10 Questions You Should to Know about Aluminium silicate fibre powder

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Further studies are needed to settle the debate over the link between aluminium and aluminium in drinking water and neurological disorders and congnitive impairment. Ideally, individual level data on drinking water exposure as well as other relevant risk factors would be obtained; in the absence of this, replication of the Rondeau et al. () analysis in other study populations, with the ability to control for important confounders and effect modifiers, is needed to assess this potential risk.

In many occupational studies of aluminium workers, it was not known whether respiratory tract illness was due to exposure to aluminium or other substances. There have been very few studies of neurological effects of occupational exposure via inhalation to aluminium and aluminium compounds (as measured in serum), and it is not known if the very specific neurological deficits observed lead to more severe illness such as AD. Therefore, large-scale, longitudinal, studies of occupational exposure to aluminium and aluminium compounds via inhalation, with precise methods of exposure measurement, are needed to assess the risks of respiratory tract disease and neurological effects due to aluminium and aluminium compounds.

Occupational populations can be exposed to airborne concentrations of aluminium exceeding concentrations to which the general population is exposed by approximately three orders of magnitude (see Table 26 ). Aluminium intake resulting from these exposures is estimated to be 21 mg/day, compared to 0.06 mg/day for the general population, with uptake for occupationally exposed individuals amounting to 6 × 10 -3 mg/kg b.w./day, compared to 1.7 × 10 -5 for the general population ( Table 26 ). The resulting margin of exposure for occupationally exposed populations is approximately 8, compared to for general population exposure to airborne aluminium (see Table 27 ).

Individuals with impaired renal function do not clear aluminium as effectively as healthy individuals. This population can also be exposed to extremely high levels of aluminium that are administered inadvertently via their intravenous feeds. This route of exposure may be particularly significant because it bypasses the barrier imposed by GI absorption characteristics. Infants, especially those born pre-term, are also vulnerable to aluminium exposure due to immaturity of the GI wall, the BBB, and the renal system. In addition to their added susceptibility due to compromised renal function, patients on dialysis may be subject to higher aluminium exposure levels if dialysis or intravenous fluid becomes contaminated, a problem that was more common in the past. Although not explicitly quantified, the susceptibility of these populations suggests that the exposure level of concern is less than it is for the general population. At the same time, some sensitive populations may have been exposed to very high aluminium exposures in the past. Because of the substantial quantities of injected fluids received by dialysis patients and their increased susceptibility, the MOE for this pathway for this population may be less than unity.

Relevant exposure levels of concern for the general population identified as part of dose response assessment included: irritation following inhalation (50 mg/m 3 ), neurological effects due to drinking water exposure (100 μg aluminium/L water), reproductive toxicity due to oral intake (400 mg/kg-b.w./day), and irritation following injection (1 injection). We characterized risk (see Table 27 ) by calculating a margin of exposure, or MOE (the exposure level of concern divided by actual exposure), for each of these pathway-endpoint combinations. The MOE values were large for local irritation following inhalation () and reproductive toxicity associated with oral intake (). For irritation following injection, the MOE is less than unity, although the severity of this endpoint is limited. For neurological effects associated with drinking water exposure, the MOE may be as small as unity. The evidence supporting this effect, however, comes from studies that have a number of methodological limitations, a finding that suggests the causal nature of the association is uncertain.

Exposure assessment quantified aluminium intake and uptake (i.e., absorption of aluminium into systemic circulation) for a variety of pathways (see Table 26 ). For the general population, intake of aluminium from food (7.2 mg/day for females and 8.6 mg/day for males) dominated that from drinking water (0.16 mg/day) and inhalation exposure (0.06 mg/day). Antacids and buffered aspirin can contribute on the order of thousands of mg/day to aluminium intake. Relative contributions to uptake are ranked similarly to these intake contributions. However, because inhaled aluminium is approximately seven times more bioavailable than aluminium in drinking water, the contribution of inhaled aluminium to uptake (1.7 × 10 -5 mg/kg b.w./day) exceeds the corresponding contribution from drinking water (6.9 × 10 -6 mg/kg b.w./day). Uptake of aluminium in food is approximately 1 × 10 -4 mg/kg b.w./day. Aluminium uptakes from antacids and buffered aspirin amount to 3.1 × 10 -1 and 4.3 × 10 -2 mg/kg b.w./day, respectively.

Hazard identification qualitatively identifies adverse effects by route of exposure, and determines whether those effects are likely in humans at some level of exposure, perhaps much greater than exposure levels experienced in the population of interest. It is important to note that the identification of effects that can be caused by aluminium says nothing about how likely those effects are at exposure levels in human populations. That probability depends on the level of exposure and the dose-response relationship. This report classified the weight of evidence for each exposure pathway and health effect as strong, modest, limited, or having no clear evidence (see Table 25 ). We concluded that there is strong evidence that aluminium can cause irritation following exposure via either inhalation or injection. Modest evidence of an effect exists for reproductive toxicity following oral exposure, for neurological toxicity following either oral or injection exposure, and for bone toxicity following injection exposure. All other effects were judged to be supported by either limited evidence or no clear evidence at all. Exposure assessment, dose-response assessment, and risk characterization were conducted for those effects for which the evidence was judged to be either strong or modest. The remainder of this section describes our findings for the general population, subpopulations at special risk, and occupationally-exposed populations.

As a result of inadvertent human poisoning with excessive amounts of aluminium, there are reports of damage to bone and CNS as target organs. Further, the administration of aluminium-containing vaccines for extended time periods was found to be associated with the development of MMF at the injection site. In the past, individuals with impaired renal function receiving dialysis were reported to be at greater risk for aluminium intoxication associated with contaminated replacement fluids. However, this incidence has diminished markedly in recent years with the use of non-contaminated fluid and replacement of high-dose antacid therapy with alternatives. Although infants and children may be at higher risk for toxicity due to aluminium, a causal relationship was not confirmed. Hence, it should be noted that only at excessive concentrations of aluminium are toxic manifestations seen in human sensitive subpopulations.

Contact sensitivity to aluminium is very rare. Sensitization has occurred after injection of aluminium-adjuvant containing vaccines and pollen extracts, resulting in persistent granuloma at the injection site. These effects are much more frequent with aluminium hydroxide than aluminium phosphate adjuvants and more commonly seen following subcutaneous (s.c.) than i.m. injection. Less common is sensitivity during continuous application of aluminium-containing antiperspirants, topical aluminium application, and occupational exposure to aluminium dust and filings which result in recurrent eczema.

There is a large body of literature, mostly in the form of clinical reports, which documents the adverse effects of non-occupational aluminium exposure in individuals with impaired renal function. These patients are typically exposed to aluminium through dialysate fluid or medicinal sources. Anaemia, bone disease, and dialysis encephalopathy are the most commonly reported complications of aluminium exposure in this population.

Evidence surrounding the relationship between aluminium in food and the risk of AD is very minimal. This may be a result of the difficulty in obtaining accurate exposure information in dietary studies. One small case control study found a positive relationship between the consumption of foods containing high levels of aluminium and the risk of developing AD. These results have not been confirmed in a larger investigation.

Regular consumers of antacids represent a unique subpopulation with heavy exposure to aluminium. A significantly elevated odds ratio for AD for regular antacid consumers compared to non-regular users was found; however, when only aluminium containing acids were analyzed there was no significant association. Other studies have not found a significant association between antacid use and AD. Little is known about the impact of aluminium-containing antacids in human pregnancy and lactation.

The neurotoxic properties of aluminium are well established; however, the evidence surrounding the potential association between aluminium and neurological disorders in humans is much less clear. Aluminium exposure from drinking water has been extensively investigated in relation to the development of neurological disorders, including AD, due to the proposed enhanced bioavailability of aluminium in this form. The data surrounding this association is difficult to interpret due to the large variation in study designs and the highly variable quality of these studies. The majority, but not all, of epidemiological studies identified, reported a positive association between aluminium levels in drinking water and risk of cognitive impairment dementia, or AD. There is some evidence to suggest silica in drinking water is protective against the development of dementia. Fluoride has also been identified as having a potential protective effect. Many of the studies which have investigated the relationship between aluminium in drinking water supplies and the risk of developing AD are limited by methodological issues. These issues include: lack of individual exposure information, poor disease ascertainment, failure to adjust for important confounding factors, and small sample sizes. A recent study conducted in France is methodologically superior to the other studies conducted to date. The finding of a significant positive relationship between drinking water aluminium levels and the development of AD in this large prospective study, together with the finding of a positive relationship in a number of less methodologically sound studies, suggests that the association between aluminium and AD should be further investigated.

Changes typical of foreign body reaction, alveolar proteinosis and wall thickening, diffuse pulmonary fibrosis and interstitial emphysema, and some nodule formation but not to the extent of fibrosis caused by quartz dust were associated with occupational exposure in the aluminium industry. This was most severe in Germany during World War II, where industrial environments were heavily contaminated with airborne aluminium flake powder. Lower aluminium exposures contribute to Shaver&#;s disease, a pulmonary fibrosis seen in workers in bauxite refining or exposed to finely divided aluminium powders; and caused pneumoconiosis, fibrosis, and some cases of asthma.

Several epidemiological studies have reported an increased risk of developing lung cancer or bladder cancer for workers in the aluminium industry, however, in all of these studies the risk has been attributed to the exposure to the PAHs generated during aluminium production rather than from exposure to aluminium compounds. Studies investigating the effects of occupational exposure to aluminium are limited by many methodological issues. Rarely is a worker exposed solely to aluminium containing compounds and exposure information is often not adequate to rule out other toxic substances as the cause of the observed effect. Small sample sizes, misclassification bias, selection of inappropriate comparison groups, and lack of information to control for confounding factors are common weaknesses in these occupational studies.

Adverse neurological outcomes as a result of occupational aluminium exposure have also been extensively investigated. Aluminium exposure in these studies was estimated in a number of different ways including; exposure grading for different job categories, determination of total body burden of aluminium, number of years working in the aluminium industry, and ever v.s. never worked in the aluminium industry. Occupational aluminium exposure was significantly correlated with a variety of neuropyschiatric symptoms including; loss of coordination, loss of memory, and problems with balance. Studies which specifically examined the relationship between AD and occupational aluminium exposure did not show any significant correlation. However, these studies are limited by methodological issues.

Occupational exposure to aluminium occurs during the refining of the primary metal and in secondary industries that use aluminium products. Several studies have reported adverse respiratory tract effects in aluminium industry employees. Asthma-like symptoms, known as potroom asthma, have been the most intensely investigated respiratory effect. Wheezing, dyspnea, and impaired lung function (typically assessed by measuring forced expiratory volume (FEV 1 ) and forced volume capacity (FVC)) are the primary features of this disorder. Several cross-sectional, case-control and longitudinal studies have demonstrated increased frequency of adverse pulmonary effects in potroom workers as compared to non-exposed workers. The cause of potroom asthma has not been fully elucidated, but job specific exposure measurements based on personal sampling data and analysis of plasma levels suggests that exposure to fluorides may be an important determinant. There is some evidence to support that individuals with hay fever and individuals with elevated eosinophil counts are at increased risk of developing potroom asthma. Other studies did not find an association between allergic status and the development of symptoms. The respiratory problems documented in potroom aluminium workers are generally associated with toxic chemicals other than aluminium in the workplace. In contrast, exposure to aluminium powder is thought to be directly correlated with the development of pulmonary fibrosis in aluminium industry workers.

There is little reported for aluminium compounds in the way of immunotoxicity. There may be an altered immune response to challenge following excess aluminium exposure and this may be influenced by the health and hormonal status of the dam with increased susceptibility to bacterial infection seen in pregnancy.

Experimental aluminium inhalation has been shown to produce effects interpreted as alveolar proteinosis and lipid pneumonia. Inhalation of aluminium had some protective effect against quartz dust-induced fibrosis in some, but not all, studies. Intratracheal aluminium instillation produced nodular fibrosis. Aluminium is used as an adjuvant in vaccines and hyposensitization treatments to precipitate toxins and toxoids, enhance their antigenic properties and reduce their rate of absorption and elimination. Aluminium can produce aluminium-species-dependent dermal irritation.

Although not reported in every study, the majority of studies that utilized high doses of aluminium reported significant reductions in weight gain, particularly in studies initiated in young animals. The physiologic basis for this outcome is unclear, but it was reported that animals exposed to high doses of aluminium in drinking water consumed less food. Whether general effects of aluminium on metabolic processes depress metabolism or reduce nutritional efficiency remains to be resolved.

From the present data, however, it is difficult to determine what level of exposure poses a risk for human health or which systems are most vulnerable. Based on projections from studies in dogs, individuals with sustained aluminium levels in serum that are 10-fold higher than the average range, or 1-2 μg/L, may be at increased risk for bone abnormalities. The exposure levels at which other systems might be affected are more difficult to project, particularly when trying to assess risk for late-onset illnesses.

Aluminium may also have negative effects on hematopoiesis. However, these effects are relatively mild unless animals are deficient in iron. In this latter setting, there will be increased levels of free Tf, which can then bind aluminium and compete for Tf receptor; further limiting the amount of iron available for erythrogenesis. Aluminium may also interfere with the metabolism of other metals. On this latter point, the strongest data, meaning most reproducible, suggest that aluminium exposure can lead to increased excretion of phosphorous.

Outside of the nervous system, the data regarding the potential for alumimium to cause abnormalities is mixed. There is clear evidence that sustained exposure to high levels of aluminium can cause bone abnormalities. Aluminium is clearly deposited in bone at sites of new growth. Bones in animals exposed to aluminium may show increased weakness and increased brittleness. Deficiencies in calcium or magnesium may exacerbate the effects of aluminium. Aluminium overload leads to PTH suppression and with regards to the bone, may be associated with altered calcium homeostasis.

However, there has not been strong evidence from animal studies that aluminium directly modulates cognitive function. As described in Effects on Laboratory Mammals and In Vitro Test Systems, Neurotoxicity,Behavioural Studies of Laboratory Animals Exposed to Aluminium, there have been several studies that have examined the cognitive abilities of mice and rats exposed to aluminium. For the most part, these studies did not report profound cognitive impairment even when exposed to very high levels of aluminium. Therefore, it seems unlikely that aluminium might lower the threshold for AD by blunting cognitive ability of adults.

Apart from the potential that aluminium might interact directly with molecules implicated in AD and related neurodegenerative disorders, studies in animals have revealed potential mechanisms by which aluminium might indirectly impact on the function of the nervous system. In Effects on Laboratory Mammals and In Vitro Test Systems, Neurotoxicity, Alzheimer&#;s Disease, studies are described that reported aluminium may affect levels of cholesterol, which has been suggested in numerous studies as a potential modulator or Alzheimer-type amyloid formation. Effects on Laboratory Mammals and In Vitro Test Systems, Neurotoxicity, In Vivo Models, Rodent Models of Aluminium Toxicity by Direct Injection describes several studies that have reported elevated levels of markers of oxidative stress in animals exposed to aluminium. These studies suggest potential mechanisms by which long-term exposure to aluminium could be deleterious and could synergistically worsen cognitive abilities in individuals that have pathologic abnormalities associated with AD.

In regards to mechanisms by which aluminium could play a role in AD, there are both direct and indirect modes of potential action. In a direct mode, aluminium could potentiate the aggregation of molecules known to form pathologic lesions in AD. There is evidence that aluminium can promote the aggregation of β-amyloid peptide in vitro. However, whether aluminium would dissociate from Tf at an appreciable rate and bind β-amyloid peptide in vivo is unclear. One study found no association between AD-like pathology and long-term ingestion of aluminium. Indeed in this study of older patients, the incidence of AD-associated pathology in patients with DAE was no different from controls. Although these studies would suggest that there is little direct evidence for an association between AD and aluminium, a study of transgenic mice that produce Alzheimer-type amyloid pathology noted that mice feed diets high in aluminium showed increased levels of amyloid (see Effects on Laboratory Mammals and In Vitro Test Systems, Neurotoxicity, Alzheimer&#;s Disease). Moreover, it is well established in the rabbit that exposure to aluminium induces the formation of filamentous structures containing cytoplasmic neurofilament protein (see Effects on Laboratory Mammals and In Vitro Test Systems, Neurotoxicity, Motor Neuron Disease). Therefore, it is difficult to determine how a life-time of exposure to aluminium might influence the development of Alzheimer-type pathology by affecting the folding or clearance of &#;at-risk&#; proteins such as β-amyloid, tau, and α-synuclein.

