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DEUT. MED. WOCHENSCHR. 98 2311-U (1973) CHRONIC TOIIC LIVER DAMAGE IN THE CASE OP WORKERS IN PVC PRODUCTION H. J. Marsteller, et al. BFG65529 DEUT. MED. WOCHENSCHR. 9, 2311-14 (1973) CHRONIC TOXIC LIVER DAMAGE IN THE CASE OP WORKERS IN PVC PRODUCTION by H. J. Mars teller, W. K, Lelbach, R. Milller, S. Jiihe, C. E. Lange, H. G. Rohner and G. Veltman Medical Clinic (Director: Prof. H. J. Dengler) Pathological Institute (Director: Prof. P. Gedigk) and Skin Clinic (Director: Prof. A. Leinbrock), at the University of Bonn. For more than 30 years, polyvinylchloride (PVC) has been valued in many branches of industry as a versatile, useful plastic, and consequently it has been produced on a large scale 3 industrially, worldwide. The fact that until 1966 no observa tions concerning chronic intoxication had been published in the Western Literature explains the widespread conception that only relatively inert substances appear in the PVC production. The re-publication elsewhere 4 years later 19 of a Roumanian paper appearing for the first time in 1963 1 h concerning illnesses caused by vinyl chloride, in which Raynaud syndrome, dermatitis, "sclerodermia", thyroid insufficiency and hepatomegalies were 24 7 reported, was followed by publications from France, ' England , the USA^'^'6,13,14,22 an(j Germany**'9,10,17^ ^ the basis of 55 descriptions of cases, altogether, these made known the picture BFG65530 of illness, narrowed to "occupational acroosteolysis". An extensive symptomatic picture with the suspicion of liver function disturbances was present in only 8 of the 55 workers 7,8,9,10 _______ With the designation of occupation acroosteolysis, the view of the liver damage observed for the first time in 1949 in the 21 USSR within the framework of PVC production was obscured; these have been described as more or less pronounced "hepatitis" (in the case of 15 out of 48 workers). The cited Roumanian observation of toxic limited hepatomegalies (in about 50 to 168 __-- _ 1819 * 15 people investigated) ' and Russian communications concern ing partially subclinical "chronic epithelial hepatitis" (in 15% of the workers investigated) also thus have remained un- ' - -- noticed. ***'*** Results. Detectable esophagus varices and splenomegalies in some workers in a plant producing PVC,.together with uncharacter istic changes in the liver parenchyme, as well as the literature references which were difficult to classify, concerning "subclinical'! liver damages, gave us the incentive to investigate the morphological substrate of the liver changes by detailed laboratory diagnostic X-rays and scintigraphic investigations by means of laparoscopy and directed liver biopsy. Thus, up to the present time we have correspondingly investigated up to 20 out of 45 mole autoclave workers in a PVC production installation BFG65531 (30 to 56 years old, duration of exposure 1-1/2 to 21 years), with the suspicion of liver damage*. In this case, we obtained the results shown in Tables 1 and 2. In addition to this, the following parameters have been tested (repeatedly, for the most part), and had proven to be entirely unsuspicious or normal: hypostasis reaction, blood picture, blood sugar, urine status, lues reaction, LDH, choline sterase, acid phosphatase, iron and copper in the serum, thymol test, serum protein and electrophoretically separated subfractions, cholesterol, B-lipoprotids, triglycerides, as well as plasma coagulation factors. Of the immunological parameters, the rhcuma factors, antineuclear factors, LE cells, immune globulin fractions G, A, and M, the complement fraction B^A and the cold antibody have at first been