Document aJZbOyGRkOxbO4Bx4MjqQg0DX

-SV braR'1 lO' 1.. rill YAl I. JIIUIINM OV mot OliY AND Mr.pn INK 51 (IV78), 67-KO 'Hie Hepatic Role in Carcinogenesis and Its Early Detection--The Vinyl Chloride ModelU1 CARLO H. TAMBURRO University of Louisville Sclutol of Medicine, Louisville, Kentucky Received October 17, 1977 The liver s ule in vinyl ehlondc toxicity and carcinogenicity is providing a better understanding of the chemical cuiemogcncsis mechanism. A variety of both malignant and benign hepatic tumors has been demonstrated with prolonged exposure to vinyl chloride. The multisystem involvment of this carcinogen and toxm has provided a model for the study of chemical carcinogenesis common to both man and animal. 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* olixm by the liv cr of vinyl chlondc-produced intermediates which are mutagenic in bacterial systems and m.iy be the ultimate carcinogen*. Hepatic subccllulur cn/yme studies prove preliminary evidence of cellular adapt.a ion and met eased detoxification. Disruption of this oxidization and dctoxifiialion balance may he t|ic kev to the malignant transformation ot ceils. A working hypothesis is presented which may explain the itn i.iUdisiu of vinyl chloride mto mutagenic mtctmediaies by the liver cell and the develop ment ol malifn.nn naiistormution by extra hepatic sinusoidal lining cells, lung cells, and brain tissue. INTRODUCTION Currently there is u growing concern that chemical compounds may be respon sible tor most human cancer through environmental contact. Although 100.000 to 200,000 new chemicals are introducejlimo industry each year, little is known about their effects, l ltcsc compounds arc 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-C1 monochloroethyene, a gas) is the basic molecule or monomer of polyvinyl chloride 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's) vinvl chloride was regarded as being rela tively non-toxic Ll.i], Initially this opinion s_eemed to be supported bv the facts that it was used transiently as an anaesthetic and had been used commercially in indus try tor many years ii|. 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 ' Portions of this work were supported by a gram from Manufacturing Chemist* Association ;uul by National Cancer Uutitutes Contrast ^NObCN-55212. lThtt article t* the ilurtccmh in a xcnc* entitled, "Seminars on Liver Disease.'' that have been presented as pari of ifcc Training Program in lavcr Disease at the Veterans Adunmsl rat ion Hospital, West (Liven, Connecticut. Dr HwoUO.Conn, Prutessor ol Medicine, Yale University ScUiotot Medicine, and Dircetoi of the Training Program in liter Dhcaac. is guest editor. V^aCkUrctt reprint requests to. Carlo H. Tumbunu. M.D. Piolessor oi Medicine, Onel. Digestive Discuses and iMiMttDivtuon, Uirectui. Vinyl Chloride Project. 511 Sooth Hoyd Street, P.O. Box 352M), Louisville, KY 40232 t WM086/78/5101-0067 SO 1.40 -OwWl 1S7> by The Yale Journal of Uiology and Medicine. Inc. Rpnduclio* m any lorn reserved. VC5770 CARLO H. TAMBURRO ;/iiy as an anaesthetic |4,5|, and from study of the cases of vinyl chloride poison ing contracted during industrial use F>, 7, 8, 9]. 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 chieily involved the tubule and the interstitial lining somewhat like that of carbon tetrachloride damage [10, II, 12]. BACKGROUND The literature, however, contained virtually no information on damage to man alter chronic exposUie until Filatova cl al. reported disturbances of the blood vessels and nerves in individuals exposed with 20-300 ppm of vinyl chloride on a continuous basis ] 13). Cordieret al. [14] and Wilson et al. 115] 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 acroosteoly.sis. In 1971, Violiet al. | lft| while exposing animals to 30.000 ppm to induce acroostcolysis, accidentally discovered cancer. Malkmi et al. [17] while studying various levels of exposure demonstrated that angiosarcoma occured at 250 ppm; the Manufacturing Chemists Association's studies [ I8| demonstrated these liver cancers even at 50 ppm. Al the same time. Or. 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-chloroethylenc, 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 of these physical properties may Ik important in determining how this agent produces a cumulative effect in the environment which ultimately leads to cancer formation. Vinyl chloride is both Loxic 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 VC5771