In the studies of animals, it is important to note that a few reports have documented a pathologic accumulation of aluminium in intracellular lysosome-derived structures. Aluminium accumulation in lysosome-like cytoplasmic granules of retinal neurons in rats exposed to very high doses of aluminium was reported (see Effects on Laboratory Mammals and In Vitro Test Systems, Neurotoxicity, In Vivo Models, Rodent Models of Aluminium Toxicity by Direct Injection). Severe atrophy of the retina and loss of photoreceptors was also noted. Similarly, another study noted intracellular accumulations of aluminium in the brain of rats feed diets high in aluminium. For CNS it seems likely that the mode of delivery to the tissue is through Tf-mediated uptake. From animal studies and the clear association of aluminium exposure and DAE, it is clear that high levels of aluminium in CNS can lead to neurotoxicity. From the current literature it remains difficult to assess what a concentration of aluminium in serum (chronic levels) correlates with neurotoxicity. The effects of aluminium on the developing nervous system have also not been thoroughly addressed.

The form of aluminium most often presented to tissues outside of the blood stream is expected to be bound to Tf. In brain, aluminium is prone to dissociate from Tf as a soluble citrate salt. Most cells of the central nervous system (CNS) express Tf receptor, and thus receptor-mediated uptake would be one mechanism by which aluminium could enter cells of the brain. Free flow endocytosis of aluminium citrate could be an alternative route of uptake. As outlined in Effects on Laboratory Mammals and In Vitro Test Systems, Neurotoxicity, In Vivo Models, Neuropathology, there is at least one example of human pathology which is consistent with this mode of tissue exposure. Choroid plexus epithelia, cortical glia, and cortical neurons of patients exhibiting dialysis associated encephalopathy (DAE) develop intracellular argentophylllic granules that are lysosome-derived and intracytoplasmic. Uptake of aluminium-Tf complexes via receptor-mediated endocytosis would be expected to produce just such pathology. Whether aluminium, of any amount or speciation, escapes these compartments to impact on intracellular processes in humans is unknown. If relatively high doses produce pathology of such a distinctive nature, then it is reasonable to presume that lower doses of aluminium would follow similar pathways into the nervous system of humans.

Oral administration of aluminium did not affect reproductive capacity in males or females. Exposure to aluminium during gestation did not affect maternal health or development of the foetuses and neonates. Further, there was no evidence of teratogenic alterations in the foetuses of mothers fed dietary aluminium. Maternal dietary exposure to excessive amounts of aluminium during gestation and lactation resulted in neurobehavioural abnormalities in mouse offspring. At physiological concentrations the reproductive system does not appear to be a target for aluminium-induced effects; and if there is exposure during pregnancy, the growth and development of offspring of metal-treated mothers is not adversely affected.

Regardless of the duration of exposure, the toxicity attributed to aluminium is dependent upon the physiochemical properties (solubility, pH, bioavailability, etc.), type of aluminium preparation, route of administration, and physiological status (presence of renal dysfunction). Following oral exposure, aluminium distributes throughout the organism with accumulation in bone, kidneys and brain being of concern to humans with evidence of renal dysfunction, anemia or neurobehavioural alterations reported after excessive doses. The presence of aluminium in vaccines was found to be associated with macrophagic myofasciitis (MMF) at the site of i.m. injection. The toxicity of aluminium is affected by chelating agents and ligands although the mechanisms underlying toxicity remain unknown. However, it should be noted that only at excessive concentrations of aluminium are toxic manifestations seen and, hence aluminium is considered to possess a &#;low&#; potential for producing adverse effects.

Following i.v. injection, ~ 0.001 to 0.01% of the aluminium dose enters each gram of brain and ~ 100-fold more each gram of bone. Brain aluminium uptake across the blood-brain barrier (BBB) may be mediated by Tf-receptor mediated endocytosis (TfR-ME) and a Tf-independent mechanism that may transport aluminium citrate. There appears to be a transporter that effluxes aluminium from the brain into blood. Aluminium distributes into the placenta, foetus, milk, hair, and can be quantified in all tissues and fluids. Greater than 95% of aluminium is eliminated by the kidney, probably by glomerular filtration. Less than 2% appears in bile.

The volume of distribution (V d ) of aluminium is initially consistent with the blood volume, and then increases with time. Steady state serum to whole blood aluminium concentrations are ~ equal. Greater than 90% of serum aluminium is bound to Tf. Although aluminium has been reported in many intracellular compartments, concentrations were often greater in the nucleus. Ferritin can incorporate aluminium.

Absorption of aluminium from the gastrointestinal tract (GI) appears to be primarily in the distal intestine. There is evidence supporting several mechanisms of intestinal aluminium absorption, including sodium transport processes, an interaction with calcium uptake, and paracellular diffusion. Aluminium penetration of the skin is very shallow. Aluminium may be able to enter the brain from the nasal cavity by a direct route, bypassing systemic circulation, but convincing evidence is lacking. Absorption of aluminium from intramuscularly (i.m.) injected aluminium hydroxide and aluminiun phosphate adjuvants is significant, and may eventually be complete. Tissue aluminium concentration increases with age.

Serum aluminium > 30 μg/L in dialysis patients has been associated with osteomalacia and related disorders and > 80 μg/L associated with encephalopathy. Up to 5 mg/kg of desferrioxamine once or twice weekly has been shown to be safe and effective for long-term treatment of aluminium overload.

Biological monitoring of human aluminium exposure has been conducted with urine, which is thought to indicate recent exposure, and plasma, which is thought to better reflect the aluminium body burden and long-term exposure. However, neither is a very good predictor of the aluminium body burden, which is better estimated by bone aluminium, the desferrioxamine challenge test, or combined measurement of serum iPTH (parathyroid hormone) and the desferrioxamine test.

Greater than 95% of aluminium is eliminated by the kidney; ~ 2% in bile. Occupational aluminium exposure increases urinary more than plasma aluminium concentration above their normal levels. Depending on the type and route of exposure, aluminium clearance has been characterized as having multiple half-times and are estimated in hours, days, and years. Most of the Al was eliminated within the first week; the terminal half-life probably represents < 1% of the injected aluminium.

Tissue aluminium concentration increases with age. Some studies have reported that the aluminium concentration in the bulk brain samples, neurofibrillary tangles (NFT) and plaques was higher in AD subjects than controls. Other studies have found no difference. Hair aluminium concentration has been described but its value as an indicator of aluminium body burden has not been demonstrated.

Steady state serum to whole blood aluminium concentrations are ~ equal. Slightly > 90% of plasma aluminium is associated with transferrin (Tf), ~ 7 to 8% with citrate, and < 1% with phosphate and hydroxide. Normal plasma aluminium concentration is believed to be 1 to 2 μg/L. Normal tissue aluminium concentrations are greater in lung (due to entrapment of particles from the environment) than bone than soft tissues. Approximately 60, 25, 10, 3 and 1% of the aluminium body burden is in the bone, lung, muscle, liver and brain, respectively. Higher concentrations are seen in uraemia and higher still in dialysis encephalopathy.

Oral aluminium bioavailability is greater from water than from aluminium hydroxide or sucralfate. Oral aluminium bioavailability from aluminium hydroxide is &#; 0.1%, and is less with higher doses. Increased oral aluminium absorption has been suggested in Alzheimer&#;s disease (AD) and Down&#;s subjects. Oral aluminium bioavailability from the diet has been estimated to be ~ 0.1 to 0.3%, based on daily aluminium intake and urinary elimination. Results of a few studies with a controlled diet and tea are consistent with this estimate.

The use of 26 Al as a tracer and accelerator mass spectrometry has enabled safe studies of aluminium toxicokinetics with real exposure-relevant doses in humans. Aluminium bioavailability from occupational inhalation exposure is ~ 2% whereas oral aluminium bioavailability from water has been reported to be 0.1 to 0.4%. Oral aluminium bioavailability is increased by citrate, acidic pH, and uraemia and may be decreased by silicon-containing compounds. Oral aluminium bioavailability is also inversely related to iron status.

Workers in the aluminium production and user industries, as well as aluminium welders, experience considerable exposures to the metal and/or its compounds. In absence of occupational exposures and chronic use of aluminium-containing antacids and buffered aspirin, food is the major intake source of aluminium, followed by drinking water. When considering bioavailability, namely the fraction that is actually taken up into the blood stream, food is again the primary uptake source for individuals not occupationally exposed. However, chronic use of antacids, buffered aspirins and other medical preparations would likely constitute the major uptake source, even when exposed at work.

Aluminium may be designated as crustal in origin, and thus surface soils at uncontaminated sites constitute a source of soluble aluminium species in surface water and aluminium-containing particulates in sediments and ambient-air aerosols. Not surprisingly, the latter are present extensively in air samples in agricultural communities and when road dust is extensive. Environmental acidification is known to mobilize aluminium from land to aquatic environments. Interestingly, aluminium levels and its various forms (species) are often similar in source water and after its treatment with potassium alum as a flocculent during drinking water purification.

Aluminium has not been classified with respect to carcinogenicity; however, &#;aluminium production&#; has been classified as carcinogenic to humans by the International Agency for Research on Cancer (IARC) (for further explanation, please see Effects on Humans, Effects from Occupational Exposure, Cancer). Occupational limits exist in several countries for exposures to aluminium dust and aluminium oxide. For non-occupational environments, limits have been set for intake in foods and drinking water; the latter are based on aesthetic or practical, rather than health, considerations.

The largest markets for aluminium metal and its alloys are in transportation, building and construction, packaging and in electrical equipment. Transportation uses are one of the fastest growing areas for aluminium use. Aluminium powders are used in pigments and paints, fuel additives, explosives and propellants. Aluminium oxides are used as food additives and in the manufacture of, for example, abrasives, refractories, ceramics, electrical insulators, catalysts, paper, spark plugs, light bulbs, artificial gems, alloys, glass and heat resistant fibres. Aluminium hydroxide is used widely in pharmaceutical and personal care products. Food related uses of aluminium compounds include preservatives, fillers, colouring agents, anti-caking agents, emulsifiers and baking powders; soy-based infant formula can contain aluminium. Natural aluminium minerals especially bentonite and zeolite are used in water purification, sugar refining, brewing and paper industries.

Bauxite is the most important raw material used in the production of aluminium. Bauxite is refined to produce alumina from which aluminium metal is recovered by electrolytic reduction; aluminium is also recycled from scrap. Aluminium hydroxide is produced from bauxite. In , primary aluminium was being produced in 41 countries, the largest producers being China, Russia, Canada and the United States. In that year, worldwide production of primary aluminium, alumina and aluminium hydroxide reached about 30, 63, and 5 million tonnes per annum, respectively. More than 7 million tonnes of aluminium is recovered annually from recycled old scrap.

Aluminium and its compounds comprise about 8% of the Earth&#;s surface; aluminium occurs naturally in silicates, cryolite, and bauxite rock. Natural processes account for most of the redistribution of aluminium in the environment. Acidic precipitation mobilizes aluminium from natural sources, and direct anthropogenic releases of aluminium compounds associated with industrial processes occur mainly to air. Certain uses lead to the presence of aluminium in drinking water and foodstuffs.

A compendium is provided of aluminium compounds used in industrial settings, and as pharmaceuticals, food additives, cosmetics and as other household products. Most aluminium compounds are solids exhibiting high melting points. The solubility of aluminium salts is governed by pH, because the aluminium(III)-cation (Al 3+ ) has a strong affinity for the hydroxide ion, which promotes precipitation. Like Mg 2+ and Ca 2+ ions, Al 3+ in most situations seeks out complexing agents with oxygen-atom donor sites such as carboxylate and phosphate groups, including in biological systems. Aluminium oxides, hydroxides and oxyhydroxides occur in numerous crystallographic forms, which exhibit different surface properties. Few compounds of aluminium are classified in Annex 1 of the European Economic Union Council (EEC) Directive 67/, with aluminium powder and sodium aluminium fluoride (cryolite) as examples of exceptions, as well as compounds in which the anion renders them reactive such as aluminium phosphide. And finally, the more recent analytical methods available for the study of chemical speciation in solids and solution, and for quantitative analysis, have been applied to the determination of aluminium and the identification of its various forms.

26 Al is a rare radioactive isotope of aluminium and is produced in particle accelerators by bombarding a magnesium target with deuterons. It is radioactive and has a long t ½ (716,000 years) and can thus be detected radiometrically or by mass spectrometry ( Priest, ). Whole-body counting is possible and increases the versatility of this technique. It has been employed in determining the human toxicokinetics, and the tissue distribution, bioavailability and GI uptake of aluminium ( Priest, ).

Ellis et al. () illustrated that in vivo monitoring of skeletal aluminium burden in patients with renal failure using neutron activation analysis (NAA) was possible. However, the research reactor required is not widely available. The promise of a portable instrument for an accelerator-based in vivo procedure for detecting aluminium body burden by NAA has recently been reported ( Comsa et al., ).

Limitations of the latter approach have recently been demonstrated for localizing aluminium in maize root tissue ( Eticha et al., ), although Ruster et al. () recommended this technique for quantifying deposition of aluminium in bone. In , Verbueken et al. critically reviewed studies that examined the localization of aluminium in histological sections, namely, by electron probe X-ray microanalysis, secondary ion mass-spectrometry and laser microprobe mass analysis (LAMMA). These techniques are used in conjunction with scanning electron microscopy (SEM) or transmission electron microscopy (TEM); thus the microanalytical results are correlated with tissue structure. Further details about these and related microanalytical techniques are outlined by Ortner et al. () . Verbueken et al. () concluded that all three techniques are helpful in localizing aluminium in tissues, but LAMMA provides the greatest sensitivity (i.e., can detect lower concentrations). Recently, accumulation of aluminium was detected in newly-formed lamellar bone after implantation of titanium plates containing 6% aluminium employing energy dispersive X-ray spectrometry (EDXS) in conjunction with SEM. Similarly, the use of micro-beam proton-induced X-ray emission (PIXE μbeam) confirmed that aluminium leaked diffusely from a titanium-aluminium-vanadium alloy dental implant into the surrounding bone, while vanadium did not ( Passi et al., ).

Of the three substances reviewed in detail in this report, only aluminium powder is classified in Annex 1 of the European Economic Union Council Directive 67/548. Indeed, very few of the compounds listed in Tables 1 and 3 are classified; those that are listed are recognized as hazardous and are widely used, such as cryolite and aluminium phosphide (see Identity, Physical and Chemical Properties, Analytical Methods, Identity).

Adsorption capacity is central to some of the major uses of Al 2 O 3 , Al(OH) 3 and other aluminium compounds (e.g., aluminium phosphate, AlPO 4 ). Adsorption of antigens onto Al(OH) 3 and AlPO 4 constitutes the basis for their use as vaccine adjuvents ( Gupta, ). At neutral pH, gels of these compounds have different charges, the phosphate being negative and the hydroxide positive. This is important, relative to the charge borne by the antigen at physiological pH. The various forces described are optimized by adjustment of the pH and ionic strength of the medium, temperature, particle size of the adsorbent, and the surface area of the latter ( Gupta, ). Similarly, the natural hydrophilic surface characteristic of Al 2 O 3 is central to its use as solid-phases in chromatography. More recently, stable surface coatings have been developed which render the Al 2 O 3 surface hydrophobic, which makes it even more versatile in chromatographic applications. Al 2 O 3 and the aluminium oxyhydroxides are used to remove moisture from gases such as argon, alkanes, and sulphur dioxide. They are also used to remove hydrogen fluoride (HF) from air by adsorption; fluoride ions can also be removed effectively by them from water. Fluoride is adsorbed on to alumina at low pH values and can be desorbed on increasing the pH. Clearly, the inhalation of particulates of Al 2 O 3 and related oxyhydroxides in aluminium smelting operations may constitute a delivery vehicle for adsorbed HF ( Höflich et al., ; L&#;vov et al., ). Finally, the use of finely divided aluminium metal, Al(OH) 3 , aluminium potassium silicate and other aluminium compounds to generate dye (colour) lakes (see Table 2 ) stems from the surface adsorptive forces/capacities described.

In simple terms, the surface layer of a metal binary compound has exposed metal ions (and anions) with reduced coordination number, which can behave as Lewis acids (or bases). At the solid-solution interface, proton association and dissociation can lead to pH-dependent surface charges and complexation. This is further complicated by specific adsorption of cations or anions right at the solid/solution interface, with some ordering of counter-ions in a more diffuse layer at points further into the solution ( Stumm & Morgan, ). A zero point of charge occurs, which is pH dependent. It is also influenced by the extent of specific ion adsorption. In addition to surface electrostatic and complexation reactions, hydrogen-bonding and London-van der Waals forces can be involved in the adsorption of surfactants, non-polar organic solutes, polymers and polyelectrolytes ( Stumm & Morgan, ).