tested because of the delineation from the Out of a total of about 120 PVC workers in the plant, 45 have thus far been examined in the University Skin Clinic at Bonn, a smaller portion because of manifest skin phenomena, but also for reasons of prophlyaxis. In the case of most of these 45 workers, there was clinically and (or) biochemically a sus picion of an etiological unclear liver damage. Up until May 1973, it was possible for 20 of them to be laproscoped, primar ily those in which this suspicion appeared to be well-founded. Naturally, we could not make any statements concerning the frequency of such liver damage on the basis of these numbers). BFG65532 4 Case number Table 1. Anamnestic data, clinical and clinic-chemical findings in the case of 20 PVC workers. For bilirubin, transaminases and alkaline phosphatase, maximum values are given from 3-6 determinations, and for the bromsulfleiii sample the maximum values from 2 determinations. (A 0) (/) C<Dt} w ab)fl rut p*& 3o: t0MU'0CX3/))L, v--MrO>t>' iC-CO0aHSOT)J. 0CSrct) 1 tH . ooc Va. Xoo iHu < co <aPu. V3) CJ *o C0co-I)u'us-' OX aaa>). aJ a> xa s . o CH H X b 3P c H O CQ A 01 W rH 4> O. *J gn 3c t/> H ca in 0) C Ft 4-4 o f-H +J 3 lw U1 <d a o l/) ii3- /--N i-H CM W CM r-H * * A* H E- s o^ U 3. CO s /-> to to '* * CM * /\ ha Cl ^ CJ 3. tco a 0) r00t ci x a. tn O J= -H a. a 0) 2. cs H 00 rt sr M HA < r--\ o o tn to a> /--\ 1 'N ro on X E LO -- o B ^4 o V. X) r^5 to c o^ o O Jh t-4 o X Xc X H to H </l po-4 O 4-* Ti o o1 u , i 33 A 3'/. a) leer 3 2 .i 32 A+ 35/< a) leer 5 3 35 A 9 a) leer liU.ische - njBicr 4 41 A+ 3'/ a) leer 1 Flasche us h)Bier 5 34 A 5 a) leer 1 Flasche -- h)Bier 6 '47 A+ 18 bl972 Billroth II 3 Cal Asiite* 7 Jl A4- 1&V a) leer ) 3-4 Flnschen Bier 3 8 45 A 8'/t a) leer 1 Flasche Bier 9 42 A 6*1* a) leer .. 1 G1m 1J Bier u 10 31 A 4 a) ,eef _-- 11 47 A 12 c) scit 1967 0 bis 2 Hyperlipidiimie, Flnschen I.eberschn<Jcn Bier 12 56 A+ 18 ( is Druckschmerz iflasihen 1.S 1 imiechten rJ Bier Oberbauch 13 36 A *J4 35 A 15 36 A 4`/ a) leer 4/4 a). leer l/ a) leer 1 Flasche l) Bier 1 Flasche l) Bier 1 Glas j J Bier " w 3 16 50 A+ 21 }) 1955 lkterus. 1968 chroni;.cher Lcberschailen - u 17 44 A 13'/ a) leer ..Idas J J Bier 18 41 + l'/i [) Druckscnmen 0b,l - 1 ini rcchten Flaschen Oberbauih Bier 19 30 A 4- 2'/. a> leer - 1.5 7.0 30 A4- 4 a) ,ecr bis 2 , kl.iM.bun *0 Bier 3 - 3 3 14 5 3 - 3 14 - - - -- -- 6,8 23 17 12,5 19 16 l.i 15,1 19 17 1.1 8,6 19 15 214 21 23 (40) 15,6 19 9.1 19 17 8,8 13 13,8 25 23 (63) 14 7,1 (28) 6,2 15 15 6,1 7,6 84 32 (27) 64 17 8,7 15 30 17 15 15 6,1 19 17 (47) 8,4 17 74 15 15 74/99/119/133 149/163/173 4- % 62/63/63/70/94 133 + 37/64/73/74/75 76/81/81 99/111/114/210 283 .. 116/119/137 . 140/163/175 T 81 80/90/90/100 -- 40/45/52 -; 17/25/30/37/38 -- 128/176/214 230/235 92/122/122 51/87/99/13.1 --' ~i 70/122/125/141 99/144/171 112/114/132 156 56 113/134/211 124/174/176 187/19J 146/140/152 251 143/160/189 189/224 111/157/202 94/128/15? 248 --j 1 --i __ i i -1 l 1 i "P* J ! i __ i i j BFG65533 Table 1. (continued) Key: a) None b) 1972 Billroth II Ca? Ascites c) Since 1967, Hyperlipidemia' "liver damage" d) Pressure pain in the upper abdomen e) 1955 icterus, 1968 chronic liver damage f) Pressure pain in upper right abdomen g) 1 glass of wine h) 1 glass of beer i) 3-4 bottles of beer j) 1 glass of beer k) up to 2 bottles of beer *A * autoclave cleaner, A+ autoclave cleaning and other work in the production process. **Numbers in parentheses values in the substrate optimization method. BFG65534 -6- sclerodermia; however, because of the generally uncharacter istic findings, control measurements of these were no longer made later, with increasing clarification. The Australia (SH) antigen was always negative. A cholelithiasis was found only in 1 patient (case 15): a solitary concretion, shifting posi tions, without hindering excretion. Table 2. X-ray and laparoscopic-histological findings in the case of 20 PVC workers (autoclave cleaners). Case No. X-ray for esophagus (0) or fundus (F) varices Laparoscopy Histology 1. 