This MiniReview updates and expands the MiniReview of aluminium toxicokinetics by Wilhelm et al. published by this journal in 1990. The use of 26Al, analyzed by accelerator mass spectrometry, now enables determination of Al toxicokinetics under physiological conditions. There is concern about aluminium in drinking water. The common sources of aluminium for man are reviewed. Oral Al bioavailability from water appears to be about 0.3%. Food is the primary common source. Al bioavailability from food has not been adequately determined. Industrial and medicinal exposure, and perhaps antiperspirant use, can significantly increase absorbed aluminium. Inhalation bioavailability of airborne soluble Al appears to be about 1.5% in the industrial environment. Al may distribute to the brain from the nasal cavity, but the significance of this exposure route is unknown. Systemic Al bioavailability after single underarm antiperspirant application may be up to 0.012%. All intramuscularly injected Al, e.g. from vaccines, may eventually be absorbed. Al distributes unequally to all tissues. Distribution and renal excretion appear to be enhanced by citrate. Brain uptake of Al may be mediated by Al transferrin and Al citrate complexes. There appears to be carrier-mediated efflux of Al citrate from the brain. Elimination half-lives of years have been reported in man, probably reflecting release from bone. Al elimination is primarily renal with < or = 2% excreted in bile. The contribution of food to absorbed Al needs to be determined to advance our understanding of the major components of Al toxicokinetics.

Low and high doses of a dopamine blocking agent had effects on lever pressing for intravenous amphetamine reward which resembled the effects of reward reduction and reward termination, respectively. Noradrenaline blockade had no such effects. A role in central mediation of reward perception is suggested for dopamine but not for noradrenaline.

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The chemical forms (species) of aluminum in blood plasma and brain extracellular fluid are considered, as they are the candidates for brain aluminum uptake and efflux. The blood-brain barrier is the primary site of brain aluminum uptake. The mechanism of brain uptake of aluminum transferrin, long thought to be mediated by transferrin-receptor mediated endocytosis, requires further investigation. Brain Al citrate uptake has been attributed to the sodium-independent Lglutamate/L-cystine exchanger system, system Xc-. Reports have suggested aluminum can compromise blood-brain barrier integrity, however the studies were conducted with aluminum concentrations greatly exceeding those seen in human blood plasma. Aluminum appeared in cerebrospinal fluid suggesting it can cross the choroid plexus and in brain after intranasal application suggesting it can be taken up by cranial nerves, but neither of these routes has been definitively demonstrated. Brain aluminum efflux appears to be carrier-mediated, however the mechanism has not been identified. A small increase in brain aluminum seems sufficient to produce neurotoxicity. Once aluminum enters the brain it persists there for a very long time; estimates of the half-life range from 20% of the lifespan to greater than the lifespan. Al persistence in bone, which maintains the majority of the body burden, may influence brain Al, due to equilibrium among the body's organs. Chelation therapy with desferrioxamine has been shown to reduce some manifestations of aluminum toxicity although it may increase redistribution of aluminum to the brain to increase aluminum-induced neurotoxicity. An orally-effective aluminum chelator that is an improvement over desferrioxamine has not yet been demonstrated. Although a non-essential metal, there are mechanisms enabling aluminum to get into the brain, accumulating over the lifespan, and creating the potential to contribute to many neurodegenerative disorders.

My colleagues and I investigated the sites and mechanisms of aluminum (Al) and manganese (Mn) distribution through the blood-brain barrier (BBB). Microdialysis was used to sample non-protein-bound Al in the extracellular fluid (ECF) of blood (plasma) and brain. Brain ECF Al appearance after intravenous Al citrate injection was too rapid to attribute to diffusion or to transferrin-receptor-mediated endocytosis, suggesting another carrier-mediated process. The brain:blood ECF Al concentration ratio was 0.15 at constant blood and brain ECF Al concentrations, suggesting carrier-mediated brain Al efflux. Pharmacological manipulations suggested the efflux carrier might be a monocarboxylate transporter (MCT). However, the lack of Al 14 C-citrate uptake into rat erythrocytes suggested it is not a good substrate for isoform MCT1 or for the band 3 anion exchanger. Al 14 C-citrate uptake into murine-derived brain endothelial cells appeared to be carrier mediated, Na independent, pH independent, and energy dependent.