Gibbsite, γ-Al(OH) 3 [CAS No -49-3] is one of the three minerals that make up bauxite ore; the others being Al 2 O 3 and the oxyhydroxides boehmite [α-Al 2 O 3 &#; H 2 O or α-AlO(OH)] and diaspore [β- Al 2 O 3 &#; H 2 O or β-AlO(OH)]. Of the latter, diaspore is the high temperature/high pressure form ( Pearson, ). Gibsite has three structural polymorphs, namely bayerite [α-Al(OH 3 ); CAS No -20-9], nordstandite [β-Al(OH 3 ); CAS No -05-6] and doyleite which is rather rare ( Mineralogy Database, ). On heating the Al(OH) 3 , polymorphs follow a different Al 2 O 3 transition sequence in reaching the high temperature α-Al 2 O 3 form ( Pearson, ).

Aluminium oxide (Al 2 O 3 ) occurs in two major forms. α-Al 2 O 3 [corundum; CAS No -74-5] constitutes a high temperature form and is formed on heating aluminium hydroxide, Al(OH) 3 , at a temperature of °C or above. It is very hard and resistant to hydration and attack by acids; it occurs in nature as corundum ( Cotton & Wilkinson ). γ-Al 2 O 3 is generated at 500°C and readily takes up water and dissolves in acids. Other minor forms generated when heating Al(OH) 3 include: χ-, κ-, δ-, θ-Al 2 O 3 ( Pearson, ; Trunov et al., ). Recent studies suggest that the structure of the surface layers of α-Al 2 O 3 depends on hydration: on the surface of a highly polished single crystal, the aluminium atom (more correctly Al 3+ ions) are exposed, while in the ideal (unrelaxed) structure the oxygen atoms (actually oxide anions, O 2- ) are at the surface. On hydration, the latter are overlaid by a semi-ordered absorbed water layer with the presence of extensive hydrogen bonding and hydroxyl groups resulting in a relaxed structure. In fact, the hydrated surface structure appears to be in between that of the ideal α-Al 2 O 3 surface and that of γ-Al(OH) 3 . The Al 3+ ions in the Al-terminated surface are strong Lewis acids and react strongly with water, while surface hydroxyl groups are Lewis bases that interact with metal ions ( Eng et al., ). Surface reactivity constitutes the basis for the use of aluminium oxide and hydroxide as industrial catalysts, absorbents and chromatography packing materials (i.e., as stationary phases). Not surprisingly, the reactivity of solid Al 2 O 3 depends on its specific crystal structure and hydrophilic/hydrophobic surface properties, and thus the degree of surface hydration ( Pearson, ).

The reactivity of aluminium powders depends on their morphology (size, shape and surface area), bulk density and aluminium content. For example, Ilyin et al. () , have demonstrated that nanoparticles of fine aluminium powders exhibit maximal values of oxidation (combustion) rates compared to microparticles, and this occurred at lower temperatures. Not surprisingly, because of their thinness and corresponding high surface area, aluminium flake powders (see Sources of Human Exposure, Anthropogenic Sources, Uses, Aluminium Powders) also are relatively reactive. Trunov et al. () and Meda et al. () have reported similar findings. Consequently fine and ultrafine aluminium powders show better promise as propellant additives than do the more conventional-sized (of the order of 10μm) aluminium powders. Interestingly, the combustion products of nano-sized aluminium powders are also different, such as a higher proportion of low-temperature aluminium oxide polymorphs ( Meda et al., ) (see below) and product morphology. Ilyin et al. () demonstrated that combustion of spherical micro-sized aluminium powders resulted in spherical products, while spherical fine powders produced submicron needles. As explained in the next paragraph, this is important for human exposure characterization.

The formation of aluminium fluoride complexes in fluoridated drinking water has been debated extensively. Fluoridation of municipal drinking water supplies is a common practice for the prevention of dental caries; fluoride is added at a concentration of around 50 μmol/L (1 mg/L), corresponding to a pF (that is a &#;log[F]) of 4.3. Further, the pH of municipal water supplies is typically 8.0 ± 0.4 (e.g., Nieboer et al., ). Consequently, and with reference to Figure 3 , the distribution curves depicted for pH 7.5 are the most relevant. Thus, again, Al(OH) 4 &#; is the dominant form in which Al 3+ occurs, with little evidence for complexation with the fluoride ion.

From Figure 1 , it is clear that, at physiological pH of 7.4, little or no free (hydrated) Al 3+ exists in aqueous solution; the anion Al(OH) 4 &#; predominates. The distribution curve in Figure 2 illustrates the competition between hydroxide and citrate as ligand molecules. Under the conditions indicated in the legend to Figure 2 , the competition with the OH &#; is suppressed by the citrate tetra-anion. At physiologic pH, the AlLH -1 (OH) 2- complex dominates.

Mole fraction of Al(III) v.s. pH distribution curves (solids) for a solution containing 0.1 mM citrate, 3 mM Ca 2+ , and 1 pM total Al(III). The distribution is only very weakly dependent on the concentrations of the three components. The dashed line labelled pX refers to the scale on the right, where pX= -log(mole fraction of free Al 3+ ). Thus we have, at pH 7.4, pX = 7.7. Since we also have pAl = pX - log [Al(III)], for 1 μM total Al(III), pAl = 7.4 + 6.0 = 13.7. Reprinted with permission from Martin () . Copyright American Chemical Society. Note that LH denotes the citrate tri-anion, with all three of its three carboxylate groups deprotonated; LH -1 denotes the tetra-anion of citrate, which involves a further loss of a proton from its lone alcohol functional group. Also pAl= -log (concentration of free Al 3+ ) and Al(III) represents Al 3+ in all of its forms.

Formally, the definition of elemental speciation is limited to a chemical perspective; thus a chemical species is defined as: &#;a specific form of a chemical element, such as a molecular or complex structure or oxidation state&#; ( Caruso et al., ; Templeton et al., ). However, Nieboer et al. ( ; ) subscribe to a broader working definition of &#;speciation&#;, that is: &#;an interdisciplinary field of activity concerned with all dimensions of the occurrence and measurement of an element in separately identifiable forms (i.e., chemical, physical or morphological)&#;. The former and more restrictive definition is employed below for the solution chemistry of Al 3+ , while the latter is helpful when considering the reactivity of aluminium oxide and aluminium hydroxide solids.

In biological systems, Al 3+ , like Mg 2+ and Ca 2+ , seeks out carboxylate and phosphate groups linked to macromolecules (i.e., proteins, RNA and DNA) or as constituents of low-molecular-mass ligands such as amino acids, nucleotides, citrate, phytates, lactate, carbonate, phosphate and sulphate ( Harris, ). Because of the small size of the unhydrated Al 3+ , it can also bond to the phenolic group of the amino acid tyrosine in proteins. Most of the Al 3+ in human serum is bound to the protein Tf (see Toxicokinetics, Distribution (Including Compartmentalization), Human Studies, Transport in Blood), which is a recognized carrier of trivalent metal ions, especially Fe 3+ ( Barker et al., ; Harris, ; Harris et al., ). Involvement of tyrosine phenolate groups in the Fe 3+ -Tf complex is well established ( DaSilva & Williams, ). Under certain instances, such as in its citrate complex, Al 3+ can also bind to a deprotonated alcohol group ( Feng et al., ).

In terms of chemical reactivity, the following compounds are notable for their reactions with water: aluminium alkyls, alkyl halides, hydrides; the anhydrous halides (namely bromide, chloride and iodide); and the carbide, chlorate, nitride and phosphide. Explosive gases are released on contact with water, specifically hydrogen (H 2 ) from the hydrides and methane (CH 4 ) from the carbide. Release of toxic gases on hydration can also occur, that is chlorine dioxide (ClO 2 ) from the chlorate; ammonia (NH 3 ) from the nitride; phosphine (PH 3 ) from the phosphide; and hydrogen sulphide (H 2 S) from the sulphide.

The water solubility of aluminium compounds is limited except for its salts, namely the chloride, nitrate, sulphate and chlorate (often as a corresponding hydrate). Salts of low molecular organic acids also have some water solubility (e.g., acetate, benzoate and lactate), as do salts containing aluminium anion complexes (e.g., ammonium hexafluoroaluminate and tetrachloroaluminate; sodium and potassium aluminate.) As explained in Identity, Physical and Chemical Properties, Analytical Methods, Physical and Chemical Properties, Chemical and Morphological Speciation, pH is often a factor that can limit solubility in water. Solubility of inorganic aluminium compounds in organic solvents is limited to those which are anhydrous such as the bromides, chlorides, and iodides. Aluminium alkyls, alkyl halides, alkoxides and complexes of long-chain FAs and of high molecular mass organic ligands exhibit solubility in organic solvents.

Table 3 summarizes the available physico-chemical properties of the compounds. Most of the aluminium compounds are solids exhibiting high melting points; some are liquids. No gaseous substances were identified. Only a few of the compounds sublimate, namely anhydrous aluminium chloride and fluoride, aluminium nitride and sulphide, as well as the complex with 8-hydroxyquinoline. Most of the substances are white or colourless.

In spite of aluminium being highly electropositive (i.e., readily forming positive ions), it is resistant to corrosion because of the formation of a hard, tough surface film of its oxide ( Cotton & Wilkinson, ). Fresh aluminium surfaces achieve this by reacting with water or molecular oxygen. Hydrothermal oxidation of aluminium powders at 150-250°C and water vapour pressures of 500- kPa suggest that surface-adsorbed water oxidizes the aluminium with the release of molecular hydrogen and the formation of aluminium hydroxyoxides on the particle surface ( Tikhov et al., ). Similarly, thermogravimetric studies of aluminium powders have shown that oxidation with molecular oxygen generates surface layers composed of various aluminium oxide polymorphs, specifically the γ-, θ-, and α- forms depending on the temperature ( Trunov et al., ) (see also Identity, Physical and Chemical Properties, Analytical Methods, Physical and Chemical Properties, Chemical and Morphological Speciation). Furthermore, aluminium metal is soluble in dilute mineral acids, but is inactivated (passivated) by concentrated nitric acid; it is attacked by hot alkali hydroxides ( Cotton & Wilkinson, ).

Aluminium is a ubiquitous element in nature and as the metal that has gained industrial and commercial use based upon certain physical and chemical properties such as low specific gravity, high tensile strength, ductility, malleability, reflectivity, corrosion resistance, and high electrical conductivity. Aluminium alloys are light, strong and readily machined into shapes ( IPCS, ; see Sources of Human Exposure, Anthropogenic Sources, Uses for listings of industrial and non-industrial uses).

Most of the substances listed in Tables 1 and 2 are generally available in high purity and thus impurities are not an issue from a risk assessment perspective. However, it is clear that for many of the aluminium compounds, the degree of hydration can vary. Recently, the presence of a thin surface coating of ultrafine particles of sodium fluoride on aluminium oxide particulates has been demonstrated for aerosols collected in an aluminium refinery ( Höflich et al., ; L&#;vov et al., ).

Tables 1 and 2 indicate that the primary identification of aluminium compounds is by the CAS Registry Number. Other numbering systems are not as widely accepted and are thus not as useful. For example, European Inventory of Existing Commercial Substances (EINECS) numbers are available for aluminium (013-001-00-6), aluminium oxide (215-691-6) and aluminium hydroxide (244-492-7) through the International Uniform Chemical Information Database. However, most of the chemicals listed in Tables 1 and 2 are indicated as not having been assigned such a number ( ESIS, ). Exceptions are those compounds that exhibit high toxicity or are widely used, such as aluminium phosphide (EINECS # 015-004-00-8) and cryolite (-52-3). Note that for the three substances that form the focus for this review, the common names assigned in the tables are the same as the EINECS names.

The focus of this document is on aluminium metal, aluminium oxide and aluminium hydroxide; however, in order to more fully understand their toxicity and related human health effects, other pertinent studies involving aluminium compounds were reviewed. The basis for this is that the chemistry and biochemistry of the aluminium ion (Al 3+ ) dominate the pathways that lead to toxic outcomes. Most aluminium compounds currently used in industry, pharmaceuticals, food additives, cosmetics and other household products are identified in this section (see Tables 1 and 2 ). Many of the compounds listed in these tables have been studied in health-related research and are featured in the critical assessments detailed in subsequent sections of this risk assessment document.

In the absence of a consensus on the acceptable &#;safe&#; concentration of aluminium in plasma to guide therapy, it was suggested that 0.5 to 1.9 μM (13.5 to 51 μg/L) be considered as reflecting increased exposure, 2.0 to 2.9 μM (54 to 78 μg/L) excessive exposure, and > 3 μM (81 μg/L) a toxic concentration, that perhaps warrants mobilization ( Fenwick et al., ).

The Kidney Disease Outcomes Quality Initiative suggested Al-based antacids could be used in patients with chronic kidney disease who have serum phosphorus levels >7.0 mg/dL (2.26 mmol/L) as a short-term (4 weeks) therapy, and for one course only, to be replaced thereafter by other phosphate binders and that more frequent dialysis should also be considered in these patients ( National Kidney Foundation, ).

The U.S. Association for the Advancement of Medical Instrumentation has issued a standard in which it is recommended that water used in the preparation of dialysate solution contain less than 10 μg/L Al in order to limit the unintentional administration of aluminium to dialysis patients ( AAMI, ; ATSDR, ). However, there is concern that unless long-term exposure is limited to lower aluminium concentrations, there will be slow, but permanent, exposure of a greater percentage of dialysis patients to aluminium ( Fernandez-Martin et al., ). These authors suggested the recommended level should be 2 μg/L.

The WHO has not proposed a health-based guideline for aluminium in drinking water because of the limitations in the animal data; however, it has derived &#;practicable levels&#; of &#;0.1 and &#;0.2 mg/L for large and small facilities, respectively, based on optimization of the coagulation process in water treatment plants that use aluminium-based coagulants ( WHO, ). A health based maximum contaminant level (MCL) has also not been promulgated for aluminium under the U.S. Safe Drinking Water Act; a secondary non-enforceable MCL has been set at a concentration range of 0.05 - 0.2 mg/L ( ATSDR, ; EPA, ; IRIS, ). The EU directive for aluminium in drinking water is 0.2 mg/L as an &#;Indicator Parameter&#; ( Lenntech, ). Australia has also recommended a drinking water guideline value of 0.2 mg/L based on aesthetic considerations ( Queensland Government, ). Canada has not set a health-based guideline. However, it is recommended in the Canadian Guidelines for Drinking Water Quality, &#;as a precautionary measure&#;, that water treatment plants using aluminium-based coagulants optimize their operations to reduce residual aluminium levels in the treated water to the lowest extent possible. Where aluminium-based coagulants are used in conventional treatment plants, the operational guidance level is <0.1mg/L (based on a 12 month running average of monthly samples); for other types of treatment systems using such coagulants, the operational guidance value is <0.2 mg/L ( Federal-Provincial-Territorial Committee on Drinking Water, ).

The Joint Food and Agriculture Organization (FAO) / World Health Organization (WHO) Expert Committee on Food Additives and Food Contaminants recommended a provisional tolerable weekly intake (PTWI) of 7.0 mg/kg b.w.; this value includes the intake of aluminium from its use as a food additive ( FAO/WHO, ; IPCS, ). In , the PTWI was lowered to 1.0 mg/kg b.w. citing that aluminium compounds may exert effects on reproductive and developing nervous systems at lower doses than were used in setting the previous guideline ( FAO/WHO, ). In the United States, an intermediate duration oral exposure Minimal Risk Level (MRL) of 2.0 mg/kg/day has been developed ( ATSDR, ; IRIS, ) based on neurotoxicity in mice ( ATSDR, ; Golub et al., ). No MRLs for any duration of inhalation exposure have been set for aluminium and the EPA has not designated aluminium or its compounds as hazardous air pollutants under the Clean Air Act; however, the EPA has regulated aluminium and certain aluminium compounds under this Act ( ATSDR, ).

The U.S. Occupational Safety and Health Administration (OSHA) requires employers to reduce exposures to aluminium to or below an 8-hr time-weighted average (TWA) of 15 mg/m 3 for total aluminium dust or 5 mg/m 3 for the respirable fractions ( NIOSH, ). Limits have also been set for aluminium in the workplace by the ACGIH () ( ATSDR, ) and the National Institute for Occupational Safety and Health ( NIOSH) ( ) in the United States; these values are listed in Table 10 . In general, in the absence of occupational limits, countries in Europe also use those established by the ACGIH (E. Nordheim, personal communication, ).

