Document MG01Y4YDpmbrqEv8YwaVN9NjV

. . riir. yai i joCKNAi 01 moi w;y ano Mr.m< ini. SI <1478). C>7-8() The Hepatic Roie in Carcinogenesis and :/ Its Early Detection--The Vinyl Chloride Model1,2 CARLO H. TAMBURRO University of Louisville School of Medicine, Louisville, Kentucky Kcccivcd October 17, 1977 Hti/6 The liver's ioIc in vinyl chloride toxicity and carcinogenicity is providing a heller understanding of the chemical carcinogenesis mechanism. A variety of both malignant and benign hepatic tumors has been demonstrated with prolonged exposure to vinyl chlondc. The multi-system involvment of this carcinogen and toxin has provided a model for the study of chemical carcinogenesis common to both man and animat. Clinical studies have shown the usefulness of biochemical, radioisotopic, and radiological studies in the detection of toxic and carcinogenic lesions. Animal studies have demonstrated the biochemical metab olism by the hver of vinyl chloridc'produced intermediates which arc mutagenic in bacterial systems and may be the ultimate carcinogens. Hepatic suhccllular enzyme studies prove preliminaty evidence of ccllulai adapt.ii ton and met cased detoxification. Disruption of (his oxtdi/.utum and detoxification balance may be the key to the malignant transformation of cells. A working hypothesis is presented which may explain the metabolism of vinyl chloride into nmtageme intci mediates by the liver cell and (he develop ment id malignant tuuistormatinn by extra hepatic sinusoidal lining cells, lung cells, and biain tissue. *r'-r 11 y* 4- si -\*X i ill INTRODUCTION Currently there is a growing concern that chemical compounds may be respon sible for most human cancer through environmental contact. Although 100,000 to 200,000 new chemicals are introduced into industry each year, little is known about their effects. These compounds are primarily synthetics and thus not natural to the environment. The view that industrial chemicals may be latent carcinogenic hazards has again been brought into sharp focus by the discovery of vinyl chlorideinduced angiosarcoma. Vinyl chloride (CHi = CH-Cl monochloroethyene, a gas) is the basic molecule or monomer of polyvinylchloride and its co-polymers and one of the most important organic intermediates in the plastics industry. The resulting plastic resin, polyvinyl chloride, is used in innumerable consumer and industrial products, such as containers, wrapping film, electrical insulation, pipelines, credit cards, etc. Until recently (early 1970'sl vinvl chloride was regarded as bcine rela tively non-toxic 11,2J. Initially this opinion seemed to be supported bv the facts that if was used transiently as'an anaesthetic and had been used commercially in indus try for many years 13j. The direct information on the toxicity of vinyl chloride to man was obtained from experiments by research workers on themselves, from the evaluation of its suit- 67 1Portions of ibi.v work wert? .supported by a gram from Mamtfacun ing ChemiMs Association and hy National Cancer Institute* Contract 0NOI-CN-55212. *Thii article is the thirteenth in a series entitled, "Seminars on Liver Disease," that have been piescnted as part of tbc Training Program in Liver Disease at the Veterans Administration Hospital. West Haven. Connecticut. Dr. HatoUO. Conn. Prolessor of Medicine, Yale University School of Medicine, and Dirccioi of (he hauling Piogtam in liter DivCavc. is guest editor. i- ' address reprutt rcMuestx tot Carlo H.Tambui io, M.D.. Piofcssnrof Medicine, Chief, Digestive Diseases and H ffl^ifcuDivnion. Dirccioi, Vinyl Chloride Project, 511 South Hoyd Street, P.O. Box 35260. Louisville, KY 40232 *i|t 00444)086/78/5101-0067 $01.40 o I?7* by The Yale Journal of Biology and Medicine. Ine. , al reproduetion in any form reserved. m56fcl*$W V&r R??:vrf-r EC- 1414 -6y\.?V',*..: CARLO II. TAMItURRO lily as an anaesthetic |4,5], and from study of the cases of vinyl chloride poisonfng contracted during industrial use [(>, 7, 8, 9J. Sporadic studies with vinyl chloride polymerization workers demonstrated vary ing degrees of hepatic biochemical derangements, hematological abnormalities, and skin changes |9]. Acute short term exposures led to disturbances of the central nervous system, cardiac arrythmias, severe irritation of the mucosal membrane of the eyes and the respiratory tract, and in some cases--severe pulmonary edema with obstruction of the liver and kidneys. Chronic inhalation trials in animals clearly showed that vinyl chloride was toxic to the liver and kidneys as well as irrita ting to the mucosal membranes and the lungs. Microscopic examination of liver sections showed degeneration of the central lobules while the damage to the kidneys chiefly involved the tubule and the interstitial lining somewhat like that of carbon tetrachloride damage [10, 11, 12J. BACKGROUND The literature, however, contained virtually no information on damage to man alter chronic exposure until Filatova et al. repotted disturbances of the blood vessels and nerves in individuals exposed with 20-300 ppm of vinyl chloride on a continuous basis | !3|. Cordier et al. [14] and Wilson et al. 1151 were the first to re port the hitherto unrecognized disorder termed occupational acroostcolysis (AOL) which included the symptoms of tenderness of the fingertips, gradual destruction of bony integrity of the fingers and a Raynaud's-like phenomena. Studies were initiated in animals to reproduce the acroostcolysis. In 1971, Violi et al. 116j while exposing animals to 30,000 ppm to induce acroostcolysis, accidentally discovered cancer. Maltoni et al. [17J while studying various levels of exposure demonstrated that angiosarcoma oceured at 250 ppm; the Manufacturing Chemists Association's studies [18] demonstrated these liver cancers even at 50 ppm. At the same time. Dr. John Creech, at the B.F. Goodrich Chemical Company Plant in Louisville, Kentucky, discovered an hepatic angiosarcoma in one employee. Creech, recalling an earlier hepatic angiosarcoma at the plant, reviewed the medical histories of previous employees. Four additional angiosarcomas were found, further supporting the connection between vinyl chloride exposure and tumor development. Measures to control the levels of vinyl chloride exposure were then instituted following federal regulation. THE CHEMICAL Vinyl chloride's chemical structure is a double-bonded, 2-carbon halogenated hydrocarbon which has structural similarities to tri-chloroethylene. an inhalation anaesthetic. As previously noted, vinyl chloride was once considered as an anaesthetic but was discarded because it caused myocardial irritability. Some of its important physical properties include a low boiling point, a high specific gravity, a low solubility in water, and a half-life in air which ranges from 3-20 hours. Knowledge olThe.se physical properties may be important in determining how this agent produces a cumulative effect in the environment which ultimately leads to cancer formation. Vinyl chloride is both toxic and carcinogenic, as recognized by the wide variety of associated disorders which have been found among vinyl chloride polymeri zation workers and vinyl chloride-exposed animals. A yet incomplete list of these