Mode of action for inorganic arsenic toxicity and carcinogenesis

Inorganic arsenic (iAs) at high doses is a known human carcinogen, inducing tumors of the skin, urinary bladder, and lung. It is also associated with noncancer toxicities. An understanding of the mode of action (MOA) for arsenic-induced effects is needed to develop a scientifically-based risk assessment. To determine an MOA for iAs induced toxicities, it is necessary to understand the metabolism, kinetics, cell transport, and interaction with specific proteins of iAs. Based on in vitro investigations using animal and human cells, studies from animal models, and clinical and epidemiological studies, we have proposed an MOA involving formation of sufficient levels of reactive trivalent metabolites which interact with critical free sulfhydryl groups, leading to cytotoxicity and regenerative cell proliferation. There is a strong correlation between in vitro cytotoxicity ([0.1 lmol/L trivalent arsenicals) and the no effect levels in rodents [approximately 1 ppm (1 ppm = 1 mg/L) of water or diet]. In epithelial target tissues, the cytotoxic effects of iAs result in chronic precursor lesions which have the potential for an increased risk of developing cancer. In non-epithelial tissues, noncancer toxicities such as hypertension and atherosclerosis develop. This MOA implies a non-linear, threshold dose– response relationship for both non-cancer and cancer end points of exposure to iAs.