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ia v i ^Tri --Ti jhiiinr 488 HANS POPPER cinoma (75). A few cases of carcinoma have been reported in man following vinyl chloride exposure (76). Guided by the doses found to be effective in experimental animals, the vinyl chloride concentration permissible in the ambient air of fac tories has been reduced by regulatory action to levels which should avoid initia tion of additional angiosarcomas or their precursor lesions. Because of the long period of promotion in carcinogenesis in general and particularly in factories where low-grade but still dangerous levels of vinyl chloride existed, it is still possible that additional cases of hepatic angiosarcoma will occur in the foresee able future. To date, 64 angiosarcomas following vinyl chloride exposure in man are on record (77). The same morphologic and clinical sequence has been observed in a small number of cases following exposure to inorganic arsenic, either in Fowler's solu tion (78, 79) used for the long-term treatment of psoriasis and asthma, or in pesticides applied in vineyards, particularly in Germany (80), where use of arsenic-containing pesticides has been discontinued. In the latter group, car cinoma has been reported. But an experimental counterpart of the arsenic-induced hepatic malignancy does not exist. Possibly, excess arsenic exposure in industrial settings or in drinking water may account for cases of human angiosarcoma with out established etiology (81). Such cases may constitute approximately threefourths of all cases of human angiosarcoma. The same morphologic sequence, including carcinoma, mainly cholangiocarcinoma, has also been observed in some individuals years after the administration of thorium dioxide for radiologic visualization, especially of brain lesiohs (82, 83). Again, worldwide this sequence represents only a small fraction of all hepatic malignancies, with fewer than 100 known cases. Thorium dioxide administration produces angiosarcoma in animals (84). Other forms of radiation rarely seem to produce hepatic tumors in man (85)1" The entire group of tumors induced by sex steroids and environmental agents (the latter causing the sequence terminating usually in angiosarcoma) appears characterized by a relatively small number of cases. However, the strong causal relationship between the etiologic factors and hepatic malignancy is reflected both in animal models and the absence of cirrhosis. In cases of angiosarcoma this relationship is further supported by the rarity of these tumors in the general population. Prevention of both medicinal and industrial exposure appears to be easy and seems, to a great extent, to have been accomplished. In passing it should be mentioned that a quantitatively small group of hepatol cellular carcinomas are associated with metabolic alterations (8). Within this group, the most frequent association is with iron overload disease of the type of hemochromatosis. A less common association occurs between hepatocellular car cinoma and porphyria, a,-antitrypsin deficiency, Wilson's disease, and tyrosinemia (the latter in children). PECULIARITIES OF HUMAN HEPATIC MALIGNANCIES Ever since the 1930s, when Yoshida and Kinosita produced hepatocellular car cinoma in rats by chemical agents, an increasing number of such agents have been shown to produce the tumor, often preceded by a nodular lesion, in experimental i m URL 19113 HEPATIC CANCERS IN MAN 489 animals, including primates (86). The long list of chemical agents known to have hepatic carcinogenic potential in animals includes food additives (such as safrole and ponceau red), pesticides, industrial agents, such as polyhalogenated bi phenyls, dioxan, phenobarbital in mice, and many others, which have been listed in many excellent reviews (87, 88). The carcinogenic potential of these agents in animals has led to the assumption that chemical factors cause also hepatocellular carcinoma in man. However, a review of the literature reveals a dearth of information about substantiated carcinomas in man by the large number of these agents (89). For instance, in one case of hepatocellular carcinoma re corded years after injury from carbon tetrachloride, alcoholism was also present (90). The same lack of substantiated information applies to production of human cirrhosis (as a precursor of carcinoma) by these agents and by other industrial compounds. One apparent exception to this are compounds like trinitrotoluene, which have been associated with hypersensitivity reactions (89). Table 1 corre lates the rate of incidence, certainty of