2. 3. + (0) indicated capsule fibro sis, spenomegaly. clear capsular fibrosis, beginning disorganiza tion, considerable splenomegaly, clear capsular fibrosis, beginning disorganiza tion, localized spotty reddening and vessel drawing, splenomegaly. centrolobular collagenization of sinsusoid walls, localized stellate cell activation, localized fatty degeneration, centrolobular collapse fields, slight enlargement of collagen fibrilles in the portal fields. BFG65535 Table 1. (continued) Case X-ray for Laparoscopy No. esophagus (0) or fundus _________ (F) varices.______ _______________________ _ 4. - network capsular fibrosis, heptomegaly. Histology collagenization of sinusoid walls, slight cellular fatty degeneration, stellate cell fibrosis. slight portal fibrosis local ized fatty degeneration (moder ately large drop size), slight stellate cell activation, hydropic 6. + swelling. (0 and F) beginning to complete Septal and central fibrosis, disorganization, portal hypertonus, ascites, clear splenomegaly. 7. + (0 and F) network to surface-like irregular to septal fibi-osis, capsular fibrosis, begin- localized round cell infiltra- ning disorganization, be- tion of portal field, leucocyte ginning portal hyper- delineated cell necroses, local- tonus, clear spleno- ized stellate cell activation, megaly. BFG65536 Table 2. (continued) Case X-ray for No. esophagus Laparoscopy (0) or fundus _______ (P) varices_______ _____________ 8. - spotty capsular fibrosis. 9. - slight capsular fibrosis, splenomegaly. 10. - clear capsular fibrosis, beginning disorganization, clear splenomegaly. 11. - indicated capsular fibrosis, questionably beginning disorganiza tion. 12. ? irregular capsular fibrosis, hephalmegaly. Histology indicated fibrosis of the portal fields, isolated 1 air drop, fatty degeneration, indicated septal fibrosis of the portal field, centrolob ular collagenization of the sinusoid walls, localized large-drop fatty degeneration, stellate cell activation, fine septal fibrosis, localized cellagenization of sinusoid walls. moderate fibrosis of the portal fields, fine septal intralobular fibrosization without inflamma tory activity, slight dissemi nated large-drop fatty degen eration. septal fibrosis of the portal fields, narrow intralobular BFG65537 -y- Table 2. (continued) Case X-ray for No. esophagus (0) or fundus _______ (F) varices 12.(cont) Laparoscopy 13. - slight capsular fibrosis. 14. slight capsular fibrosis. 15. clear capsular fibrosis, hepatomegaly. 16. - slight capsular fibrosis. Histology septa, slight cholestasis, slight dissemination, fatty degeneration. slight fibrosis of the portal fields, slight cholestasis, localized large-drop fatty degeneration, individual cell necrosis , glycogen nuclei, intralobular fibrosization regions, moderate disseminated large-drop fatty degeneration, indicated septal fibrosis of the portal fields, largo-drop fatty degeneration, localized stellate cell activation, slight fibrosis of the portal fields, moderate disseminated fine large-drop fatty degener ation, stellate cell activation, numerous glycogen nuclei. BFG65538 Table 2. (continued) Case No. X-ray for esophagus (0) or fundus (F) varices Laparoscopy 17. clear capsular fibrosis. 18. m fine-moderately coarse knotty disorganization. 19. - no definite pathological findings. 