Neurotoxicity of aluminum

Although neurotoxicity of aluminum has not been established or adequately studied in people who are healthy (i.e., have normal renal function), there is conclusive evidence that aluminum compounds are neurotoxic in orally-exposed animals. As discussed below and in Section 2.2.2.6, numerous intermediate-duration studies in mice and rats found various neurotoxic effects in exposed adults and developing offspring. 

Information on chronic oral neurotoxicity of aluminum in animals is limited to a 20 month diet study in mice which found no histopathologic changes in the brain following ingestion of estimated doses as high as 979 mg Al/kg/day as dietary aluminum potassium sulfate (Oneda et al. 1994). These doses do not include aluminum in the base diet. 

The neurotoxicity of aluminum is well-documented in animals and has been manifested following various routes of exposure, including neuromotor, behavioral, and cognitive changes in orally-exposed adult rats and mice (Bilkei-Gorzo 1993 Bowdler et al. 1979 Commissaris et al. 1982 Connor et al. 

Marquis JK. 1989. Neurotoxicity of aluminum. In Lewis TE, ed. Environmental chemistry and toxicology of aluminum. Chelsea, MI Lewis Publishers, Inc., 289-298. 

Neurotoxicity of aluminum and copper are associated with the upregulation of stress-related gene expression patterns. Whole human genome microarray data... 

Maines MD, Kappas A (1976) Studies on the mechanism of induction of haem oxygenase by colbalt and other metal ions. Biochem J 154 125-131 Marquis J (1989) Neurotoxicity of aluminum. In Lewis TE (ed) Environmental chemistry and toxicology of aluminum. Lewis, Chelsea, MI, pp 289-298 Martin RB (1988) Bioinorganic chemistry of aluminum. In Sigel H (ed) Metal ions in biological systems, vol 24. Dekker, New York, pp 1-58 Martin RB (1992) Aluminum speciation in biology. In Chadwick DJ, Whelan J (eds) Aluminum in biology and medicine. Wiley, New York, pp 5-25 (Ciba foundation symposium 169)... 

Aiuminum-containing antacids - Constipation (may lead to intestinal obstruction) aluminum-intoxication osteomalacia and hypophosphatemia accumulation of aluminum in serum, bone, and the CNS (aluminum accumulation may be neurotoxic) encephalopathy. 

The neurotoxic effects of aluminum were first observed in people undergoing dialysis for treatment of kidney failure. This syndrome, called dialysis dementia, starts with speech disorders and progresses to dementia and convulsions. Symptoms corresponded with elevated aluminum levels commonly found in bone, brain, and muscle following 3 to 7 years of treatment. Elevated levels of aluminum were also found in the brains of people suffering from Alzheimer s disease. Despite considerable research, it is not clear if the aluminum accumulation in the brain is a cause of Alzheimer s disease or a result of changes in the brain associated with the disease. 

In general, these occupational exposure studies poorly characterize aluminum exposure. Some of the studies reported aluminum air concentrations for a single time period (Dick et al. 1997 Sim et al. 1997 Sjogren et al. 1996 White et al. 1992), but did not have earlier monitoring data when aluminum exposures were higher. The lack of adequate exposure monitoring data and the different types of aluminum exposure makes it difficult to compare these studies and draw conclusions regarding the neurotoxic potential of inhaled aluminum in workers. 

Many of the animal neurotoxicity studies are complicated by a lack of reported information on aluminum content in the base diet. This is an important issue because, as discussed in the introduction to Section 2.2.2, commercial rodent laboratory feed has a high aluminum content which can significantly contribute to total exposure. Dosages in studies with insufficient information on aluminum content in the base diet therefore must be assumed to underestimate the actual experimental dosages. The magnitude of the underestimate may be considerable, particularly for maternal dietary intake during lactation (an exposure period used in many neurobehavioral studies of aluminum in mice), which can be markedly... 

Neurotoxicity. Various neurotoxic effects of aluminum have been induced in animals, ranging from neurobehavioral and neurodevelopmental alterations following repeated oral exposures in mice and rats to neurodegenerative pathological changes in the brain caused by acute parenteral administration in... 

Several animal studies have examined potential age-related differences in the distribution, neurotoxicity, skeletal toxicity, and interactions of aluminum. However, conflicting results have been found and the database is not adequate to assess whether these differences are due to the animal species tested, the aluminum compound used, or the route of exposure. Additionally, there are no studies on the influence of immature renal function on aluminum retention in the body and no studies on the long-term effects of aluminum exposure on skeletal maturation or neurotoxicity. Multiple species studies examining a wide range of effects in immature, mature, and older animals would be useful in assessing the children s susceptibility to the toxicity of aluminum. 

Numerous mechanistic studies of aluminum neurotoxicity have been performed, but the main sites of action have not been discerned as discussed in Section 2.4.2 and by Strong et al. (1996). Additional studies could help identify a single unifying mechanism that can explain and reconcile the wide variety of pathological, neurochemical, and behavioral effects of aluminum induced by oral exposure and in various model systems (e.g., intracerebral and intracistemal administration), but these kinds of studies are unlikely to better characterize neurotoxicity NOAELs and LOAELs relevant to MRL assessment. The relationship between aluminum exposure and neurotoxicity is an active area of research. 

Comparative Toxicokinetics. The animal data indicate that the nervous system is a sensitive target of toxicity for aluminum following oral exposure, as summarized in the Data Needs sections on Neurotoxicity. Although the interpretation of the human data is limited by poor exposure characterization, the occupational exposure studies suggest that neurotoxicity is also a sensitive end point following inhalation exposure (Hanninen et al. 1974 Hosovski et al. 1990 Rifat et al. 1990 Sim et al. 1997 Sjogren et al. 1996 White et al. 1992). The toxicokinetic properties of aluminum have been extensively studied in human and animals. The results of these studies suggest that the absorption, distribution, and excretion properties of aluminum are similar across species. 

Julka D, Gill KD. 1996a. Altered calcium homeostasis A possible mechanism of aluminum-induced neurotoxicity. Biochim Biophys Acta 1315 47-54. 

Strong MJ, Garruto RM, Joshi JG, et al. 1996. Can the mechanisms of aluminum neurotoxicity be integrated into a unified scheme J Toxicol Environ Health 48 599-613. 

Voroniuc O, Mancas G, Gavt V, et al. 1997. Neurotoxic effects of aluminum from drinking water. Neurotoxicology 18 1092. 

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