamburro 132 verification of their cellular type must be done before any definitive conclusions can be drawn from these preliminary observations. They do, however, suggest that metabolic differences of the various cell types may play an Important role in the ability of cells to oxidize and/or detoxify potential carcinogens. Pathogenesis via Human Case Studies: The co-factor role of such agents as alcohol in the pathogenesis of vinyl chloride carcinogenesis may be suggested by a naturally paired two-case 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 16 years, and estimated exposure during this time ranges from 50-10,000 ppm of vinyl chloride. He had a history of extensive alcohol consumption and was discharged from employment because of this in 1963. In 1962 he had the first clinical abnormalities related to liver injury, and these'were-identified histologically as being alcohol induced in 1964. His alcohol consumption was greater than 512 cc per day. Case B - this Individual was also employed in the same polymerization plant and began working at Che same time and at the same jobs and from 1947 until Case A was discharged 18 years later. Case B continued to work in poly merization plant process for an additional ten years at exposure panges of 50-10,000 ppm. In 1974 during the medical surveillance program's Initial phase. Case B was^-ldencified 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 peraay. He did, however, have a history of malaria during his military service prior to vinyl chloride exposure and was transiently HB^Ag positive in 1974. 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 hepatls, sinusoidal cell activation, focal sinusoidal dilacation and ufe- areas of rounded portal fibrosis. Histologically, the hepatoeytes showed jj| atypical change consistent with hepatocellular carcinoma and the sinuHH soidal lining cell changes characteristic of angiosarcomatous tissue. 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 role in the hepacocyte's inability to detoxify the vinyl chloride metabolites, there by causing DNA injury and ultimately leading to the development of primary hepatocellular carcinoma. JlSome recent animal studies by Dr. Martha Radike and her group (8) in 'll Cincinnati have shown a four-fold increase In hop.-ii-ir tumors among lalcohol-fcd rats exposed to"vinyl chloride inconerast to those exposed v*to vinyl chloride alone. The role of secondary or co-factors in the development of chemical carcinogenesis needs much further study, both in fio (/> O -4 CD O R&S 110761 , Health Effects of Vinyl Chloride/Tat-burro animals and in human observations. The importance of the hepatoc'/te's ability to adequately metabolize vinyl chloride is further illustrated by the preliminary reports of Dr. X.iltoai et al., (9), indicating that newborn rats exposed to vinyl chloride develop a_four-fold increase in primary hepatocellular cancer. In con trast, the adult rat oT thd Saae Sp6dles"daveiops angiosarcomas. Review of Prospective Medical Surveillance System: It is highly unlikely that any singular approach to the understanding of the chemical carcinogenesis (l.e., chemical structure studies, animal experiments or human epidemiological studies) will completely succeed in characterizing the pathogenic sequence. Structural studies of chemicals can help direct attention to those agents which may be more carcinogenic. However, metabolic activation of chemicals also needs to be done and further studied in Anes-cype bacterial systems to determine whether the metabolites are the potential mutagen/carcinogens. Even with this in formation, the methods by which these agents produce cancer must be Illustrated in animals so that we may develop earlier and more effective means of prevention and screening of our industrial workers. Although vinyl chloride has demonstrated both in animals and humans almost identical histological and morphological changes, this illustra tion 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 ment the effectiveness of our prevention methods and surveillance pro grams, which are often instituted on the basis of limited knowledge and in time of crisis. To this point, a prospective medical surveillance system has been designed and initiated by the University of Louisville in collaboration with the B. F. Goodrich Company and its unions (Distil lery Workers Union, International Brotherhood of Electrical Workers, International Association of Machinist Workers, and Pipefitters Union). This prospective prototype system is based on the classification of in dustrial environments into three categories (10). Type A or possible carcinogenic: This would