20. - hepatomegaly, questionable beginning disorganization, fatty degeneration of the liver. Histology septal cirrhotic disorganization, localized knotty cell regeneration. septal fibrosis, localized collagenization of sinusoid walls, moderate disseminated fatty degeneration, stellate cell siderosis. indicated septal fibrosis of the portal fields, slight localized large-drop fatty degeneration, slight stellate cell activation. indicated septal fibrosis of the portal fields, moderate disseminated large-drop fatty degeneration, indifiduui cell necrosis, stellate cell aetivation. BFG65539 From Tables 1 and 2, it may be seen that in most patients neither the biochemical parameters for the evaluation of liver function alone, nor the laparoscopic and histological findings alone could have stimulated special attention. The deviations from the standard which were detected in each individual in vestigation were in any case not very pronounced, not constant, and ambiguous. Only the frequency of a similar liver surface picture and identical histological evaluations with the back ground of identical occupational exposure with otherwise not striking anamnesis led to special weighting. Setting up the noteworthy findings according to their frequency (Table 3) shows that in the group presented here the acroosteolyses named pre viously had not been the leading symptoms of the occupationally caused damage within the framework of the PVC production ' 14 ' 22 , but instead there were thrombocytopenias and more or less strongly pronounced chronic-toxic liver damage with splenomegaly and signs of portal hypertension in individual cases. BFG65540 Table 3, Frequency of pathological findings in the case of 20 PVC workers. Symptoms Number of cases Increased bromsulfalein retention Thrombocytopenia Liver-spleen changes found by laparoscopy* Splenomegaly in selective spleen scintigrams (in liver scintigram in 2 other patients) Splenomegaly, clinical Hepatomegaly, clinical Acroosteolyses Esophagus varcises (simultaneous fundus varcies in 2 patients 19 16 14 7 7 6 4 3 Histologically, small to moderately severe hepatic alterations in all 19 cases. Discussion. Since no measurements of workplace concentrations have thus far been possible, and we have only knowledge full of gaps con cerning details of the course of production, the questions of the etiological relationships and pathogenesis remain open, for the time being. The morphological picture is completely compatible BFG65541 with the assumption of a chronic-toxic liver damage, such as can appear, for example, in the continuous or repeated administra tion o chlorinated hydrocarbons. In addition to various other unexplained points, in the formal genesis of the liver changes, the question of how we arrive at portal hypertension in some cases is also unsolved, above all, and is of a special theoret ical interest as well as practical-clinical interest. The classification of these cases into the group of intrahepatic, presinusoidal or intrasinusoidal block forms, as is obvious from the histological picture on the basis of the septal fibro- sization of the portal fields and the wire-rmesh fibrosis with collagenization of the sinusoid walls^'^'^ is still not guaranteed because of the*lack of measurements of the liver vein occlusion pressure and the portal vein pressure in these patients. The relative frequency of moderate to pronounced splenomegalies permits us, to be sure, to presume the pressure- mechanical significance of the liver fibroses. Corresponding preventive investigations in other plants manufacturing or processing PVC appear to be indicated accord ing to our findings. Continuing investigations in our patients and detailed animal experimental studies for the explanation of the picture of the illness are planned. Received 26 September 1973. BFG65542 Literature 1. Bianchi, L.: The problem of Liver Fibrosis. Schwiz. med. Wschr. 