association, animal models, and ap proaches to the prevention of different human hepatic malignancies. A reliable estimate as to the total yearly number of cases of hepatocellular carcinoma in the world is impossible. A conservative assumption based on a 5/100,000/year inci dence worldwide would account for at least 150,000 cases per year which are presumably induced by the three common factors discussed. This contrasts with at most 30 cases per year worldwide by the known industrial and therapeutic factors. It should be emphasized that the two apparently most important carcinogens incriminated in human cancer in other organ sites have not been unequivocally associated with hepatocellular carcinoma in man, even though they are metabo lized in the human liver. Specifically, polycyclic hydrocarbons do not produce hepatic tumors in any species, and there is no evidence that nitrosocompounds, potent hepatocarcinogens in many species, including primates (86), cause human TABLE 1 Etiolooic Factors in Human Hepatic Malignancies i "Carcinogens'* Incidence Animal model Certainty of association Prevention Hepatitis B i Alcoholism Aflaloxin 1. Anabolic steroids i* Contraceptive i steroids Vinyl chloride Inorganic arsenic f Thorotrast Common hepato carcinogens in experimental animals (87, 88) Highest High High Very low Very low Very low Very low Very low 0 0 *+ +. ++ 0 + 7 +++ + + ++ +++ +++ ++ +++ 7 Vaccine Immunoglobulin Life style change?? Technologic? Possible Possible Possible Possible Possible m mm- URL 19114 v l 490 HANS POPPER hepatocellular carcinoma. This peculiar protection of the human liver, particularly in adults, can possibly be explained by its biochemical and biological characteris tics (91). The liver is rich in hydratases, which can remove ultimate carcinogens; it has high activity of endonucleases, which excise altered DNA; and the turnover of hepatocytes favoring carcinogenic transformation is particularly low. This does not exclude the possibility that these substances, many of which are stored for a long time in human fat tissue, have effects on hepatic metabolism which are detrimental. In animals, the vast majority of these substances enhance the enzymatic action of the microsomal biotransformation system, which poten tially increases both the amount and the life span of the ultimate bioactive car cinogen, which binds to macromolecules, particularly to DNA. This "induction" of the biotransformation occurs in man, but its long-term effects in man are not known except in relation to adverse drug reactions (92). Induction in epileptics as a result of specific drug therapy has not resulted in an increased incidence of tumors which cannot otherwise be explained (93). However, both the establish ment of induction in man and its epidemiologic consequences as far as car cinogenesis in the liver and in other organ sites is concerned require further study. CONCLUSIONS The geographic distribution of human hepatic malignancies strongly suggests a causative role of environmental factors. The vast majority of malignancies in all areas of the world are usually associated with cirrhosis and one of three factors: hepatitis B infection, alcoholism, or aflatoxin exposure. The greatest chance for the prevention lies in limiting hepatitis B infection. Although they constitute only a very small number of all hepatic malignancies, some tumors not associated with cirrhosis have been caused by industrial and therapeutic factors and prevention of these tumors is being accomplished. However, the correctable environmental, including industrial, burden is small. A large number of common carcinogens in experimental animals, many of them environmental and industrial agents, have so far not been proven to produce hepatic malignancies in man. Nevertheless, these substances may alter the hepatic metabolism with consequences for the liver and other organs which still require establishment. As long as the consequences of exposure to these agents remain unproven, there can be no justification for any relaxation of vigilance. REFERENCES i 1. Linscll, D. A., and Higginson, J. (1976). The geographic pathology of liver cell cancer. In "Liver j Cell Cancer" (H. M. Cameron. D. A. Unsell, and G. P. Warwick, Eds.), pp. 1-16. Elsevier/ North-Holiand Biomedical Press, Amsterdam. . 2. Kew, M. C. (1978). Hepatocellular cancer in southern Africa. In "Primary Liver Tumors" (H. j Remmer, H. M. Bolt, P. Bannasch, and H. Popper, Eds.), pp. 179-183. MTP Press Limited, t Lancaster. 3. Bradshaw, E., and Harington, J. S. (1977). 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