Include those Industries utilizing materials not yet studied for their carcinogenic potential. Type B or probably carcinogenic: This would include those Industries utilizing a material or materials suspected to be potentially carcinogenic. Type C or actual ly carcinogenic: This would Include all industries utilizing a material known to be cancer-producing either in animals or man. The basic epidemiological data required from the various industrial categories is based upon the possible, probable or actual presence of a carcinogen. Those Type A industrial environments would need to collect or record minimal epidemiological data, almost 90E of which is already being recorded or collected by most industries for other socio-economic reasons and would require only.minimum outlay of cost and personnel time. This basic data would include an employee work history, a job exposure history, and a medical illness history composed of three parts. First, a record of previous medical illnesses based on pre-employment history Uc.il th Effects of Vinyl ChloriiWTai-.burro 134 and examination. Second, a record of all medical illnesses and hospi talization during employment. In most cases, with certain modifications, this can be obtained by way of third party insurance payments. Third, a 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. Uhere possible, area monitoring data should be utilized for these rank orderings, and preferably, when scientifically available, individual monitoring would be substituted for Che 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 $10/person for the initial updating. The cost of maintenance of such records is estimated to be less than $3/ person/year employed. *. Xn 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 Typ.e C industrial en vironments, collaborative and cooperative efforts among the industrial community, the labor force, and the scientific community are essential in order to allow an accurate, ongoing systematic collection and analysis of the epidemiological information. These data will help resolve the 1 pInrobolredmesr otof ascacfeomepxlpisohsutrhe isle, veexlspa, nfsrieoqnueonfcey doufcastcioreneanl inpgrognreaemdsedw, itehfifnec- ;j tthiveesneesinsduosf tsricerseeinsinnge,edaendd athnde miduestntbieficcaotniotinnuaanldly eIfmfepcrotveodf acnod-faucptdoartsed. juApnoyninindduisvtirdyuwalosrkeinxgpowseidth topoascstibulael ccaarrcciinnooggeennss. programs directed not only at their employees, bshuot ualdlsohavceheeidr ufcaa'mtijorilnieasl , ItNheDUmSTaRnIaAgLeHriEaAl LpTHersEoDUnCnAeTl,IONand union representatives. In chose 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 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 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 X Qo C/3 Nl O) ro Health Effects of Vinyl* Chloride/Tamburro 135 R&S 110763 not involved in' similar use of carcinogens, so chat they may better understand the health and safety of tfiese employees, Tr.a lac'-; of under standing on the part of the non-involvcd business and indue trial cc-umunities can lead to unnecessary socio-economic stigmatization or eco nomic difficulties. As evidence of the potential effectiveness of such medical surveillance systems in an actual carcinogenic environment, Table III illustrates the compliance rates for medical screening over the past three years. This high voluntary compliance on the part 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 become clear in our past four years, that industry's need for scientific expertise and assistance must be coupled with the medical and scientific communities' better understanding of the work environment and its socio economic relationship. The conducting of medical surveillance programs on an ongoing, long-term basis requires adaptation of our present methods of medical screening 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 is needed in adapting such systems and demonstrating their implementability 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 communi ty, and the scientific communities (local or regional ones). Regional and 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 genicity. SUMMARY 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 in animals causes body cells to make adaptive changes which may prepare them for / malignant transformation and appear to precede evidence of morphologicalJ' Injury. These findings appear to occur before a low-grade chemical in- 4j jury occurs. Vinyl chloride chemical injury in man appears to follow jlj r the same pattern. Present clinical data in humans now demonstrate evi- dence of pre-cancer injury and cancer transformation of various types ofj cells in different organs of the body. Manifestations of yre-canccrous Injury to organs other than the liver (such as the lung, heart, snleen. lnvestlgation. Early detection of these pre-cancerous chemical Injuries requires a prospective ongoing system of surveillance and the development of diag nostic methods which can identify specific causal agents in the presence of non-specific injury. Such a systematic approach has been developed and is now in operation. Its initial achievements appear to be die Hu.