100 (1970) 1214. 2. Chatelain, A., P. Motillon: A syndrome of acroostelysis of occupational origin, and new proof in France. J. Radiol. Electrol. 48 (1967), 277. 3. Cook, W. A., P. M. Giever, B. D., Dinman, H. J. Magnuson: Occupational acroosteolysis II. An industrial hygiene study. Arch, environm. Hlth. 22 (1971) 74. 4. Cordier, J. M., C. Fievez, M. J. Lefevre, A. Sevrin: Acroosteolysis and skin lesions associated with two workers concerned with cleaning autoclaves. Cah. Med. Travail 4 (1966) 14. 5. , Dinman, B. D., W. A. Cook; W. M. Whitehouse, H. J. Magnuson, T. Ditcheck: Occupational acroosteolysis I. An epidemiological study. Arch, environm. Hlth. 22 (1971) 61. 6. Dodson, V. N., B. D. Dinman, W. Whitehouse, A.N.M. Nast, H. J. Magnuson: Occupational acroosteolysis. III. A clinical study. Arch, environm. Hlth. 22 (1971) 83. 7. Harris, D. K., W. G. F. Adams: Acroosteolysis occurring in men engaged in the polymerization of vinyl chloride. Brit. med. J. (1967/3). 712. 8. Jvihe, S., C. E. Lange: Skin changes resembling sclerodemia, Raynaud Syndrome and acroosteolysis in workers in industries producing PVC. Dtsch. med Wochenschr. 97 (1972), 1922. BFG65543 15 9. Jiihe, S., G. Veltman: Clinical data on th@ so-called vinyl chloride disease. First International Symposium of Plant Physicians in Chemical Industry. 27.4. (1972) 10. Jiihe, S. , C. E. Lange, G. Stein, G. Veltman: Clinical data on the so-called vinyl chloride disease. Congress of the German Society for Occupational Medicine, Dortmund, 1972. 11. Klinge, O., H. W. Altmann: Morphology of toxic hepatoses. Munch med. Wschr. 113 (1971) 1529. 12. Lange, C. E., S. Jiihe, H. J. Mars teller, R. Muller, G. Veltman: Liver damage within the framework of the so-called vinyl chloride disease. Congress of the German Society of Occupational Medicine, Munich 1973. 13. Markowitz, S. S., C. J. McDonald, W. Fethiere, M. S. Kernzner: Occupational acroosteolysis. Arch. Derm. 106 (1972) 219. 14. McCord, C. P.: A new occupational disease is born. J. Occup. Med 12 (1970) 234. 15. Puschin, G. A.: [Translators Note: the title of this article has been transliterated from the Russian into German; a re transliteration is not possible. Article appears to concern diseases of the liver in workers in the plastics industry.] Sov. Med. (Moscow)2 (1965), 132. 16. Schmid. M: Liver histology of the various forms of portal hypertension. In: Markoff, N. G. (ed): The therapy of Portal Hypertension (Thieme: Stuttgatt 1968). 17. Stein, G., S. Jiihe, C. E. Lange, G. Veltman: BFG65544 Osteolyses in the form of bands in the terminal phalanges of the hand skeleton. Fortsche. Bontgenstr 118 (1973) 60. 18. Suciu. I., I. Drejman, M. Vavaskaii: Contribution to study of illnesses caused by vinyl chloride. Med. interna (Bucharest) 15 (1963) 967. 19. Suciu, I., I. Brejamn, M. Valaskait: Study of illnesses caused by vinyl chloride. Med. d. Lavoro 58 (1967) 261. 20. Randon, B. N., R. Laksminsrayanan, S. Bhargava, N. C. Hyak, S. K. Sama: Ultrastructure of the liver in non-citrohotic portal fibrosis with portal hypertension. Gut II (1970) 905. 21. Tribuch, S. R., et al. (cited from Puschin, G. A.): Gig. Sanit. (Moscow) 10 (1949) 38. 22. Wilson, R. H., W. E. McCormick, C. F. Tatum, J. L. t Creech: ; Occupational acroosteolysis. J. Amer. med. Assoc. 