Project Summary (2000-2005)

Physiologically-based kinetic models are increasingly being incorporated into the assessment of risk arising from exposure to toxicants. Development of models of the kinetic behavior of metals, including arsenic, has been actively investigated for several years. A rational approach to the development of a complex kinetic model such as that required for arsenic (with the several chemical forms that it can take) involves establishing the most fundamental components of the model first upon which higher levels of interaction can be built. Exposure of the cells of target tissues requires first that the toxicant cross cell membranes to access intracellular sites of intoxication. The principal aim of this project is the elucidation of the major arsenic transport processes within cells of two tissue/organ systems which play central roles in the elimination of arsenic from the body: the kidney (with an emphasis on the proximal tubule), and the urinary bladder (which is an important target of arsenic carcinogenicity). The studies will determine how the major forms of arsenic enter and leave cells of the kidney and bladder. The study is defining the mechanisms of cellular transport of As(III), As(V), methyl arsonic acid and dimethylarsinic acid, and determining the kinetics of their transport in each test tissue. The investigators are testing the novel hypothesis that endocytosis plays a quantitatively significant role in the entry of and exposure to arsenic in bladder cells. These data will provide a means for understanding the cellular basis of arsenic bioavailability to these important epithelial barrier tissues, and the net effect of different transport processes on overall arsenic flux in these tissues. These results can be expected to provide needed refinements to ongoing efforts to develop a physiologically-based kinetic model for the behavior of arsenic in biological systems.