Inorganic
arsenic is clearly a human
carcinogen causing
tumors of the skin, lung, urinary bladder, and possibly liver (IARC, 2004). At the time of construction of this monograph, the evidence for
arsenic as a hepatocarcinogen in humans was considered controversial and in rodents considered insufficient. However, recent data has accumulated indicating hepatocarcinogenicity of
arsenic. This forum reevaluates epidemiology studies, rodent studies together with in vitro models, and focuses on the liver as a target organ of
arsenic toxicity and
carcinogenesis.
Hepatocellular carcinoma and hepatic
angiosarcoma, have been frequently associated with environmental or medicinal exposure to
arsenicals. Preneoplastic lesions, including
hepatomegaly, hepatoportal
sclerosis,
fibrosis, and
cirrhosis often occur after chronic
arsenic exposure. Recent work in mice clearly shows that exposure to inorganic
arsenic during gestation induces
tumors, including
hepatocellular adenoma and
carcinoma, in offspring when they reach adulthood. In rats, the methylated
arsenicals,
dimethylarsinic acid promotes
diethylnitrosamine-initiated liver
tumors, whereas
trimethylarsine oxide induces liver
adenomas. Chronic exposure of rat liver epithelial cells to low concentrations of inorganic
arsenic induces malignant transformation, producing aggressive, undifferentiated epithelial
tumors when inoculated into the Nude mice. There are a variety of potential mechanisms for arsenical-induced hepatocarcinogenesis, such as oxidative DNA damage, impaired DNA damage repair, acquired apoptotic tolerance, hyperproliferation, altered DNA methylation, and aberrant
estrogen signaling. Some of these mechanisms may be liver specific/selective. Overall, accumulating evidence clearly indicates that the liver could be an important target of
arsenic carcinogenesis.