201 (1967) 577. Dr. H. J. Marsteller. Dr. H. G. Rohner, Dr. W. K. Lelbach University Medical Clinic University Lecturer Dr. R. Miiller Pathological Institute of the University Dr. Susanne Jiihe, Dr. C. E. Lange, Prof. Dr. G. Veltman University Skin Clinic 53 Bonn 1, Venusberg BFG65545 K `Oft y-/ \/f5f36uirf /Litton. fabLdry // 5i *2 >^o ^i/>. ;TC : r UaiwOSi'-: V BlOCAS* H TSST J.C0- A 'A/ops/ A _^ A ^ A z K) Aj LcfiJlyose otocy 3 A -* *J aj BFG65546 FORM FOR ABSTRACTS TO BE k'LBLISHI.D IN HASTROh\II.Kol.OH Y Type Abstract in Space Below HEPATOTOXICITY AMONG POLYVINYL CHLORIDE fPVC) PRODUCTION WORKERS DURINC FIRST YEAR r.p SURVEILLANCE PROGRAM. J.L. Creech, L. Hnkk, J.G. Whelan, Jr. and C.il. Tanburro. Department of Medicine, Division of Digestive Diseases, University of Louisville School of Medicine and St. Anthony Hospital, Louisville, Kentucky. Vinyl chloride and polyvinyl chloride (PVC) have been causally linked with hepatic fibrosis and angiosarcoma. All 1,183 employees of a PVC production plant were screened for hepatic lesions; 309 worked in PVC production areas, 411 in non-PVC pro duction areas, and 463 in maintenance and administrative areas. Surveillance included history and physical examination with emphasis on toxic, chemical, drug and viral ex posure, and biochemical liver function tests including alpha feto proteins, carcinoembryonic antigen (CEA) and hepatitis B antigen. Heavy ethanol consumption occurred in 237. of employees. Abnormal liver function tests were present in 277. (315), and were persistently abnormal in 77. (75). Initially, abnormal liver functions were found equally among PVC (257.) and non-PVC (277.) workers, however, persistent abnormalities were almost three times as frequent among PVC (11% vs 4.5%) workers. Of the 182 pa tients screened by isotope scans, 19 (117.) liver scans and 23 (137.) spleen scans were abnormal. Thirty-two biochemically abnormal but asymptomatic employees were biopsied; 14 had varying degrees of fibrosis; 8 had marked portal fibrosis, dilated sinusoids, atypical sinusoidal lining cells and diffuse subcapsular fibrosis, 2 angiosarcoma, 1 fatty liver and 1 sarcoidosis. Angiographic studies were performed on 30, one half of whom had evidence of portal hypertension. Angiosarcoma tumors show a character istic tumor blush which may differentiate it from other lesions. This data indicates that seemingly mild but persistent biochemical abnormalities are often the only indication of far advanced or severe hepatic injury in PVC workers. Early histological and angiographic studies appear to be required for complete evalu ation. MAILING ADDRESS OF PRINCIPAL AUTHOR Carlo H. Tamburro, M.D. College of Medicine and Dentistry of New Jersey 100 Bergen Street Newark, N.J. zm. 07103 Check the most appropriate category below. Absorption Secretion Motility SI Liver Bile Salt-Biliary Tract Clinical Disorder Endoscopy Miscellaneous S Please publish this abstract in GASTROENTER OLOGY at a cost of SI3.00. My check payable to the American Gastroenterological Association is enclosed. S Please bill me -- payment to be made prior to publication. "'Please do nut publish this abstract in GASTRO ENTEROLOGY. Waiver -- support for this must be made in writing and accomoanv this abstract. Received Accepted Session Date Time Date Presentation BFG65547 Dr. Schanker, Dr. Senior, members and guests: The development of angiosarcoma among vinyl chloride workers initiated a surveillance program, one of whose purpose is to determine the effectiveness of liver function studies in the detection of vinyl chloride liver injury. 315 or 27% of the 1,183 employees of a polyvinyl chloride production plant were initially found to have abnormal liver function tests. Persisting abnormalities were found in 75 or 7% and occurred three times more frequently among the vinyl chloride workers. 