Systemic aluminum produces encephalopathy and osteomalacia in humans, but environmental toxicity has been considered minimal because of low oral bioavailability. However, in pilot work we have demonstrated neurotoxicity in lactating mice fed diets containing 500ppm aluminum, one order of magnitude above human exposure levels. In addition, developmental toxicity including growth retardation, developmental delay and depressed immune function was seen in offspring. In the proposed experiments, we have hypothesized that interaction with essential trace element metabolism leads to enhanced susceptibility to oral aluminum toxicity during developmental periods. The experiments include studies of vulnerable periods, dose-response relationships, maternal-fetal transfer, interaction with trace metal deficient diets and definition of """"""""no observable adverse effect"""""""" levels. Swiss-Webster mice will be fed purified diets with precisely controlled levels of essential trace metals and supplemented with aluminum lactate at levels of 100, 500 or 1000 ppm elemental aluminum. Diets will be fed for a six week period to nonpregnant, pregnant or lactating female mice. The design includes pair fed controls. Dams will be evaluated for neurotoxicity (functional signs and neurohistopathology), immunotoxicity and tissue concentrations of essential trace metals (Zn, Cu, Mg, Fe, Ca) and aluminum. Offspring will also be evaluated for tissue trace metal levels as well as growth, developmental delay and behavioral and immune function. Behavior and immune function will be evaluated at weaning and again two weeks after termination of aluminum exposure to determine residual effects. Further experiments evaluating developmental and neurotoxicity will be selected by relying on a structured decision tree format. This research will be valuable in determining acceptable levels of aluminum intake via oral exposure routes from environmental sources.
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