Due to hepato-, skeletal and neurotoxicity seen in premature infants that received aluminium as a contaminant in total parenteral nutrition solutions (see Effects on Humans, Effects from Non-Occupational Exposure, Bone and Effects on Humans, Subpopulations at Special Risk, Infants and Children) the U.S. Food and Drug Administration enacted a labeling requirement, that went into effect July 26, , which permits no more than 25 μg Al/L in large volume parenterals and a statement of the exact amount of Al present in small volume parenterals ( US FDA, ).

Classification and labelling requirements in the European Union (EU) are based on inherent hazardous properties of a substance, and are laid down in Directive 67/548 ( EEC, ) and later amendments and adaptations. The requirement covers physico-chemical properties, human health, and environmental toxicity. The classification is based on the results of specific prescribed tests, generally test guidelines developed by the Organization for Economic Cooperation and Development. Discussions regarding the classifications with respect to considerations for either health or environment are conducted in EU expert groups which evaluate the test data and propose the classification. This proposed classification is set out in Directives from the Commission. The classification of aluminium compounds is summarized in Identity, Physical and Chemical Properties, Analytical Methods, Classification.

The carcinogenic risk from aluminium and its compounds has not been evaluated by IARC. However, IARC has deemed that that there is sufficient evidence to show that certain exposures occurring during the production of aluminium cause cancer in humans; therefore &#;aluminium production&#; has been classified as carcinogenic to humans (Group I) ( IARC, ). The U.S. Environmental Protection Agency (EPA) has not classified aluminium for human carcinogenicity ( ATSDR, ; IRIS, ) and the American Conference of Governmental Industrial Hygienists (ACGIH) has designated aluminium as a group A4 substance (&#;not classifiable as to human carcinogenicity&#;) ( ACGIH, ; ATSDR, ).

Aluminium hydroxide is used widely in non-prescription stomach antacids, in buffered analgesics and other pharmaceuticals, and in antiperspirants and dentifrices, as a filler in cosmetics, plastics, rubber and paper and as a soft abrasive for brass and plastics ( ATSDR, ; HSDB, ); it is also used pharmaceutically to lower the plasma phosphorus levels in patients with renal failure ( ATSDR, ; Budavari et al., ). Aluminium hydroxide is also the basis for producing fire retardant materials.

Aluminium metal and its alloys are used extensively in building construction (e.g., siding, roofing, doors, windows), in transportation (in the manufacture of automobiles and aircraft), in packaging (e.g., for beverage cans), and in electrical equipment. Other uses include die-cast motor parts, cooking utensils, decorations, road signs, fencing, beverage cans, coloured kitchenware, food packaging, foil, corrosion-resistant chemical equipment, solid fuel rocket propellants and explosives, dental crowns, jewellery and denture materials. Aluminium is also used for power lines, electrical conductors, insulated cables and wiring ( ATSDR, ; IAI, b ). The largest markets for aluminium are transportation (27%), building and construction (23%), packaging (16%) and electrical equipment (10%). Transportation uses are one of the fastest growing areas for aluminium use showing a growth rate of about 4% per annum in ( Wagner, ). Table 8 lists the approximate distribution of the different product segments in which aluminium is used on a global basis (E. Nordheim, personal communication, )

Aluminium metal is light in weight and is durable because surfaces of products made from it are oxidized to form a thin protective coating of aluminium oxide (alumina). However pure aluminium is extremely soft and therefore is often mixed with other metals and elements (e.g., copper, magnesium, manganese, silicon, lithium and zinc) to form alloys which are stronger and harder and hence of increased versatility ( ATSDR, ; Wagner, ). The tensile strength of some copper-aluminium alloys can exceed that of mild steel by as much as 50% ( Wagner, ). Reference to the uses of aluminium thus normally relates to those for aluminium as an alloy.

The recycling of aluminium requires much less energy than that used to recover the metal from its ores. The annual amount of aluminium recovered from purchased and tolled (new and old) scrap was about 15 million tonnes in ( IAI, ). The automotive industry is the largest consumer of recycled cast aluminium accounting for about 70% of production. It was expected that demand for secondary aluminium would increase significantly as the automotive industry addressed the growing need for lighter vehicles ( Wagner, ).

In addition to primary aluminium production, more than 7 million tonnes is produced per year from post consumer (old) recycled scrap. Almost 100 per cent of all production scrap and over 60 per cent of all old scrap are recycled; it has been noted that the proportion of aluminium produced from scrap (&#;recycled aluminium&#;) is rising rapidly ( IAI, ).

It is noted by the International Programme on Chemical Safety (IPCS) ( IPAI, ; IPCS, ) that annual worldwide production of primary aluminium was 14.8 million tonnes in ; by production essentially doubled to 29.6 million tonnes ( Table 5 ). Between and production increased by between 6 and 8% per annum. In , primary aluminium was being produced in 41 countries, the largest producers being China (22% of world production) followed by Russia (12%), Canada (9%), the United States (8.5%), Australia (3.8%), Brazil (5%), and Norway (4.5%) ( USGS, ). China and Russia surpassed the United States as the largest producers of primary aluminium in ( Figure 4 ).

In , worldwide production of bauxite was 106 million tonnes; based on a comparison of this quantity with the quarterly average values for and , production in major producing countries appeared to be fairly constant ( IPCS, ; World Bureau of Metal Statistics, ). However, by world mine production of bauxite had reached approximately 146 million tons (150 million tonnes) and rose to about 156 million tons (160 million tonnes) in ( USGS, a ) 1 .

Secondary aluminium refining, also referred to as smelting or more commonly recycling, involves recycled aluminium scrap as feed. The scrap is melted in furnaces, fluxes are added, unwanted constituents are removed in the form of dross, and other metals are added if the final products are alloys ( Healy et al., ). Dross forms on the surface of molten aluminium and consists of aluminium oxide, entrained aluminium, and smaller amounts of aluminium nitride, aluminium carbide and magnesium oxide ( Staley & Haupin, ). This is further processed to recover the aluminium content.

Aluminium produced by the Hall-Héroult electrolytic reduction process may be refined to a purity of up to 99.9% by the Badeau low-temperature electrolytic process ( ATSDR, ; HSDB, ). This process is not the only primary refining method. Other approaches have been successfully developed, especially for the production of high purity (99.995%) aluminium ( Staley & Haupin, ).

Aluminium is first extracted at 140 - 250°C with caustic soda from the bauxite, precipitated as aluminium hydroxide after the removal of iron and silicon impurities, and subsequently converted to aluminium oxide in a calcination process. These steps encompass the Bayer process ( Sleppy, ). In the second stage, the aluminium oxide is dissolved in molten cryolite (Na 3 AlF 6 ) and electrolyzed at temperatures of 920-980°C at carbon electrodes to yield the pure molten metal at the cathode and carbon dioxide at the anode (as well as some carbon monoxide and oxygen). The electrolytic cells are referred to as pots and the work area is the potroom. Because the anodes are consumed, they need to be replaced or generated in situ. In the first instance, pre-bake anodes are employed, while in the second approach (referred to as the Søderberg method) the anode is baked on site and carbon, in the form of a paste of petroleum coke and coal tar, has to be added to the top of the pot ( Abramson et al., ; Kongerud et al., ; Staley & Haupin, ). Pre-baked anodes are produced in a separate department by moulding petroleum coke and coal tar pitch binder into blocks and baking at -°C. Casting constitutes the final third step and is carried out in the foundry. It involves the pouring of aluminium ingots. Note that aluminium trifluoride (AlF 3 ) is an important additive for the potroom electrolyte. It is prepared from Al 2 O 3 and hydrogen fluoride ( Sleppy, ; Staley & Haupin, ).

Bauxite, a naturally occurring, heterogeneous material, is the most important raw material used in the production of aluminium ( ATSDR, ; Dinman, ). Bauxite is made up primarily of one or more aluminium hydroxide minerals together with various mixtures of silica, iron oxide, titania, aluminium silicates, and other impurities in minor or trace amounts. The commercial sources of bauxite consist mainly of gibbsite or boehmite. Bauxite is extracted by open-cast mining ( Dinman, ; IPCS, ). Nepheline and alunite are minerals which have also been used as raw materials for production of aluminium oxide. They are still used at some plants in the Commonweath of Independent States, but are a minor part of world production ( Kammer, ).

Aluminium is released and dispersed in the environment by natural processes and from human activity. Natural processes account for most of the redistribution of aluminium in the environment ( ATSDR, ; IPCS, ; Wagner, ) as a result of the weathering of rocks and minerals in which it is present. Mobilization from natural sources can, however, also result from the deposition of acidic precipitation ( IPCS, ; Wagner, ). Direct anthropogenic releases of aluminium compounds occur primarily to air and these are associated with industrial processes. Thus, the mining and processing of aluminium ores and the production of aluminium metal, alloys and compounds can lead to the release of aluminium compounds into the environment. The use of aluminium and its compounds in processing, packaging and storage of food products, and as flocculants in the treatment of drinking-water may contribute to its presence in drinking-water and food stuffs ( ATSDR, ).

Aluminium and its compounds are major constituents of the Earth&#;s crust, comprising up to about 8% of the Earth&#;s surface. It is the third most abundant element (after oxygen and silicon) and the most abundant metallic element, and is found in combination with oxygen, fluorine, silicon, sulphur and other species; it does not occur naturally in the elemental state ( ATSDR, ; Brusewitz, ; Wagner, ). Naturally occurring aluminium is present in silicates such as feldspars and micas, complexed with sodium and fluorine as cryolite, and in bauxite rock (comprising hydrous aluminium oxides, aluminium hydroxides and impurities such as free silica) ( IPCS, ).

Estimates of the bioavailability of aluminium for the various sources and pathways are summarized in the right-hand column of Table 16 . They are based on comparing aluminium intakes by inhalation and ingestion with its urinary excretion (output), as well as toxicokinetic studies. Details are provided in Toxicokinetics, Absorption, Studies in Humans. Food is the primary source for uptake for individuals not occupationally exposed. However, chronic use of antacids, buffered aspirins and other medicinal preparations would likely constitute the major uptake source, even when exposed at work. In the absence of such medicinal usages, occupational exposure would be expected to contribute more to the body burden than food and drinking water.

Estimates of daily aluminium intakes are provided in Table 16 . For an individual who is not occupationally exposed and does not use antacids, buffered aspirin, or antiulcerative or antidiarrheal preparations (see Human Exposure, General Population Exposures, Medical), food is the major intake source of aluminium. If antacids, buffered aspirin, and other medicinal preparations are used, the food contribution will be relatively insignificant. The same is true for workers with occupational exposures, although in this case inhalation could be relatively more important than food as a source. The potential for anti-perspirants to contribute significant aluminium absorption through the skin has been suggested, but not well demonstrated (see Toxicokinetics, Absorption, Studies in Humans, Dermal Exposure).

As described in Identity, Physical and Chemical Properties, Analytical Methods, Physical and Chemical Properties, Properties of Aluminium Compounds / Chemical and Morphological Speciation, and Identity, Physical and Chemical Properties, Analytical Methods, Classification, explosivity, flammability, oxidizing potential and related reactivities are not considered to be of primary interest with respect to assessing the health impacts of exposure to aluminium and its compounds.

In the past, iatrogenic aluminium poisoning has been a serious issue ( Savory, ). This was due to the use of aluminium contaminated dialysis solutions and aluminium-based phosphate binders in patients with chronic renal failure and, similarly, contaminated human serum albumin and other biological products employed in i.v. therapy (see Nieboer et al. ( ) for a detailed summary; also see Effects on Humans, Subpopulations at Special Risk). The aluminium contamination of total parenteral nutrition solutions (see Sources of Human Exposure, Anthropogenic Sources, Legislative Controls, Classification and Labelling) has been mainly introduced in calcium gluconate and phosphates obtained from small volume parenteral vials ( Mouser et al., ).

Based on the aluminium compounds added to non-prescription drugs and anti-ulcerative drugs, the following daily doses (in mg) have been estimated: 840- (antacids); 130-730 (buffered aspirins) and 830 (anti-ulcerative) ( ATSDR, ; IPCS, ; Soni et al., ). These intakes are massive compared to the dietary intakes discussed in Human Exposure, General Population Exposures, Food and Beverages / Drinking Water. Antidiarrheal agents also contain considerable levels of aluminium additives, as much as mg per dose ( ATSDR, ). Of course, other medical uses of aluminium compounds mentioned in Table 7 and in other sections of this document provide exposure opportunities, namely as astringents, antiseptics, analgesics, antimicrobial agents, vaccine adjuvants, topical drugs, and compounds of dental materials and prosthetics, among others.

Aluminium concentrations in bottled commercial drinking water have been reported in a small number of instances. Rosborg et al. () report a median level of total aluminium of 1.33 μmol/L (36 μg/L). Interestingly, when they compared carbonated samples from a single brand, one contained in a plastic bottle and the other in an aluminium can, the respective concentrations were 0.63 μmol/L (17 μg/L) and 2.7 μmol/L (72 μg/L) respectively. Gillette-Guyonnet et al. () reported that aluminium concentrations in 3 of 8 commercial mineral waters obtained in were below the detection limit of 0.1 μmol/L (3 μg/L), while the remainder had values between 0.2 μmol/L (5 μg/L) and 1.2 μmol/L (32 μg/L). By comparison, levels for 6 city water supplies sampled in the same time period ranged from 0.4 μmol/L (10 μg/L) to 2.3 μmol/L (63 μg/L), and another was 2.2 μmol/L (60 μg/L) in -. Finally, López et al. () found a mean ± SD of recoverable aluminium (that found on digestion at 120°C for 90 minutes) of 2.1±1.6 μmol/L (58±43 μg/L) in both 15 regional samples of tap water and 11 samples of glass bottled water bought in supermarkets. By contrast, mineral water purchased in plastic bottles had considerable higher concentrations, namely 4.5±1.2 μmol/L (121±32 μg/L). Leaching from the plastic storage bottles was suspected in this case.

Many of the organic and inorganic water-soluble species discussed in Identity, Physical and Chemical Properties, Analytical Methods, Physical and Chemical Properties, Chemical and Morphological Speciation and those shown to exist in surface waters and soil extracts (see Human Exposure, Environmental Levels, Water) may be expected to be stable at the pH values of drinking water.

Intakes for infants appear considerably lower; for example, a 4-month old infant consuming cow&#;s milk-based formula was estimated to take in 0.03-0.05 mg/day, compared to 0.27-0.53 mg/day when fed soya-based formula ( MAFF, ; also see Dabeka & McKenzie, ; and Pennington & Schoen, ). Navarro-Blasco & Alvarez-Galindo () have reported comparable findings (based on the previous PTWI of 7 mg/kg b.w., rather than the current value of 1 mg/kg b.w.): &#;Standard formulae gave lower intakes amounting to about 4% PTWI; specialized and preterm formulae resulted in moderate intake (11 to 12 and 8 to 10% PTWI, respectively); and soya formulae contributed the highest intake (15% PTWI)&#;.

In the IPCS () monograph, estimates of the average adult dietary daily intake of aluminium are tabulated for 8 countries. These data and other reported values for adults are depicted in Figure 5 . It is clear that, since the mid s, the estimates fall below 15 mg/day. As suggested in the IPCS () review, the lower values in this group likely reflect reduced use of aluminium food additives in some of the countries. The intakes in Figure 5 estimated for or reported in or before of 20-25 mg/day may be due to the inclusion of larger portions of food items with additives, although analytical limitations cannot be excluded.

For systemic effects of a toxicant, uptake into the blood stream is required. Consequently, from this perspective the PM 10 aerosol fraction is more pertinent than the PM 2.5 fraction. Particles are swallowed quickly when deposited in the nasopharynx region of the respiratory tract (inhalation through the nose) and when deposited in the oropharynx region (mouth breathing) ( NRC, ). Similarly, deposited particles cleared by way of mucous from the ciliated nasal passages and the tracheobronchial tree are either expectorated or swallowed. Because deposition in the entire respiratory system (i.e., upper and lower) is included in the inhalable fraction (see Identity, Physical and Chemical Properties, Analytical Methods, Physical and Chemical Properties, Chemical and Morphological Speciation), it is for this reason that the inhalable aerosol fraction (see Identity, Physical and Chemical Properties, Analytical Methods, Physical and Chemical Properties, Chemical and Morphological Speciation) is recommended in the workplace when assessing potential systemic toxic outcomes ( Nieboer et al., ; Vincent, ). Relative to this, the &#;total&#; aerosol fraction discussed in Human Exposure, Occupational Exposure would be second best, followed in order by the PM 10 and PM 2.5 fractions.