45 of the 75 persistently abnormal employees have been etiologically investigated. May I have the FIRST SLIDE PLEASE? Only three biochemical liver function tests, serum glutamic pyruvic transaminase, gamma glutamic transpeptidase, and alkaline phosphatase correctly indicated liver dysfunction in 80 or more percent of the cases. As shown here in RED, in 75% of the individuals, however, the Gamma GGT was abnormal in the absence of any other biochemical, radiological or histological findings. All other liver function studies were either less effective, as shown here, or have not as yet been found useful. ICG and bile acid clearances are presently under study. NEXT SLIDE PLEASE 447 employees have received radioisotopic liver and spleen scans, 40 of whom were biochemically and histologically studied. As shown on the left in YELLOW, 50% had abnormal liver scans and biochemical and histological abnormalities. However, as shown in RED, 11% had abnormal liver scans, but were biochemically and histologically normal. In contrast, as shown on the right in YELLOW, 35%. had normal liver scans, but were found to be biochemically and histologically abnormal. BFG65548 33 of these individuals had angiographic and hemodynamic studies. As shown in the NEXT SLIDE, on the left in YELLOW, 332 of these indivi duals had radioisotopically enlarged spleens and an elevated wedged hepatic vein pressure of greater than 17 mnHg. 112, however, as shown in RED, had enlarged spleen scans, but normal wedged hepatic vein pressures. Moreover, as shown on the right in YELLOW, 112 had normal spleen size, but had elevated wedged hepatic pressures. As seen in the NEXT SLIDE, angiographic studies of angiosarcoma, demonstrated a characteristic tumor blush as shown here at 8 seconds. Most liver tumor's blush occur in the arthrially phase 7 to 9 seconds after injection and are completed by the portal venus phase at the most 20 seconds after injection. As shown in the NEXT SLIDE, angio sarcoma's tumor blush remain visible far beyond the venus phase as seen here, 38 seconds after injection. May I have the LAST SLIDE PLEASE? Liver histology in these 40 individuals demonstrated various histological lesions including portal fibrosis, atypical sinusoidal lining cells, subcapsular fibrosis, fatty infiltration, increased vaculated muclei and angiosarcoma. As shown here in the first column on the left in RED, only one of the 17 individuals with less than four year's exposure to vinyl chloride had significant pathological findings. In contrast, similar histology was found in one of the 12 individuals with four to ten year's exposure, in three of seven with 10 to 19 year's exposure, two of whom had angiosarcoma and in 3 of 4 with 20 year's exposure, one of whom also had angiosarcoma. May I have the LIGHTS PLEASE? BFG65 In summary; No singular biochemical or radiological test is sufficiently sensitive to include all possible hepatocellular injury due to vinyl chloride exposure, and when used singularly, may lead to false indications of liver cell injury. Secondly, angiosarcoma of the liver produces a very late venus phase tumor blush, which can assist in its differential diagnosis. Thirdly, liver injury, characterized by biochemical, histological, and hemodynamic abnormalities appears to occur more frequently with increasing exposure to vinyl chloride and/or its associated products. Finally, angiosarcoma appears to develop after prolonged exposure and with the development of excessive fibrosis and hepatocellular injury. Thank you. This speech was presented at the 25th Aniversary Meeting of the American Association for the Study of Liver Disease on October 29, 1974 at the Ambassador Hotels in Chicago, Illinois, by Dr. Carlo H. Tamburro. BFG65550