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THE DOW CHEMICAL COMPANY Zc September 22, 1978 BENNETT BUILDING 2030 DOW CENTER MIDLAND, MICHIGAN 4S640 Joseph T. Seawell MCA 1825 Connecticut Avenue, NW Washington, D. C. cc: MCA Vinyl Chloride Research Coordinators Dear Mr. Seawell: This is to call to your attention a paper by Hans Popper et al. It is a long article with 6 pages of photographs. Note that in the discussion section, the authors state they can not tell a vinyl chloride angiosarcoma from any other. Sincerely, T. R. Torkelson, Chairman MCA Technical Panel on Vinyl Chloride Research Enclosure mh ucc X 0223q VINYL CHLOltlDH REFEAHCU COOK PI NATOKS Or. T. R. Torkcl.son, Chairman Occupational Health Associate The Dow Chemical Company Bennett Building Corporate Medical Department 2030 Dow Center Midland, MI 48640 517/636-5197 Dr. 2. G. Bell, Jr. Manager, Environmental Health & Toxicology PPG Industries, Inc. One Gateway Center Pittsburgh, PA 15222 412/434-2585 Mr. it. n. Whrolor Production Manager Chemicals & Plasticr, Division Union Carbide Corporation P. O. Box 0004 S. Charleston, WV 25303 304/747-2164 Dr. Gary Ter Haar Director Toxicology and Industrial Hygiene Department Ethyl Corporation 451 Florida Avenue Baton Rouge, LA 70801 504/388-7853 Dr. W. D. Harris industrial Toxicologist UNIROYAL, Inc. Oxford Management & Research Center Middlebury, CT 06749 203/573-2139 Dr. M. N. Johnson, Director of Environmental Health The BFGoodrich company. Chemical Division Medical Center 500 South Main Street Akron, OH 44318 216/379-3298 or 3299 Dr. C. D. Kary Shell Chemical Company One Shell Plaza BOX 2463 Houston, TX 77002 713/241-0039 r. W. M. !*<mi l It Group R&D Coordinator Air Products & Chemicals, P. 0. Box 538 Allentown, PA 18104 215/395-7215 Inc. ucc N 002240 Development of Hepatic Angiosarcoma in Man Induced by Vinyl Chloride, Thorotrast, and Arsenic Comparison With Cases of Unknown Etiology Hans Popper, MD, PhD. Louis B. Thomas, MD, Norman C. Telles, MD, Henry Falk, MD, and Irving J. Selikoff, MD Examples of human angiosarcoma following exposure to vinyl chloride, Thorotrast, or arsenic (medicinal and industrial) and cases, including children, of unknown etiology were studied to establish diagnostic criteria and to study their evolution. The uniform evolution suggests an environmental factor also in the cases of unknown etiology, which may be established by epidemiologic studies. A precursor stage is characterized by areas of combined hyperplasia of hepatocytes and a variety of sinusoidal and perisinusoids! cells associated with excess of rcticulin and with sinusoidal dilatation. The diagnostically useful picture in silver impregnations indicates reticulum formation by the perisinusoidal cells, presumably the lipocytes. The hepatoeytic proliferation suggests a hcpatocarcinogcnic but usually ndt fully expressed potential. The mixed hyperplasia of the. various sinusoidal cells proceeds to an overgrowth of angiosarcoma cells, presumably derived from endothelial cells. In early stages they are usually in contact with hepatocytes (intralobular growth). A trabecular arrangement results from' loosening of the lobular plate arrangement by dilatation of sinusoids, leading to primary peliosis. With disappearance of the hepatocytes, various growth patterns develop, terminating in nodular, solid angiosarcoma composed of either spindle-shaped or polyhedral cells which undergo necrosis or hemorrhage (secondary peliosis). The interaction between hepatocytes and sinusoidal cells requires elucidation. (Am J Pathol 92:349-378, 1978) The recognition of the association between exposure to gase ous vinyl chloride during its polymerization to the common plastic poly vinyl chloride and the appearance of hepatic angiosarcoma1 has increased the interest in this tumor. This concern was accentuated by its production in rodents exposed experimentally to vinyl chloride before the human lesion was recognized.* Until then, hepatic angiosarcoma had been con sidered rare in man, although it has been known that exposure to thorium dioxide (Thorotrast)* and inorganic arsenicals 4 may be followed by de- Frurn the Stratton Ldnmq for Liver Disrate, Mount Sinai School of Medldne of the City I'nivcnity of New York, New York, New York; the Laboratory of Pathology, National Cancer Institute, NIH. Bcthcada. Ifaqlnd; the Office of Medical Affairs, Bateau of Radiological H*aMk FDA. Rockville. Maryland; tW Chronic Disease Division, Bureau of Epidemiology, Center fur Disease Control, USPHS, Georgia; and the Environmental Sciences Laboratory, Mount Sinai School of Medicine nf die Cty University of New York. New York. New York. Supported In part by Na^mal Institute of Occupational Safety and Health (NIOSH) Contract 210-75-0044. Accepted for psibikatina March 30.1978- Atldrcss reprint mpants la Louts & Thomas, MD. Chief. laboratory ol Pathology. National Cancer Institute. NIH. RsrtUbg Ilk Room 2A27. Bethnda, MD 20014. 0002-9440/78/0810-0349S91DO 349 !/oU^r <73-/4 /lolvSTtf 7t ` m 360 POPPER ET At IMTIMOtULM AS WITH FWIOHASA American Journal of Pathology StCMOAtV KUOM TtxT-nam l--Proposed schema of evoliition of hepatic anttiowranma (ASX ?ri '-.f. giopericytoma, mixed mesenchymoma, hemorrhagic hepatocellular carci noma, or various types of metastatic tumor were diagnosed as angiosar coma. -The mixed hyperplastic areas are not readily diagnosed in needle biopsy specimens. Silver stains are then most helpful. Discussion Morphologic study of a large number of cases of angiosarcoma and their developmental stages revealed few, if any, differences between the eases induced by agents such as vinyl chloride* arsenic, Thorntrast and those in which no etiologic agent has been established. Intensive study of a far larger number of cases did not confirm our early impression that vinylehloride-related angiosarcoma differs morphologically from cryptogenic cases.* This suggests that in cryptogenic cases, environmental factors are responsible, the nature of which is being sought by intensive epidemio logic studies,1* The available surveysl,J* indicate a recognized environ mental etiology in only a small percentage of cosds of hepatic angiosar coma. The observations, provided information of potential assistance in the diagnosis of the lesion, including the precursor stage. This inftvmatiun should Ik* helpful in the diagnosis of industrial hazards. The enforcement of strict hygienic regulations has reduced the levels of vinyl chloride in the polymerization plants or other places where polyvinyl chloride is proc- UCC 002242