In Table 13 , aluminium concentrations in the PM 2.5 and PM 10 aerosol fractions are compiled. In the corresponding text (Human Exposure, Environmental Levels, Air), it was pointed out that the mean total particulate mass found for the PM 2.5 and PM 10 fraction measurements were near or exceeded the U.S. EPA&#;s annual standards in most instances for non-remote sites. A perusal of the aluminium-specific data in Table 13 indicates that mean PM 2.5 concentrations were in the range 0.035-1.82 μg/m 3 and 0.58-6.97 μg/m 3 in the PM 10 fractions. For agricultural communities, the maximum aluminium concentrations were 4.8 μg/m 3 (PM 2.5 ) and 17.3 μg/m 3 (PM 10 ), and 2.7 μg/m 3 (PM 2.5 ) and 5.4 μg/m 3 (PM 10 ) downwind of large urban centres. As pointed out in Human Exposure, Environmental Levels, Air, the natural crustal origin of aluminium accounts for the fact that the highest concentrations are being observed in agricultural areas.

Occupational exposures in workplaces using non-powdered aluminium metal well below its melting point (see Identity, Physical and Chemical Properties, Analytical Methods, Physical and Chemical Properties, Properties of Aluminium Compounds, Table 3 ) may be expected to be considerably lower than those in primary and secondary aluminium refineries. By contrast, exposures in the manufacture of products involving aluminium powder (see Tables 1 and 2 and Identity, Physical and Chemical Properties, Analytical Methods, Physical and Chemical Properties, Properties of Aluminium Metal and Identity, Physical and Chemical Properties, Analytical Methods, Physical and Chemical Properties, Chemical and Morphological Speciation) are likely to be comparable to those experienced in powder production. Similarly, workers involved in alloy production are likely to have aluminium exposures like those associated with comparable operations described for secondary refining and casting in primary refining. By contrast, exposures for aluminium welders have been reported extensively. Exposures depend on the type of welding: metal inert-gas (MIG), tungsten inert-gas (TIG), or manual metal (MMA) welding, as well as the type of welding electrodes (with or without flux). The following &#;total&#; aerosol fractions have been reported: 5-10 mg/m 3 ( Apostoli et al., ); 0.3-10.2 mg/m 3 with a mean of 2.4 mg/m 3 ( Sjögren et al., ; MIG); 0.2-5.3 mg/m 3 with a mean of 1.5 mg/m 3 ( Sjögren et al., ; mostly MIG); 0.2-6.1 mg/m 3 with a mean of 1.4 mg/m 3 (( Nielsen et al., ; MIG and TIG); 0.17 mg/m 3 (electrodes without flux) and 0.81 mg/m 3 (flux-coated electrodes) ( Vandenplas et al., ; MMA)). The particles generated in MIG welding have a mass median diameter of about 0.4 μm, with those for TIG welding being somewhat smaller ( Sjögren et al., ).

An extensive survey of 7 secondary aluminium smelters in the UK found inhalable aluminium air concentrations of 0.04 to 0.90 mg/m 3 , with a mean value of 0.31 mg/m 3 . These measurements are comparable in magnitude to the concentrations reported in Table 14 for jobs involving slag treatment. Healy et al. () did indeed identify the slagging out of rotary furnaces as a dusty operation. Comparable concentrations have been reported for two foundries in South Africa: 0.17 mg/m 3 for smelters; 0.027 mg/m 3 for operators; and 0.58 mg/m 3 for fettlers (i.e., those lining furnaces) ( Rollin et al., a ).

The reports by Röllin et al. ( ; ) suggest that newer potroom technologies can substantially reduce exposure to aluminium. In a new primary smelter, the median &#;total&#; aluminium levels were 0.03 to 0.084 mg/m 3 , while in a plant using the more standard potroom smelting approach exposures were: mean (range) in mg/m 3 of 1.47 (1.25-1.66), potroom 1; 0.35 (0.20-0.57), potroom 2; and other operator, 0.036 (0.02-0.13).

Several noteworthy trends are evident from the data in Table 14 . Exposure to bauxite, aluminium and the metal (as powder or sheets) is associated with low concentrations of water-soluble aluminium, by contrast to exposures in the potrooms, secondary smelting, and AlF 3 production. Consequently, one might expect to observe higher urinary aluminium concentrations among workers in the latter group, which was indeed the case. Surprisingly, the aluminium powder workers exhibited substantially higher before-shift concentrations in urine than other workers. This observation suggests that particulates that deposited and accumulated in the respiratory tract serve as sinks. Further, Gitelman () and Gitelman et al. () conducted a survey involving 40 control subjects and 235 workers employed in 15 plants in the USA engaged in primary and secondary aluminium refining and in the manufacture of products (e.g., powder technologies, cables, rolling mills). Personal exposures ranged from 0.01-1.20 mg/m 3 , with a median of 0.025 mg/m 3 for respirable fractions (<10 μm), and 0.001-3.0 mg/m 3 with a median of 0.10 mg/m 3 for the &#;total&#; aerosol fractions. The maxima in their survey likely pertained to primary refining and work with powders.

Although personal measurements of exposure to dust containing aluminium oxide and other aluminium compounds have been made in the aluminium production industry, they are not extensively documented in the published literature. The emphasis has rather been on PAHs, fluorides and HF measurements ( Benke et al., ). However, the reports by Pierre et al. ( ; ) provide a helpful overview. They surveyed 234 workers employed in primary aluminium refining, 88 in secondary aluminium refining and 13 in aluminium powder production. A summary of their findings is given in Table 14 . Aluminium air concentrations were measured as the &#;total&#; aerosol fraction. Relative to the inhalable aerosol fraction defined in Identity, Physical and Chemical Properties, Analytical Methods, Physical and Chemical Properties, Chemical and Morphological Speciation, &#;total&#; personal samplers undersample particles larger than 15 μm ( Vincent, ). Unfortunately, for most of the worker groups surveyed, only mean values are available.

Bioconcentration of aluminium in aquatic plants and plants grown on low pH soils is known ( Gallon et al., ; IPCS, ). Aerial deposition appears to contribute to plant surface levels of aluminium, as illustrated for spruce needles. Because of its high concentrations in sediments, it is difficult to interpret the aluminium concentrations reported ( IPCS, ) for crustaceans such as crayfish, and bottom feeders such as carp. In other fish, little aluminium seems to be present in edible tissue, but with the gills showing preferential accumulation ( IPCS, ; Reid et al., ; Wilkinson et al., ). As reviewed in Human Exposure, General Population Exposures, Food and Beverages, grains, vegetables, legumes, and especially herbs and spices, exhibit significant tissue concentrations of aluminium.

Dermal contact with and ingestion of sediments and soils is not expected to constitute significant exposure routes, even though the aluminium contents of these media are substantial as mentioned in Human Exposure, General Discussion. Typical aluminium concentrations for major sediments are 9,000 &#; 94,000 μg/g and 700-300,000 (median 71,000) μg/g in soils ( ATSDR, ; Bowen, ; IPCS, ; Sanei et al., ). As described in the previous section, soils are a source of soluble aluminium species for surface water and, of course, of sediment particles as well ( Sanei et al., ). Further, aluminium partitions from water to sediment and particulates. Consequently, soils and sediments are determinants for the level and forms of aluminium in surface water and thus raw water as a source for drinking water.

A study by Schintu et al. () provides insight about the levels and speciation (i.e., its chemical and physical forms) of aluminium in raw water and in water after its treatment in the production of drinking water. It corroborates the wide variability of aluminium concentrations and speciation in surface water and that the corresponding parameters for drinking water are more uniform. In characterizing aluminium exposure, some recent epidemiological studies of AD have considered aluminium speciation in their statistical analyses (e.g., Gauthier et al., ). Consequently, it is relevant to explore this aspect in some detail here for raw water and in Human Exposure, General Population Exposures, Drinking Water for drinking water.

Environmental acidification is known to mobilize aluminium from land to aquatic environments, and this process has been demonstrated to vary with the seasons or major storm events ( ATSDR, ). Anthropogenic point sources can add to the aquatic aluminium burden. It is clear from Fig 2.1 in Identity, Physical and Chemical Properties, Analytical Methods, Physical and Chemical Properties, Chemical and Morphological Speciation that aluminium becomes markedly more soluble below a pH of about 5.

In terms of human health risk, dermal contact with and consumption of water are pertinent pathways of exposure. Consequently, aluminium concentrations in surface and drinking water are of primary interest. Further, as documented elsewhere ( ATSDR, ; IPCS, ), aluminium concentrations in marine waters tend to be considerably lower than in fresh water. The latter, therefore, will be the focus in this section.

Prior to , it was the practice to measure particulate air pollution levels as total suspended particles (TSP) ( Samet et al., ). TSP constitutes air-borne particles with d ae <30 μm ( Cyrys et al., ). In , annual and 24-hr standards were promulgated by the U.S. EPA for the PM 10 aerosol fraction (see Identity, Physical and Chemical Properties, Analytical Methods, Physical and Chemical Properties, Chemical and Morphological Speciation) of 50 and 150 μg/m 3 , respectively. In , this agency added standards for PM 2.5 , namely 15 (annual) and 65 μg/m 3 (24-hr) ( EPA, ). Both the PM 10 and PM 2.5 aerosol fractions have been associated with adverse health effects as reported in Identity, Physical and Chemical Properties, Analytical Methods, Physical and Chemical Properties, Chemical and Morphological Speciation. Reported ambient aluminium concentrations in these fractions are summarized in Table 13 . A perusal of these data indicates mean PM 2.5 aluminium levels were in the range 0.035 to 1.82 μg/m 3 (excluding the arctic and Antarctica sites) and 0.58-6.97 μg/m 3 for PM 10 . By comparison, the mean total particulate mass reported in the PM 2.5 and PM 10 fractions for non-remote sites were near or often exceeded the annual standards indicated. Detailed analyses of these data outlined in the original publications have identified the trends and interpretations summarized in the next paragraph.

Aluminium is the third most abundant element in the Earth&#;s crust with oxygen and silicon being the first and second. The respective percentages are 50, 26 and 7.5 ( Williams & Fraústo da Silva, ). It is therefore not surprising that soils and weathered rocks constitute the major sources of aluminium in environmental media ( Bowen, ). The mobilization of these natural sources far exceeds the anthropogenic releases into air, in waste-water effluents and industrial waste ( ATSDR, ). The environmental mobilization, transport and distribution of aluminium, as well as the levels observed in air, water, soils, sediments and food items have been extensively summarized in previous monographs ( ATSDR, ; IPCS, ) and in topic-specific reviews. Rather than reproducing these efforts, only the seminal features of these issues will be highlighted in the present chapter. However, all recent developments and topics pertinent to human risk assessment are reviewed and discussed in detail.

There are no published reports of physiologically based pharmacokinetic (PBPK) modelling of aluminium. The International Commission on Radiological Protection concluded that the t ½ would be 100 days, based on 61 mg of aluminium in the human body (21 mg in the skeleton), daily intake of 45 mg in food and fluids, fractional absorption of 0.01 from the GI tract and from inhalation, and distribution of 30% of the aluminium that leaves systemic circulation to bone and 70% to all other organs and tissues ( ICRP, ). Much of the data obtained during the past 40 years are different from the assumptions used in this prediction. A model with a plasma and two tissue compartments was developed based on t ½ s of 10.5 and 105 hr, that fit plasma and urine 26 Al after 26 Al citrate ingestion reasonably well ( Fifield et al., ; Priest, ). Similarly, an 8 compartment model was based on the results obtained during 10 years after 26 Al citrate ingestion by one human subject. The model assumes distribution of 60, 24, 7.5, 5.25, 2.2 and 1.25% of the aluminium from blood and ECFs into urine, soft tissues including liver, a rapidly exchangeable bone surface pool, a slowly exchangeable bone surface pool, cortical bone mineral and trabecular bone mineral, respectively. The compartmental t ½ s were calculated to be 1.43, 6, 45, and 500 days for the five non-urine compartments, respectively ( Priest, ). Based on 26 Al in blood and urine samples after a single oral 26 Al administration to 3 healthy and 2 subjects with renal failure and i.v. in 3 healthy human subjects, Kislinger et al. () developed a tentative open compartment model to describe aluminium biokinetics. The model has a central compartment that incorporates separate plasma and interstitial fluid compartments, each with sub-compartments for aluminium Tf and aluminium citrate. It has three peripheral compartments. One is for bone connected to the interstitial citrate compartment since the authors stated that studies in rats have shown that bones are supplied with aluminium by citrate. A second compartment represents muscles and organs including liver, kidneys and spleen connected to both central Tf compartments (plasma and interstitial fluid) as those organs receive aluminium from Tf. The third peripheral compartment is of unknown identity and was arbitrarily connected to the two central Tf compartments. Aluminium input was represented from a duodenal compartment into both the blood plasma Tf and citrate compartments. Output is described from plasma citrate into urine and a minor pathway from plasma Tf into the residual (beyond duodenal) intestinal tract into the stool. Compartment volumes and transport rates between compartments were determined based on the results of 8 subjects. In another report from the same group, Nolte et al. () presented this model again, modifying the percentage of aluminium bound to citrate in plasma from 20% in the previous model to 6% and assigning the two peripheral non-bone compartments to liver and spleen that receive aluminium from plasma Tf and muscles, heart and the kidneys that receive aluminium from interstitial fluid Tf. Incorporating values reported from studies of aluminium in healthy individuals and renal failure patients, and from healthy and nephrectomized rats as well as rats in iron deficiency and iron overload, they calculated compartment volumes and transport rates between compartments. The same group reported the addition of one subject who received i.v. aluminium citrate, bringing the total to 6 healthy and 2 chronic renal-failure subjects who received 26 Al either orally or i.v. Urine samples were obtained for up to 9, and blood for up to, 512 days. Again drawing on much of the published literature, the model was tested ( Steinhausen et al., ) and the results were found to agree well with model predictions.

It has been suggested that the serum aluminium concentration should be kept below 30 μg/L ( Razniewska, ). Psychomotor function in long-term dialysis patients whose mean serum aluminium was 59 μg Al/L was significantly impaired compared to that in controls ( Altmann et al., ). Others suggested that a level of 40 to 50 μg Al/L warrants discontinuation of aluminium gels, 60 μg Al/L might indicate increased body burden, and > 100 μg Al/L indicates potential encephalopathy and the need for increased monitoring in dialysis patients. An AUC > 100 or 150 μg/L could present a risk of aluminium toxicity in these patients ( Alfrey, ) and overt aluminium toxicity has been seen when the serum aluminium concentration was > 200 μg/L ( Berend et al., ; Spencer, ). Mild neurophysiological and neuropsychological adverse effects were seen in MIG welders. The body burden threshold associated with these detrimental effects was estimated to be ~ 4 to 6 μM (108 to 162 μg/L) in urine and 0.25 to 0.35 μM (7 to 9 μg/L) in serum ( Riihimaki et al., ).

Biological monitoring of human exposure to aluminium has been conducted with urine, which has been thought to indicate recent exposure, or serum, which has been thought to better reflect the aluminium body burden and long-term exposure ( Alessio et al., ; Apostoli et al., ; Nieboer et al., ). However, neither is a very good predictor of the aluminium body burden.

As noted above, injection of 26 Al in animals increased 26 Al in bone ~ 100-fold more than in brain, yet steady state bone aluminium concentration is < 100-fold greater than that in the brain. This suggests aluminium clearance from bone is more rapid than from brain, which is reasonable considering bone turnover and lack of neuron turnover. The elimination t ½ of aluminium from human brain is predicted to be very long.

Zapatero et al. () found that serum aluminium concentration positively correlated with age in 356 healthy adults. This could not be attributed to the age-related decrease of renal function. It is unknown if it relates to the long t ½ of aluminium in one or more compartments in the human so that steady state is not reached in a lifetime, to age-related increased absorption, or to other factors. In a previous study, Naylor et al. () failed to find a correlation between age and serum, whole blood, urine or hair aluminium concentrations, in 76, 42, 42, and 42 subjects, respecively.

As discussed in Toxicokinetics, Distribution (Including Compartmentalization), Human Studies, Tissue Aluminium Concentrations, Brain, brain aluminium levels have been reported to increase with age. Slow, or no, brain aluminium elimination and continued aluminium exposure would produce an increasing aluminium burden with age, as has been seen in the human. Assuming the t ½ of brain aluminium in the human to be 20 to 50 years, the amount of aluminium that would accumulate in the brain after 60 years of daily consumption of 300 μg aluminium, assuming that 5 × 10 -3 % of each dose enters each gram of brain and resides therein with a t ½ of &#; 20 years, would equal or exceed the amount seen in the normal 60 year old human. One might then conclude that normal concentrations of aluminium in drinking water would significantly contribute to elevated brain aluminium concentrations, and therefore could pose a potential health hazard.

