AL +3 NEUROBEHAVIORAL TOXICITY: CONTRIBUTING FACTORS

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Prolonged exposure to aluminum (Al) has been shown to contribute to progressive deteriorating brain disease (dialysis encephalopathy and possible senile demetia of the Alzheimer's type) and bone disease (dialysis osteodystrophy). The factors contributing to the absorption and accumulation of Al, and the basic mechanisms by which Al is handled by the body are not well understood. The proposed studies will clarify the roles of the form of Al, impaired renal function, altered gastric integrity, and calcium deficiency on Al absorption in rabbits. Acute bioavailability studies will initially be conducted to assess the influence of each of the above variables on Al pharmacokinetics (absorption, distribution and rate of elimination). Results from the acute bioavailability studies of Al will then be applied in subchronic Al exposure studies to determine if the factors influencing Al kinetics also influence the accumulation of Al in tissues and the development of Al neurobehavioral toxicity. Al will be given orally to rabbits as soluble and insoluble organic and inorganic salts to assess the contribution of the form of Al. Chronic renal impairment will be produced in rabbits by partial renal arterial ligation. Stomach integrity will be altered by acute administration of aspirin suspension. Calcium deficiency will be produced by subchronic maintenance on a calcium deficient diet. Standard pharmacokinetic analyses of serum Al will be conducted following acute Al dosing, and numerous physiological measures (behavior, Al tissue levels and neuropathology) will be assessed following subchronic Al dosing. Studies will also be conducted to elucidate some of the basic processes controlling Al absorption and elimination, with the hopes that these results will help explain the results obtained in the acute and subchronic studies, and provide insight into the mechanisms by which Al passes throuh membranes. Rat intestinal slices will be used to elucidate the mechanisms of Al absorption. Classical renal pharmacology preparations (renal slices from rabbits and the Sperber chicken technique) will be used to elucidate the mechanisms of Al elimination. The results should provide information beneficial in selecting an Al based product when one is to be used and approaches to the treatment and prevention of Al accumulation and resultant diseases.