Impact/Purpose:

Inorganic arsenic (iAs) is a natural environmental contaminant and a human carcinogen. The US EPA is concerned about the risk of cancer in individuals who consume iAs contaminated drinking water. To aid the Agency in reducing the uncertainty in the arsenic risk assessment, our experimental goals are to determine the role of various factors that may affect the disposition of arsenic in mice. Factors examined included dose, diet, genetic polymorphisms in methylation, and acute vs. repeated exposure to iAs. Studies from NHEERL show that methylated arsenicals formed by the enzymatic conversion of inorganic arsenic are extremely reactive and toxic species. In this component of research, we have examined the metabolism of arsenic in cells and the effects of arsenicals on cellular function. In general, these studies show that methylated arsenicals containing trivalent arsenic can be formed and persist in cellular environments and can affect critical cellular functions. The Office of Water is required to reassess the toxicity of arsenicals and understanding the mechanism by which these chemicals induce their toxic effects will allow for a more scientifically based risk assessment.

Description:

Initial results from studies in cultured cells support the concept that the biomethylation of arsenic is an activation process. The metabolites of inorganic arsenic inhibit the activity of TR, an enzyme critical to maintenance of cell redox status, disrupt cell signaling pathways, and induce cell death. These processes could underlie the adverse effects of chronic exposure to arsenic. We will characterize the kinetic behavior of arsenicals in cells as a means of understanding dosimetric aspects of the effects of arsenic at the cellular level. We also interested in understanding the transcriptional regulation of the cyt19 gene and the relation between the expression of this gene that encodes arsenic methyltransferase and the metabolism of arsenic in cells. We are exploring techniques to manipulate cyt19 gene expression (RNAi and cell transduction) that will let us modify the capacity of cells to metabolize arsenic. Studies of metabolism of arsenic in cellular systems provides a powerful tool for elucidating the relation between the metabolism of arsenic and its biological effects. This information supports the development of models that integrate pharmacokinetic and pharmacodynamic data and provide new insights into the mode of action of arsenic. Development of a physiologically based pharmacokinetic (PBPK) model for arsenic provides a quantitative, mechanistically based description of the relationship between As exposure, and target tissue dosimetry and excretion that can ultimately be extrapolated to humans. This will provide an integrated understanding of kinetic and dynamic aspects of arsenic toxicity that will reduce uncertainty in arsenic risk assessment.

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