Priest et al. () provided a formula to predict the aluminium body content (B τ ) as a function of time with repeated daily aluminium exposure, B τ = 0.52(τ 0.68 -1), where τ = time in days after the start of the exposure, and B τ is expressed as a multiple of the daily systemic aluminium intake. Modification, using more recent data, suggests the aluminium body burden after long term (years) of fairly constant aluminium intake would be ~ 400 times the daily aluminium intake ( Priest, ).

The t ½ of the first phase of urinary aluminium elimination in 3 previously non-exposed volunteers exposed to aluminium welding fumes for 1 day was 8 hr ( Sjögren et al., ). In 5 aluminium welders exposed < 1 year to aluminium fumes, the t ½ was estimated to be 8 to 9 days, whereas in workers exposed > 10 years it was &#; 6 months ( Sjögren et al., ). The t ½ of aluminium elimination in two welders after 20 and 21 years exposure was ~ 3 years, based on daily urinary aluminium excretion compared to the estimated body burden of aluminium which, in turn, was based on bone aluminium concentration ( Elinder et al., ). This group calculated a t ½ of 9.8 years for aluminium elimination based on urine aluminium concentrations of 1 welder ( Sjögren et al., b ). Aluminium t ½ were estimated from urinary aluminium after termination of occupational aluminium exposure of 9 to 50 years duration. Elimination t ½ of 0.7 to 7.9 years were estimated, based on a few samples per subject ( Ljunggren et al., ). These t ½ s might be underestimates.

Following the consumption of aluminium-contaminated drinking water in Camelford, Cornwall, England, stainable bone aluminium was seen in 2 people six and seven months later whereas no stainable aluminium was seen 19 months later ( Eastwood et al., ). Aluminium was not elevated, as determined by EAAS, at either time ( McMillan et al., ).

Multiple phases of elimination were seen in a study in which one human received i.v. 26 Al citrate suggesting multiple compartments of aluminium distribution. About 85 to 90% of the aluminium was eliminated in < 24 hr. Four percent of the injected 26 Al remained after 3.2 years ( Priest et al., ) and ~ 2% after 9.2 years ( Priest, ). Calculations based on results up to 14 years after the injection suggested at least three components of the aluminium elimination with t½s of 1.4, 40 and days, and a retention t ½ of ~ 50 years ( Priest, ). This unusual kinetic behaviour might result from retention of an aluminium species other than that administered, creating a depot, probably in bone, from which the aluminium is slowly eliminated. Slow aluminium elimination coupled with continued exposure predicts an increasing body burden with age.

The t ½ of aluminium elimination positively correlated with the duration of exposure ( Ljunggren et al., ). Tissue aluminium concentrations were elevated in non-dialyzed uraemic patients ( Alfrey et al., ), suggesting uraemia facilitated tissue aluminium retention. Based on an estimated human body burden of 60 mg aluminium, a daily dietary intake of 20 mg and absorption of 1%, Jones et al. () calculated a mean retention time of aluminium in the human of 300 days and a t ½ of 210 days. This calculation assumed steady state conditions and was based on a single compartment or one compartment that is responsible for a majority of the aluminium body burden. Elimination t ½ s of hours, weeks and years were seen after termination of short-term inhalation exposure, < 1 year exposure and upon retirement, respectively ( Ljunggren et al., ). The aluminium elimination t ½ positively correlated with exposure time ( Ljunggren et al., ). These results are consistent with more than one compartment of aluminium storage. This kinetic behaviour might result from retention of aluminium in a depot from which it is slowly eliminated. This depot is probably bone which stores ~ 58% of the human aluminium body burden. Slow aluminium elimination coupled with continued exposure would be predicted to produce an increasing body burden with age, as noted above.

The concentration of aluminium in bile was greater than in urine before oral aluminium consumption (mean ~ 63 and 24 μg Al/L). Both increased comparably (~ 4 to 6-fold) suggesting to the authors that bile is an important route of aluminium elimination ( Williams & Fraústo da Silva, ). It can be noted that the daily output of bile and urine are comparable, ~ 1 to 2 litres, supporting the notion that bile might be a significant route of aluminium elimination ( Nieboer et al., ). Based on faecal 26 Al after an i.v. 26 Al citrate injection, biliary aluminium excretion was reported to account for 2.1% of the eliminated aluminium in one human ( Priest et al., ). During the first 5 days after i.v. 26 Al citrate injection in seven humans ~ 1.5% of the injected dose appeared in the faeces and ~ 70% in urine ( Priest, ). Approximately 9 years after injection, only 1% of the 26 Al being excreted in urine and faeces was in faeces ( Priest, ). The aluminium concentration in bile of dialysis patients was ~ 30-fold higher than in controls ( Di Paolo et al., ). The discrepancy between the reports of Williams et al. and Priest et al. could be due to enterohepatic recirculation. However, reports from animal studies have not shown a large percentage of aluminium in the bile. If bile was an effective route of aluminium elimination, it would be expected to reduce aluminium in severely renal impaired and anephric patients, which does not appear to be the case.

Renal aluminium and silicon excretion following renal transplantation in 15 patients generally correlated, suggesting clearance by the kidney by a similar mechanism or as a complex, such as a hydroxyaluminosilicate species ( Bellia et al., ). Renal excretion of aluminium, following consumption of 600 μmole silicic acid and 2.67 μmole of aluminium in beer, peaked at the same time as silicon ( Bellia et al., ). Administration of 600 μmole silicon in water following 26 Al administration accelerated the decline in serum 26 Al ( Bellia et al., ); an effect similar to that produced by citrate ( Birchall et al., ). It was suggested that this resulted from complexation with silicate in urine to form hydroxyaluminosilicate species, which restricted aluminium reabsorption ( Birchall et al., ). Two subjects were given oral 26 Al together with 30 or 540 μM silicon (as a high-silicate mineral water). One was also given 4 and the other 50 mM citrate. They seemed to show more rapid renal aluminium clearance in the first day after they received the higher silicon dose ( King et al., ). The appearance of 26 Al increased in the urine of the subject that received the higher silicon dose and the lower citrate dose whereas less 26 Al was eliminated in urine in the subject who received the higher silicon dose and the higher citrate dose. It is unknown if these effects would be seen in more than the one subject tested and if they are due to an effect of silicon on aluminium absorption and/or elimination. In a cross-over study, 3 humans consumed 26 Al citrate, 26 Al citrate with monomeric silica (orthosilicic acid), which is ~ 50% absorbed and excreted in the urine, or 26 Al citrate with oligomeric silica, a polymer of silicic acid that has a much higher binding constant with aluminium, that is not detectably absorbed or excreted. Serum 26 Al was lower following oligomeric silica and 26 Al ingestion compared to the other two conditions ( Jugdaohsingh et al., ). These results may explain the differences in the studies of silicon-containing compounds on aluminium absorption and elimination.

Two, five and 11 months after discontinuation of consumption of 6 g aluminium taken as an antacid over 8 years by a 39-year-old female, urinary aluminium levels were 270, 93 and 49 μg/L, respectively ( Woodson, ). Serum aluminium 11 months after discontinuation of aluminium consumption was 68 μg/L, which is also considerably above normal. Two aluminium welders with 20 and 21 years of exposure had urinary aluminium levels of 107 and 351 μg Al/L ( Elinder et al., ). Urinary aluminium was also elevated for years after termination of this occupational aluminium exposure.

There are a number of studies in which urinary, but not serum, aluminium was measured. The median urinary aluminium concentration in workers exposed to aluminium fumes and dusts in Finland from to was ~ 0.8 μM (~ 22 μg/L), compared to the upper reference limit for controls of 0.6 μM (16 μg/L) ( Kallio et al., ). Sixty-seven workers with 2 to 34 years work history exposed to a mean of 0.35 to 0.4 mg aluminium oxide/m 3 had a mean urinary aluminium concentration of 42.9 μg/L compared to 20.3 μg/L in 57 controls ( Sinczuk-Walczak et al., ). Twenty male electrolyzers in the electrolysis department of an aluminium foundry who were exposed to aluminium oxide had a mean urinary aluminium concentration of 56.8 μg/L whereas 55 others in the same department who were crane operators, metallic chargers, locksmiths, and wireman had mean values of 25 to 35 μg/L ( Trzcinka-Ochocka et al., ). Urinary aluminium concentrations in the control group of 57 wood-shop workers in the same foundry averaged 20 μg/L. A positive relationship was found between urinary aluminium concentrations after a work shift, air aluminium concentrations and duration of exposure ( Elinder et al., ; Sjögren et al., ).

Following oral consumption of 27 Al-containing antacids, urinary aluminium levels increased to a greater extent than did those of serum aluminium, suggesting urine is a better indicator of current or very recent aluminium exposure. For example, after consumption of 2.2 g aluminium in antacids, serum aluminium concentration increased 1.3 to 2.8-fold and urine aluminium concentration increased 3 to 34-fold ( Kaehny et al., ). The increases in both serum and urinary aluminium were less with an aluminium phosphate product than with aluminium hydroxide-, aluminium carbonate- and dihydroxyaluminium aminoacetate-containing products. Similarly, after aluminium-containing antacid consumption, serum aluminium concentration increased ~ 2.4-fold and urine aluminium concentration increased ~4.5-fold ( Gorsky et al., ). Urine concentration increased to a greater extent and remained elevated for a longer time than did serum aluminium concentration after oral administration of aluminium ( Williams et al., ). Increasing aluminium antacid dose increased urinary, but not serum, aluminium levels ( Nagy & Jobst, ).

The kidneys excrete > 95% of eliminated aluminium, presumably as the citrate. The urinary excretion time of aluminium, as the citrate, into the urine was calculated using the biokinetic model described in Toxicokinetics, Pharmacokinetic Modelling to be 0.4 hr in healthy, and 1.7 hr in patients with chronic renal failure, respectively ( Steinhausen et al., ).

Seminal fluid aluminium concentrations have been reported to average 3.3 mg/kg in 50 subjects ( Yamamoto et al., ), 0.54 mg/kg in 27 refinery and polyolefin factory employees and 0.87 mg/kg in 45 sperm donor candidates ( Hovatta et al., ). Although there was no significant difference between the controls and industrially-exposed subjects for seminal plasma aluminium concentration, spermatozoa aluminium was significantly higher in the controls than the industrially-exposed subjects (2.52 vs. 0.93 mg/kg) ( Hovatta et al., ). The seminal AUC in 64 apparently healthy 21 to 35 year old men was significantly higher in those with low sperm viability, averaging 1.01, 0.59 and 0.18 mg/L in the 18, 26 and 20 subjects with low, medium and high sperm viability, respectively ( Dawson et al., ). Seminal plasma aluminium concentrations averaged 0.46, 2.0, 1.53 and 0.27 mg/L in 50 adults working in a medical centre, metal ore smelter, petroleum refinery and chemical plant, respectively ( Dawson et al., ). The authors did not report aluminium in other biological fluids or tissues or the work environment to show if seminal plasma reflects body burden or occupational exposure.

The primary route of aluminium elimination is via the kidneys, and secondarily via bile. Sweat collected during exercise from 15 normal healthy subjects had a mean aluminium concentration of 15 μg/L, which was similar to their laboratory adult reference values for UK residents of 11 μg/L ( Omokhodion & Howard, ). Saliva aluminium concentrations in 6 children aged ~ 10 from North Italy averaged 54 μg/L, with a median of 43 μg/L ( Sighinolfi et al., ). Speciation calculations suggested 94% of aluminium in saliva would be associated with phosphate ( Duffield et al., ). There are no reports addressing whether aluminium in sweat or saliva reflects aluminium exposure or body burden.

No decrease of bone aluminium concentration was seen over 6 weeks following aluminium loading in rats that had undergone 5/6 nephrectomy prior to aluminium exposure ( Elorriaga et al., ). Nor was there an observable decrease of aluminium in bone, liver or brain in rats up to 30 days after oral 26 Al administration ( Jouhanneau et al., b ). Calculations conducted for the current review using RSTRIP, of the t ½ of aluminium elimination in the bone of offspring of rats that were given 26 Al injections daily from day 1 to 20 postpartum from the results of Yumoto et al. () suggest t ½ of ~ 7 and 520 days in parietal bone. After 730 days, the amount of 26 Al remaining in the liver and kidneys was ~ 2% of that seen at weaning. For liver and kidney, the t ½ were ~ 5 and 430 days and ~ 5 and 400 days, respectively. In blood the values were ~ 16 and 980 days.

Following a single i.p. injection of 26 Al and euthanasia up to 270 days later, liver 26 Al was found to decrease considerably from day 5 to 25, then to remain rather constant before beginning to increase from day 75 to 270 ( Yumoto et al., ). Blood 26 Al decreased dramatically from ~ day 35 to 75 then remained fairly constant to day 270.

After weanling rats were given a single oral dose of 0.8 mmole aluminium, as lactate, with 0.75 mmole citrate, the aluminium t ½ was found to be 16 to 24 days in bone, liver, muscle, and spleen and 8 days in kidney ( Greger et al., ). The t ½ of aluminium elimination from tibia and kidneys positively correlated with the age of rats that received a single gavage of 0.8 mmole aluminium given with 0.75 mmole citrate and were sacrificed 1 to 44 days later ( Greger & Radzanowski, ). The half lives of aluminium in rats that were 2, 8 and 19 months at dosing were 38, 58 and 173 days in tibia and 9, 12, and 16 days in kidneys. The estimate of the tibial aluminium t ½ cannot be considered very definitive because results up to ~ 3 t ½ are required for good t ½ determination. These results suggest bone aluminium levels should increase with age due to continuous exposure. The t ½ of aluminium was significantly greater in liver, muscle and serum of anaemic rats ( Greger et al., ).

Aluminium persists for a very long time in rat brain following systemic injection of very small doses of 26 Al. Rat brain 26 Al increased slightly from days 5 to 35 after an i.p. 26 Al injection ( Kobayashi et al., ), suggesting a lack of brain aluminium elimination. However, the possibility of 26 Al precipitation and delayed absorption from the peritoneal cavity, the small number of subjects (single rats 10, 15, 25 and 35 days and 2 rats 5 days after dosing) and the lack of a non- 26 Al dosed group to control for cross-contamination, are of concern. A subsequent study found no decrease in brain 26 Al concentration up to 270 days after 26 Al injection ( Yumoto et al., ). When 26 Al was given i.v. to rats that were euthanatized 0.17 to 256 days later, the t ½ of brain aluminium was estimated to be ~ 150 days ( Yokel et al., a ). As brain samples were not obtained for at least 3 t ½ , this estimated terminal t ½ of aluminium in the brain is not expected to have a high degree of accuracy. Offspring of rats that were given 26 Al injections daily from day 1 to 20 postpartum were weaned on day 20 and sacrificed on days 40, 80, 160, 320 or 730 postpartum. Aluminium concentrations decreased over the 730 days in all tissues ( Yumoto et al., ). At postpartum day 730, brain 26 Al had decreased to ~ 20% of that seen at weaning (day 20 postpartum). The authors did not determine the t ½ of aluminium elimination. Calculations conducted for the current review using RSTRIP ( Fox & Lamson, ) suggest the elimination t ½ s were ~ 13 and days in brain. There is little published information on allometric scaling of metal elimination rates that could be used to extrapolate these results from the rat to the human. 150 days is ~ 20% of, and days exceeds, the rat&#;s normal life span. For comparison, the whole-body t ½ of aluminium in the human was estimated to be 50 years ( Priest, ) (see Toxicokinetics, Elimination and Excretion, Human Studies, Elimination Rate).

The t ½ of aluminium elimination significantly increased following an i.v. injection of 1 mg Al/kg compared to injection of 0.1 mg/kg ( Xu et al., ). This can be explained by the much lower percentage (5%) of the 10,000 μg Al/L in the plasma that was ultrafilterable after the 1 mg Al/kg injection compared to a greater percentage of ultrafilterable aluminium (22%) of the μg Al/L in the plasma achieved after the injection of 0.1 mg Al/kg ( Xu et al., ).