-.Uh Effaces of Vinyl Chloride/Tiimburro 136 foundation for future success in controlling the health effects of in- fl dus trial chemicals. |j REFERENCES 1. Selikoff, I.J., Hammond, E.C., Eds: toxicity of vinyl chloride polyvinyl chloride. Ann. MY Acad. Sci. 246:1-337, 1975. 2. Tamburro, C.H.: The hepatic role in carcinogenesis and its early detection -- the vinyl chloride model, Yale Journal of Medicine and Biology (In press). 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. Pliskin, M.: Peliosis hepatis. Radiology 114:29-30. 1975. 5. Hefner, R.E., Jr., Wacanabe, F.C. Gehring, P.J.: Preliminary studies of the fate of inhaled vinyl chloride monomer in rats. Ann. NY Acad. Sci. 246:135-148, 1975. 6. Elmore, J.O., Wong, J.L., Laumbach, A.D., et al: Vinyl chloride mutagenicity via the metabolites chlorooxirane and chloracetaldehyde monomer hydrate. Biochem. Biophys. 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. NY,.Academlc Press Inc, ,2:523-578, 1967. 8. Radlke, M.: Personal communication. 9. Maitool, C.: Recent findings on the carcinogenicity of chlorinated olefins, Conference on Comparative Metabolism 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 Kupchella, 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. Nieburgs, Marcel Dekker, Inc., New York (In press, February, 1978). R&S 110764 Health Effects of Vinyl Chlorida/lanburro 137 TABLE 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 3J #> 0) o -4 0> <Ji TABLE II PROPOSED VINYL CHLORIDE METABOLISM , PATHWAY IN THE RAT 1, C1-CH=CH2----ci-ch2-ch2-oh f DEHYDROGENASE ci-ch2-cho- II. C1-CH2-CH2-0H- h2o2 CATALASE cich2-ch2oqh-- cich2-cho CICHo-COOH III. C1-CH=CH2----- 0X1PASE ,, Cl-CH^--7CH5---Cl-CH2-CH0--o-C1CH2-C00H n M c H p p c n no, Cl CO 9910VV 1910H S$H H e a lth E ffe c ts o f V iu y l C iiio r ide/L'araH u r ro CD CO TABLE III COMPLIANCE OF 992 PEOPLE EMPLOYED CONTINUOUSLY AT TYPE C PUNT (JUNE 1, 1975 to fW 31, 1977) Laboratory tests Liver-spleen scans History and physicals YEARS NONE OF* 1st 2nd 3rd 3 YEARS 86% 3 73% 85% 81% 58% 76% 69% 31 n 12% * THIS IS PERCENTAGE OF EMPLOYEES WHO HAVE NOT PARTICIPATED IN ANY SCREENING COMPONENTS DURING ANY OF THE YEARS. THE THREE * THE DECREASE IN THE 3RD YEAR OCCURRED MAINLY AMONG NON-PRODUCT ION WORKERS ESPECIALLY THOSE IN ADMINISTRATIVE JOBS, 140 Figure i. Typical portal area showing increased portal fibrosis with mild bile duct proliferation, with few inflammatory cells mainly mono nuclear cell, (low power x 100) 33 cn o -4 <J> CD Ml \ l i* i | t (r I i t.' \ I t FT2 ,si"ufoidai "llieatlon is seen with activated sinusoidal cells (arrows). Lobular architecture otherwise well preserved wi-h normal appearing hepacocycc with some increased number of bl-nuclc-r heparocytes. (Low power x 100) tULAC"' R&S 110769 M2 -i %r *1 Hw 1 ?1 .1 S .% 5A vV i j 7 \ - M *\ ** V Figure 3. Markedly atypical sinusoidal cell change with malignant transformation (arrows) and piling up of sinusoidal cells into sinu soidal spaces. (High power x 400) R&S 110770 143 R&S 110771 ICO Figure U. Frequency of biochemical abnormalities being present and correctly indicating the presence of significant histological abnor malities (SCPT alanine aminotransferase; GCT gamma glutamyl transpeptidase; ALK ?KQS * Alkaline Phosphatase; SCOT * aspartic aminotransferase; ICD isocitric dehydrogenase and ICG " indocyanine green clearance}. CANCER >10% FAT PORTAL FIBROSIS 5 o <107. FAT v> MINIMAL FIBROSIS X MINOR CHANGES normal LIVER MN7O. wBMitAhL ICO A kk A AA kk AAA A a Ak 44 kkk AA 4 lLX A A AA A AA A A 4 A, 0-O.8 10-1.8 2.0-2.9 3.0-3.8 AO-5.0 AVERAGE VC EXPOSURE INDEX Figure 5. Correlation between liver histology and indocyanine dye clearance (0.5 mg and 5.0 mg dose) abnormalities in vinyl chloride workers with increasing vinyl chloride exposure as determined by average exposure Index whore: S`*i " nunber of months at exposure _______ level E; ^i m exposure rated on a rank order scale from 1 to 6 (l-lowest; o- highest) Sn^ = total mouths servie.-:. at VC plant PERCENT OF PATIENTS 144 // Figure 6, The correlation between spleen size and wedged hepatic vein pressure In vinyl chloride workers. R&S 110772