Intestinal Aluminum Absorption and Bioavailability from Representative Aluminum Species

PROJECT SUMMARY: (a) Objectives: The primary objectives are to characterize the rate and properties of Al flux across a cell model of intestinal absorption, the Caco-2 cell, when introduced as the Al ion, Al citrate, Al fluoride, Al hydroxide or Al maitoi. The results will be used to select the compounds that will then be studied in the rat to determine the time course and oral bioavailablity of Al (and associated ligand when administered as citrate and maltol) at physiological Al doses. . (b) Experimental Approach: The flux of Al across Caco-2 cells will be determined using vertical diffusion chambers. The apparent permeability of each Al species will be calculated. The role of Al species concentration, temperature, sodium, NalK-A TPase, metabolic inhibition and possibly inhibitors of monocarboxylate transporters and organic anion transporting polypeptides on Al flux will be determined. The Kmand Vmaxof Al flux will be determined if flux is carrier mediated. The results will suggest whether intestinal Al absorption is dependent on the Al species. The results will guide selection of Al species to be studied in the rat. The oral bioavailablity of AI, dosed as 26AI, of some or all of the above tested Al species will be assessed in the rat. The time course of 26Al appearance and disappearance in the rats' serum will also be compared among the Al species and will be compared to the time course of 14Cfrom the 14C-citrate and 14C-maltolate ligands co-administered with the 26AI. This study will test the hypothesis that oral Al bioavailability is independent of the Al species consumed in water. This will be conducted by oral administration of the 26Al species, with 14C-Iabelled associated ligand when applicable, to rats during continuous infusion of 27AI, enabling determination of oral bioavaiIabiIity by comparison of the areas under the serum Al versus time curve from concurrent oral and intravenous Al administration, as we conducted in ourprev.ious EPA STAR-supported study of the Al ion only. (c) Expected Results: It is anticipated that the oral absorption of Al will not be the same for Al citrate, Al fluoride, Al hydroxide and Al maltolate. Each of these are stable Al complexes which can be expected to remain intact in the absence of competing ligands. Therefore, they should be absorbed intact unless unknown intracellular ligands can successfully compete with citrate, fluoride, hydroxide and maltolate. These studies address the relative influence of Al complexes on the distribution of aluminum and the differences among their pharmacokinetics in water, components of the RFA solicitation: HEALTH EFFECTS OF CHEMICAL CONTAMINANTS IN DRINKING WATER - Neurotoxicity of AI.