Metabolism and disposition of inorganic arsenic in laboratory animals and humans

Abstract

The carcinogenicity of inorganic arsenic in humans, particularly in the lung and skin, has been reasonably well established through epidemiological investigations. However, there is no substantial experimental evidence for carcinogenicity in animals to support the human studies. Studies of metabolism and disposition of inorganic arsenic in various animal species are particularly relevant to determining the factors that might account for the lack of an animal model. Numerous studies of this type have been reported, but there do not appear to be clear qualitative or quantitative differences in the overall fate and disposition of inorganic arsenic in most animalsversus humans, although little is known at the cellular and subcellular level.Sulphur chemistry, especially thiol status, is emerging as an important regulating factor in the overall fate and distribution of inorganic arsenic in the body, playing a role in the initial reduction of arsenate to arsenite and subsequent methylation, and possibly in determining tissue affinity and distribution properties. The metabolism of inorganic arsenic can be viewed as a redox cycle in which thiol compounds such as glutathione (GSH) possibly function as reducing agents and methyl donors as oxidising agents. One explanation for the possible sensitivity of certain malnourished human populations to the carcinogenic effects of inorganic arsenic may be related to the reduced availability of nonprotein sulphhydryl compounds such as GSH needed to drive the redox cycle and facilitate arsenic detoxification. Future carcinogenicity studies of inorganic arsenic in animals could be designed to address directly this aspect of the problem.