To determine the t ½ of aluminium elimination from organs, adult rabbits were given a single i.v. infusion of 200 μmoles Al/kg (as the lactate) over 6 hr and then terminated up to 128 days later. The t ½ of aluminium was estimated to be 113, 74, 44, 42, 4.2 and 2.3 days in spleen, liver, lung, serum, kidney cortex, and kidney medulla, respectively. Another t ½ in the kidney greatly exceeded 100 days ( Yokel & McNamara, ). The whole organism elimination t ½ was estimated to be 8 to 24 days in serum, kidney, muscle, liver, tibia and spleen of rats ( Greger et al., ). The brain aluminium t ½ was not determined in either of these studies; this has been done using 26 Al (see below). The aluminium concentration in rat tibia, kidney and brain, above that in controls, produced by 30 days of aluminium oral administration, decreased by 88, 85 and 66% respectively ( Rahnema & Jennings, ), suggesting corresponding elimination t ½ of ~ 10, 11 and 18 days. Liver aluminium concentration increased during the 30 days after completion of aluminium administration.

The aluminium concentration was determined in the reactive zone of muscle, which contained macrophage aggregation and lymphoid infiltration, 3 and 6 months after a single i.m. vaccine injection to Cynomolgus monkeys (Macaca fasciculata). The vaccines contained aluminium oxyhydroxide-adjuvated or aluminium phosphate-adjuvated diphtheria and tetanus. At 3 months, the aluminium concentration was 14,280 and mg Al/kg and at 6 months 11,000 and < 150 mg Al/kg, following the aluminium oxyhydroxide-adjuvated or aluminium phosphate-adjuvated vaccine injections, suggesting more rapid dissolution of aluminium from aluminium phosphate than from aluminium oxyhydroxide adjuvant ( Verdier et al., ). These results are consistent with the more rapid absorption of aluminium from aluminium phosphate than from aluminium hydroxide reported in rabbits (see Toxicokinetics, Absorption, Animal Studies, Intramuscular).

Following inhalation of particles of Montmorillonite (a complex aluminium magnesium silicate clay) by dogs, rats and mice, initial clearance was primarily by the GI tract. Long-term clearance of particles in dogs was predominantly to lung-associated lymph nodes in rats and, in mice, by mechanical clearance by the GI tract ( Snipes et al., ). The t ½ for the clearance of particles that went to the lung-associated lymph nodes of dogs was days and, from the GI tract, was days. For mice and rats, the long-term t ½ s were 490 and 690 days, respectively.

Clearance of aluminium from the lung of rats that inhaled fly ash was very slow. The lung concentration decreased from a mean of 53 mg Al/kg immediately after a one-month aluminium exposure, to 27 mg Al/kg six months later, and to 25 mg Al/kg ten months later ( Matsuno et al., ). The slow clearance was attributed to the solubility of the aluminium in the fly ash. Similarly, after 20 weekly intratracheal installations of 1 mg Al/kg as 1.2 μm MMAD aluminium oxide, only 9% was cleared from the lungs in the subsequent 19 weeks ( Schlesinger et al., ). A more rapid clearance of 1 to 5 μm diameter coal fly ash particles from mouse lungs after intratracheal administration was described. The aluminium concentration decreased from 980 mg/kg at 1 wk to 519 mg/kg 15 weeks later ( Ogugbuaja et al., ).

Biliary aluminium excretion has been reported to account for 0.2% of total aluminium elimination in the dog ( Kovalchik et al., ), 1.5% in the rabbit ( Yokel et al., b ), < 0.5 and 1.3% in the rat in the first 12 hr ( Xu et al., ) and 0.7% in the rat (Yokel et al., unpublished results). These values are in agreement with some of the results from the human (see Toxicokinetics, Elimination and Excretion, Human Studies, Biliary Excretion). Bile aluminium concentration did not increase with increasing oral aluminium doses of 0, 0.2, 0.4 and 0.8 mmole as the lactate given to rats with an average weight of 191 g, suggesting that the higher doses exceeded the ability to excrete aluminium in the bile ( Sutherland et al., ). Enterohepatic recirculation of aluminium has not been investigated. Considering the very low percentage of aluminium absorbed from the GI tract, it is anticipated that enterohepatic recirculation would not be great. A significant increase of biliary excretion of aluminium and Tf was seen in rats that received 5 mg Al/kg i.v. for 14 days ( Klein et al., ). These results suggest aluminium bound to Tf may be taken up by hepatocytes and, if excreted as a complex, might be well absorbed because Tf may facilitate aluminium absorption ( Jäger et al., ).

Several animal studies suggested that aluminium clearance decreases and t ½ increases with increased aluminium concentration. For example, renal aluminium clearance in the rat after an i.v. injection of aluminium (8.1 mg/kg) that produced serum aluminium concentrations of 110,000 to 400,000 μg Al/L, was reported to be 4.3 mL/kg/hr ( Gupta et al., ). Similarly, renal aluminium clearance was reported to decrease from 78 to 3.6 mL/hr as aluminium plasma concentration increased from 40 to 12,400 μg/L (up to 460 μM Al) ( Hohr et al., ). This may be due to the formation of non-filterable aluminium complexes or aggregates at the higher aluminium concentrations, reducing the plasma filterable aluminium fraction ( Lote et al., ; Xu et al., ; Yokel & McNamara, ). The very high aluminium concentrations achieved by Gupta et al. () of to 16,300 μM far exceed the Tf and citrate aluminium binding capacities of ~ 45 and 100 μM aluminium. It is likely that the aluminium was no longer in solution due to binding by phosphate, which is μM in serum, or that the aluminium was present as aluminium hydroxides.

The primary organ for aluminium elimination is the kidney, which is believed to eliminate > 95% of excreted aluminium. Dietary intakes of 3.5 to 11.5 mg Al/day result in a daily excretion of 4 to 12 μg ( Nieboer et al., ). Many of the reported rates of aluminium clearance are consistent with the glomerular filtration rate (GFR) when the free fraction is considered. Kovalchik et al. () found renal aluminium clearance to be 50% of inulin clearance (GFR) in the dog, over a range of plasma aluminium concentrations of 80 to 600 μg /L. As this range is below the saturation of Tf by aluminium, the aluminium should be &#; 90% bound to Tf. An aluminium clearance of 116 mL/hr was reported in 18 to 24 kg dogs, or ~ 5.5 mL/kg/hr, after an i.v. aluminium injection that produced blood aluminium concentrations decreasing from ~ 19,000 to ~ 14,000 μg /L ( Henry et al., ). These are well above the saturation of Tf. The authors found that the renal contribution to plasma aluminium clearance correlated well with GFR in the dog. Systemic clearance in the rabbit was found to be 53 and 72 mL/kg/hr, consistent with GFR, based on the GFR and the free fraction of aluminium in plasma ( Yokel & McNamara, ; ). A renal aluminium clearance of 36 to 60 mL/hr was seen in ~ 0.2 kg rats after an aluminium chloride infusion that produced a serum aluminium concentration of to 10,000 μg/L ( Burnatowska-Hledin et al., ). Renal aluminium clearances of 49.6, 44.4 and 41.8, and of 18.4, 18.4 and 17.2 mL/kg/hr were reported after 0.1 or 1 mg Al/kg injections in the rat, respectively, that resulted in serum aluminium concentrations of several thousand decreasing to several hundred μg /L and ~ 20,000 to 30,000 decreasing to ~ μg /L ( Pai & Melethil, ; Xu et al., ; a ). The lower clearance with the greater aluminium concentration may be due to formation of non-ultrafilterable aluminium species.

The concentration of aluminium in the hair of 10 AD patients averaged 7.5 mg/kg compared to 6.2 in 10 age-matched controls ( Shore & Wyatt, ). In another study, hair aluminium concentration in 35 cases of AD was significantly lower than in 71 comparably-aged controls ( Kobayashi et al., ). There was no significant effect of age on hair aluminium levels in either group ( Kobayashi et al., ).

The aluminium concentration in hair of 6 control subjects was reported to be 97 ± 25 mg/kg, 118 ± 46 mg/kg in 11 haemodialysis patients and 370 ± 266 in 8 non-dialyzed chronic renal failure patients ( Tsukamoto et al., ). Hair aluminium concentration positively correlated with AUC and duration of dialysis. Similarly, hair aluminium concentrations were higher in non-dialyzed and dialyzed chronic renal failure patients than in controls, whereas haemofiltered chronic renal failure patients did not have higher concentrations of hair aluminium ( Marumo et al., ). The elevated aluminium concentrations were attributed to the use of aluminium-contaminated dialysate. Hair aluminium was 10.5 mg/kg in 22 male and 10.1 in 29 female long-term haemodialysis patients who had elevated plasma and bone aluminium concentrations ( Winterberg et al., b ). There was a significant correlation between hair and bone aluminium in the males, but not the females. Hair aluminium in 18 chronic haemodialysis patients who received an average of 6.3 kg of an aluminium-containing phosphate binder that released aluminium averaged 15.4 mg/kg compared to a hair concentration of 10.5 mg Al/kg in a group of 18 chronic haemodialysis patients who received an average of 6.6 kg of an aluminium-containing phosphate binder that released less aluminium ( Winterberg et al., b ). The latter group of patients had lower aluminium in their plasma (34.6 vs.101.4 μg/L) and bone (11.6 vs. 26.2 mg/kg). Higher hair aluminium concentration was seen in 39 haemodialyzed patients (6.1 ± 2.8 mg/kg), than in 49 control subjects (3.4 ± 1.6) mg/kg ( Chappuis et al., ). Hair aluminium did not correlate with serum or bone aluminium, leading the authors to conclude that hair aluminium levels do not predict aluminium-induced osteomalacia ( Chappuis et al., ). The aluminium hair concentration of 12 home haemodialysis patients tested before introduction of water treatment by reverse osmosis was above that in controls, whereas it was not elevated in 16 patients undergoing continuous ambulatory peritoneal dialysis ( Wilhelm et al., b ). Because hair aluminium concentration did not relate to daily or cumulative aluminium intake or to bone or plasma aluminium concentrations, the authors concluded that hair aluminium is of very limited value for diagnosis of aluminium exposure.

Aluminium was shown to be taken up into human hair from aqueous solution ( Wilhelm et al., a ). Normal hair aluminium concentration was reported to be < 0.24 to 67 mg/kg in 194 people ( Imahori et al., ); 6.5 mg/kg in English samples ( Alder et al., ); 3.7 for US, 8.8 mg/kg for rural Japan, 11.9 mg/kg for Hong Kong and 13.6 mg/kg for samples from Tokyo ( IAEA, ) and 15 to 18 mg/kg in samples obtained in Kentucky, US, depending on the method used to wash the samples to remove surface contamination ( Yokel, ). A reference value for aluminium in hair of 0.1 to 36 mg/kg was derived from a literature review of studies published in the prior 30 years ( Caroli et al., ).There are a few cases reporting elevated hair aluminium in children with emotional problems ( Rees, ), but the results could be due to contamination. Unexpectedly high aluminium concentrations were observed in the hair of patients with neurological and other disorders, which was thought to be due to dolomite in many of the cases ( Roberts, ).

Hair has been used to estimate the body burden and to indicate excessive exposure to metals since the s ( Villain et al., ). For example, hair has been shown to reflect methylmercury exposure ( Johnsson et al., ) and to have a 1:270 ratio with blood mercury ( IPCS, ). The validity of hair to predict the aluminium body burden has not been well established. There can be additional problems with the analysis of hair for metals; procedures for collection have not been standardized. Although hair has been shown in some studies to correlate with other indicators of body burden, it is seldom the preferred tissue for this purpose; commercial panels that test hair for multiple metals have questionable validity ( Kales & Goldman, ; Villain et al., ).

Clinical evidence suggested that PTH had a protective effect against aluminium-induced bone disease, and encephalopathy ( Cannata et al., ). Bone aluminium did not correlate with PTH levels in uraemic patients ( Alfrey et al., ). Subtotal PTX of 10 dialysis patients who had refractory secondary hyperparathyroidism resulted in a significant increase of bone aluminium in 6 of the 7 consuming aluminium ( De Vernejoul et al., ). These results are not consistent with observations in animals (see Toxicokinetics, Distribution (Including Compartmentalization), Animal Studies).

As bone is a major site of aluminium storage, prolonged urinary aluminium excretion may reflect a prolonged t ½ of aluminium in bone. A t ½ of 7 years was estimated in one human who had received an i.v. injection of 26 Al citrate 3.2 years earlier ( Priest et al., ). An updated estimate in this individual, based on whole-body monitoring collected up to days after the injection, suggests the t ½ is ~ 50 years ( Priest, ). This prolonged whole-body t ½ may largely reflect the t ½ of aluminium in bone.

Six patients who received aluminium-contaminated TPN solutions for 6 to 72 months had bone aluminium concentrations of 14 to 265 mg/kg, well above the normal range, as well as elevated plasma aluminium (98 to 214 μg/l) and urinary aluminium outputs ( Klein et al., ). Bone aluminium concentration averaged 2 mg/kg dry weight in infants who received limited i.v. therapy compared to 20 in infants who received &#; three weeks of i.v. therapy ( Sedman et al., ).

Aluminium levels in 4 cases of Parkinson&#;s disease were compared to those in the 5 patients without neurological abnormalities in the above cited studies and were found to be significantly higher in the hippocampal gyrus, caudate nucleus, globus pallidus and substantia nigra as well as in the liver, kidney and spleen ( Yasui et al., ). Magnesium, but not calcium, levels were significantly decreased in these same brain regions, and others as well. However, aluminium was not significantly different in the frontal cortex, caudate nucleus, substantia nigra, and cerebellum of 9 Parkinson&#;s disease patients or 15 patients with other chronic neurological diseases compared to 12 controls ( Uitti et al., ).

Using neutron activation analysis, aluminium levels were reported to be higher in 3 Guamian cases than in 4 non-demented controls. The Guamian cases also had high calcium levels in grey and white matter and low zinc levels in grey matter ( Yoshida et al., ). Using PIXE, extremely high aluminium concentrations were reported in lumbar spinal cord and hippocampus of patients with ALS from Guam and the Kii peninsula of Japan, compared with those in cases with sporadic ALS and in controls ( Yoshida et al., ; Yoshida, ). Aluminium concentrations negatively correlated with calcium and magnesium contents in the birthplace area&#;s rivers ( Yoshida et al., ) and positively correlated with iron and copper, and negatively correlated with zinc, in the neural tissue ( Yoshida, ).

Using SEM with energy dispersive spectrometry, NFT-bearing neurons from ALS-PD and non-afflicted patients were found to have a high aluminium concentration ( Perl et al., ). Aluminium and calcium were co-localized in the NFT-bearing neurons. Using wavelength dispersive spectrometry coupled with electron beam X-ray microprobe analysis, aluminium and calcium were found to be co-localized in the NFTs of two Guamian PD patients but not in the non-NFT-containing regions of either the PD patients or two control lifelong Guamian residents ( Garruto et al., ). Semi-quantitative estimates of the highest concentrations were and 500 mg/kg calcium and aluminium, dry weight, respectively. Garruto & Yase () compared silicon distribution in 5 Guamian Chamorros who had PD and in 2 who had ALS with 2 Guamian and 2 Caucasian normal controls and found a similar distribution, estimated to be up to mg/kg, with no detectable silicon in the controls. The average brain aluminium concentration was higher in 6 Guam PD cases than 7 Chamorro controls (179 vs. 57 mg/kg dry weight) ( Yoshimasu et al., ). Aluminium and calcium were seen in the cytoplasm of hippocampal neurons bearing NFTs, using laser microprobe mass spectroscopy ( Perl & Pendlebury, ). Aluminium and calcium were found to be associated with NFT-bearing hippocampal neurons of PD patients, using secondary ion mass spectrometry ( Linton et al., ). Using histochemical staining, aluminium was visualized in the hippocampus, spinal cord and frontal cortex in most of 3 Guamian patients with ALS and 5 with PD who had NFTs but not in the 5 neurologically and neuropathologically normal Guamian or Caucasian patients ( Piccardo et al., ). Staining was observed in the cytoplasm, nucleoli, neuropil, white matter and some endothelial cells and walls of cerebral vessels. X-ray microanalysis confirmed the presence of aluminium.

Aluminium was significantly increased in 26 CNS regions in 2 of 6 patients with ALS compared to those in 5 patients without neurological abnormalities. Mean concentrations were 88 and 136 in the two cases vs. 26 and 23 mg Al/kg dry weight in the other 4 cases and controls, respectively ( Yasui et al., b ; c ).

The indigenous people of several western Pacific foci, the Chamorro on Guam, Japanese on the Kii peninsula of Honshu Island, Japan and the Auyu and Jakai of southern West New Guinea, developed two syndromes having features of ALS and a parkinsonism-dementia (PD). From the time this variant of ALS was first identified in until , its incidence was 50 to 150 times higher than elsewhere in the world ( Kihira et al., ). It was suggested that a high aluminium and low calcium and magnesium concentration in the environment contributed to these syndromes ( Yase, ). Although the manganese concentrations in the soil, river and drinking water were greater in ALS than control areas, the manganese content of plants, crops, livestock and fish was not ( Iwata et al., ). A specific localization of manganese, aluminium and calcium was observed in the spinal cord of ALS patients ( Iwata et al., ). Food was not found to be high in aluminium and low in calcium, but the soil was high in aluminium ( McLachlan et al., ). The aluminium, and calcium, concentration in the brain of victims of ALS has been reported to be greater than in controls, whereas magnesium was not elevated, using neutron activation analysis ( Yoshimasu et al., ; ). Brain aluminium concentrations averaged 33.1 mg/kg in 6 ALS cases and 36.8 mg/kg in 4 PD cases compared to 17.7 mg/kg in controls, determined by neutron activation analysis. Aluminium in the ALS and PD groups was statistically greater than in the controls ( Yase, ). Calcium was also elevated in the ALS and PD subjects. X-ray microanalysis showed similar calcium, aluminium and manganese distribution in spinal cord of ALS patients ( Yase, ). Using EAAS, Traub et al. () found elevated brain aluminium levels in two Guamian ALS cases to be 1.7 and 8.9 and in two Guamian PD cases to be 2.0 and 3.9 mg/kg, compared to an average of 1.38 mg/kg in 4 normal subjects. Aluminium, silicon, calcium, vanadium, iron and zinc were reported to be elevated in the frontal cortex of humans with ALS compared to normal subjects and patients with parkinsonism ( Mizumoto et al., ).

The CNS shows lower aluminium concentrations than many other tissues, even in the presence of overt neurotoxicity. Increased brain aluminium concentrations of ~ 4- to 6-fold in rabbits and somewhat higher increases in victims of dialysis encephalopathy syndrome were associated with neurotoxicity ( Alfrey, ; Crapper et al., ; Yokel, ). Results of the many studies of aluminium concentration in bulk brain samples and sub-cellular sites of AD victims inconsistently show elevated aluminium (see Tables 19 , 20 and 21 ). The magnitude of elevation of bulk brain aluminium, when reported, is generally a few-fold or less in AD victims than in controls. The inconsistent findings of a small increase in brain aluminium in AD in relation to the small increase in bulk brain aluminium sufficient to produce neurotoxicity has hindered the resolution of the role of aluminium in AD. If aluminium is elevated in AD brain, it is not reflected in CSF aluminium, which has generally not been found to be elevated ( Jagannatha Rao et al., ; Kapaki et al., ). CSF aluminium concentration was reported to be higher in patients with virus nephro infections, residual manifestations from brain and spinal cord trauma, and pain syndromes, than in controls. Blood serum aluminium concentrations were also reported to be elevated in those with residual effects of brain and spinal cord trauma (0.014 and 0.012% aluminium in the ash vs. 0.% in controls) ( Del&#;va, ).

A review of the literature on the reports of aluminium concentrations in various brain regions led the authors to conclude that aluminium is generally higher in grey than white matter ( Speziali & Orvini, ). Human brain aluminium concentration correlated positively with age in several studies. Brain aluminium concentrations in 3 subjects aged 25, 43 and 65 averaged 1.59 mg/kg (dry tissue) and 2.74 mg/kg in 6 subjects aged from 75 to 99 years ( McDermott et al., ). Brain aluminium levels in 7 subjects from premature to 6 months old were ~ 0.3 mg/kg (wet tissue), increasing as the age of subjects increased, to ~ 0.7 mg/kg in 4 subjects 80 to 99 years old ( Markesbery et al., ). Similarly, brain aluminium levels increased from ~ 0.2 mg Al/kg (wet tissue) in 21 to 30 year olds to ~ 0.55 mg/kg in > 81 year olds ( Roider & Drasch, ). Ten adults 32 to 46 years old were compared to fifteen adults 75 to 101 year old. The aluminium concentrations in the hippocampus and frontal lobe were 0.014 and 0.020 vs. 0.40 and 0.37 mg Al/kg, wet weight, respectively ( Shimizu et al., ). The increase in brain aluminium concentrations with age could be due to increased exposure with age, a decreased ability to remove aluminium from the brain with age, or very slow, or no, elimination of aluminium from the brain. Patients who had elevated aluminium intake and who received haemodialysis before successful renal transplantation up to 8 years prior to death had elevated post-mortem aluminium levels in the brain ( McDermott et al., ; Reusche et al., ), suggesting accumulation of aluminium during haemodialysis that was slowly, or not, cleared after establishment of renal function. Using morin, aluminium was visualized in the disintegrating NFT and senile plaque amyloid core of non-demented elderly subjects. In normal brain tissue, aluminium was seen in the wall of the capillary vessels of the BBB, perivascular glial supporting tissues, nuclei of astrocytes, and nuclei and nucleoli of neurons ( Shimizu et al., ). However a study of only 4 subjects who died between 58 to 74 years of age and who had a mean brain aluminium concentration of 0.54 mg/kg wet weight failed to find an association between age and brain aluminium concentration ( Jacobs et al., ). The aluminium concentration in 12 brain regions obtained from 8 neurologically normal subjects was reported to range from a mean of 58 mg Al/kg, wet weight, in the pons to 196 mg Al/kg in temporal cerebrum ( Rajan et al., ). These very much higher values do not appear to be correct, perhaps due to contamination or incorrect reporting of the units.

Gastric mucosal membrane aluminium concentration was elevated in aluminium-consuming patients with normal renal function and those with renal insufficiency who were predialysis and those receiving dialysis, compared to patients with normal renal function who were not consuming aluminium-containing antacids ( Zumkley et al., a ). The increases paralleled increases in plasma aluminium, and were attributed to consumption of aluminium antacids.

Aluminium, as the phosphate, was shown to be elevated ~ 10-fold in the synovial fluid, synovial membrane and articular cartilage of 28 chronic haemodialysis patients, some of whom took 5 to 15 g of aluminium hydroxide daily, compared to patients who had not taken aluminium ( Netter et al., ; ). Speciation calculations indicate that a major aluminium species in synovial fluid is the citrate ( Silwood & Grootveld, ).

Two male twins, 32 weeks at birth, received and mg total aluminium orally as antacids and 2.96 and 3.2 mg in total parenteral nutrition (TPN) solutions over 5 months. When they died at age 149 and 157 days, their bone, brain, liver, and lung, and in one of the two, kidney, aluminium concentrations were greater than the average values from infants that had not received i.v. fluids or TPN solution for more than 21 days ( Bozynski et al., ). Considering oral aluminium bioavailability of 0.1%, ~ ½ to &#;of the aluminium that reached systemic circulation was from the antacids. They received comparable amounts of aluminium from the TPN solution but the twin that received ~ 2-fold more from antacids had higher aluminium concentrations in all organs but the brain.

Victims of the dialysis encephalopathy syndrome showed elevated aluminium exposure in all tissues ( Alfrey et al., ). The respective mean aluminium concentrations, in mg/kg dry defatted tissue, in controls, non-dialyzed uraemic patients, dialyzed uraemic patients and dialyzed uraemic patients with encephalopathy were 4.1, 25.5, 161 and 301 in liver; 3.0, 35.3, 243 and 493 in spleen; 4.5, 27.4, 116 and 281 in bone; 1.1, 6.9, 22.5 and 42.7 in heart; 1.2, 2.6, 9.1 and 14.9 in muscle; 55, 75, 90 and 215 in lung; and 2.4, 4.1, 8.5 and 24 in brain grey matter. In a more recent episode of aluminium intoxication in dialysis patients, 10 of 17 patients exposed to dialysate prepared from tap water containing 650 μg Al/L died. The serum aluminium concentrations of those that died and those that did not averaged 808 and 255 μg Al/L, respectively. Tissue aluminium concentrations in 4 of the victims were above reference values: liver 4.7 to 51.7 (reference < 2), bone 7.5 to 88.7 (reference < 2) and cerebral cortex 1.09 to 1.78 (reference 0.14 to 0.22) mg Al/kg.

Aluminium is unequally distributed throughout the body in normal and aluminium-intoxicated humans ( Alfrey et al., ; Di Paolo et al., ). Tissue aluminium concentrations in normal adults at steady state (in mg/kg wet weight unless otherwise stated), were 20 in lung, 1 to 3 in bone (based on dry weight), 1 in liver and spleen, 0.5 in the kidney, 0.45 in the heart, 0.4 in muscle, 0.35 in brain and ~ 0.002 in blood ( Nieboer et al., ). Similar reference values, of 2.21 to 15.3 mg/kg in the lung, 1.0 to 2.45 mg/kg in the liver and 0.55 to 1.31 mg/kg in the kidneys were obtained from a review of literature published in the prior 30 years ( Caroli et al., ). With increased age and accumulation of aluminium, late life aluminium body burden has been estimated to be 25 to 50 mg in bone, 20 mg in lung, and 9 to 24 mg in soft tissue ( Keith et al., ). Based on typical organ weights for a 70 kg adult, ~ 58, 26, 11, 3, 0.95, 0.3, 0.25 and 0.2% of the body burden of aluminium would be in the bone, lung, muscle, liver, brain, heart, kidney and spleen, respectively. The higher concentration in lung of normal humans may reflect entrapment of airborne aluminium particles whereas the higher concentrations in bone, liver and spleen may reflect aluminium sequestration. Skin, taken from the back of 11 chronic haemodialysis patients, had greater aluminium concentration than from 9 controls (1.02 vs. 0.26 mg/kg) ( Subra et al., ). Skin and serum aluminium concentrations were greater in the patients who had received haemodialysis for a longer time (averages of 156 vs. 49 months) ( Subra et al., ). It has been suggested that up to 14% of the body burden of aluminium is in the skin, but the potential contribution of contamination to this value has been raised ( Priest, ). Because of its very low bioavailability by most routes of exposure and the effective urinary clearance of aluminium from blood, human tissue and fluid, aluminium concentrations are low compared to aluminium concentrations in most exposure sources.

The mean AUC in 44 haemodialysis patients who were receiving aluminium therapy was 32 μg/L compared to 10.8 μg/L in 32 not receiving aluminium ( Fenwick et al., ). Serum Al concentration was reported to be significantly higher in patients with spontaneous pneumothorax (184 μg/L) than controls (27 μg/L) ( Han et al., ). However, these values from the healthy individuals are an order of magnitude above what is accepted as the true value of serum aluminium, reducing confidence in this study.

Calculations show that insignificant amounts of aluminium fluoride species will form in the presence of normal plasma fluoride (~ 100 μg/L) and normal or elevated plasma aluminium. This suggests fluoride is unlikely to affect aluminium distribution or elimination, unless it is involved in mixed ligand complexes containing aluminium and other ligands (W.R. Harris, personal communication, ). Similarly, silicon concentrations in biological fluids are very low. It was suggested that monomeric aluminium silicate species are quite unlikely to play any significant role in the biological chemistry of aluminium after the aluminium is absorbed ( Harris et al., ). An inverse relationship was noted between serum aluminium and silicon in patients in one haemodialysis centre, raising the possibility that silicon influences aluminium distribution and/or elimination ( Parry et al., ).

Mean AUC was 92% of that seen in whole blood of 4 renal dialysis patients whose blood aluminium concentration was > 100 μg/L ( Sjögren et al., ). One hr after ingestion of 26 Al citrate by one volunteer, 99% of the aluminium was in plasma (80% with Tf and 4% in a low molecular weight fraction) and the remaining 1% was in erythrocytes. The distribution of aluminium in blood taken 880 days after 26 Al citrate injection was 86% in plasma and 14% associated with erythrocytes ( Day et al., ).

The concentration of aluminium in erythrocytes was found to be 110% of that seen in healthy human plasma ( Chernov et al., ). The aluminium concentration in plasma from haemodialysis patients showed little difference from that in blood cells ( Van der Voet & de Wolff, ). These results are similar to those from animals, above, showing similar aluminium concentrations in plasma and erythrocytes at equilibrium. In contrast, the whole blood, serum and calculated erythrocyte Al concentrations were 15 & 17, 3 & 4 and therefore 34 & 30 μl/L in two healthy subjects, resulting in serum to erythrocyte ratios of 0.08 and 0.15 ( Tamada, ). In a study in 15 long-term hemodialysis patients, of which 7 were taking Al hydroxide and 8 were not, the overall serum Al to erythrocyte ratio was 0.06. Mean serum Al was lower in those taking Al hydroxide, and averaged 32 μl/l for all patients ( Sharif et al., ). After ingestion of 26 Al by a healthy subject, plasma 26 Al concentration peaked at ~ 1.2 hr and decreased to 5% of the peak value by 24 hr, whereas erythrocyte 26 Al peaked at ~ 1.2 days, showing a 1.1 day lag. At 1.2 days, the plasma to erythrocyte concentration was 0.03 ( Fifield et al., ). However, this is not a peer-reviewed report.

Iron status negatively correlates with tissue aluminium accumulation. Ferritin isolated from the brains of 2 subjects with AD had more aluminium than that from 2 normal human subjects (18.9 vs. 3.4 mole Al/mole ferritin) ( Fleming & Joshi, ). After equilibrium dialysis of ferritin isolated from human brain and liver against 20 μM aluminium, ferritin from liver had more aluminium than from brain ( Fleming & Joshi, ). In contrast, aluminium levels were not found to be different in the brain cortex from normal, AD and chronic renal dialysis patients (6.2, 8.9 and 7.2 aluminium atoms/ferritin molecule) ( Dedman et al., b ).

NFT bearing neurons from AD brain showed several-fold more aluminium in the tangle than in the nucleus which, in turn, had 1.5 to 2-fold more aluminium than cytoplasm and neuropil. Aluminium distribution in the nucleus, cytoplasm and neuropil of tangle-free neurons was similar ( Good et al., ). Similarly, another group found more aluminium in the nuclei than cytoplasm of tangle- and non-tangle-bearing neurons of Alzheimer and non-Alzheimer brains ( Lovell et al., ).

In some studies increased levels of aluminium have been found in the brain of persons who had suffered from AD; in other studies no such increases were observed (see Table 19 ). More details of some of these studies are presented in Speziali & Orvini () . It has been noted that aluminium was reported to be higher in the cortex and hippocampus than in other brain structures in normal and AD brains ( Gupta et al., ). A review was conducted of reports of aluminium in the brain of Parkinson&#;s disease subjects compared to controls. It revealed some studies that found a significant increase in the former group. However, all of the studies were conducted by the same research team ( Speziali & Orvini, ).

The human whole body aluminium burden has been estimated to be 80 mg ( Tipton & Shafer, ), probably 35 to 40 mg ( Alfrey, ) and, more recently, 30 to 50 mg ( ATSDR, ). Slight age-related increases in blood, bone, brain, and other soft tissues have been reported. Aluminium concentrations increased from ~ 160 mg/kg (in ash) in the lung of 0 to 3 month olds, to ~ 625 in 1 to 12 year olds and to > in 19 to 89 year old adults, in liver from ~ 100 in 0 to 3 month olds, to ~ 150 in 1 to 12 year olds and to ~ 550 in adults, and in kidney from ~ 150 in 0 to 3 month olds, to ~ 300 in 1 to 12 year olds and to ~ 350 in adults ( Stitch, ). Similarly, median lung aluminium concentrations increased from ~ 150 mg/kg (wet tissue) in 0 to 12 year olds to ~ in &#; 60 year olds ( Tipton & Shafer, ), and from ~ 2 mg Al/kg (wet tissue) in 21 to 30 year olds to ~ 40 in > 81 year olds ( Roider & Drasch, ). Brain and bone aluminium increases with age, as discussed in Toxicokinetics, Distribution (Including Compartmentalization), Human Studies, Tissue Aluminium Concentrations, Brain / Bone. Kidney, liver and spleen showed a similar trend to lung and brain, an increase with age up to ~ 40 years old, a plateau or slight decrease to age 70, then an increase later in life. Ten 32 to 46 year olds had mean hippocampal and frontal cortex aluminium concentrations of 0.014 and 0.020 mg/kg (wet tissue) whereas those of fifteen 75 to 101 year olds were 0.402 mg/kg and 0.373 mg/kg, respectively ( Shimizu et al., ). Serum aluminium levels in 356 healthy 20 to 80 year olds increased with age with a significant linear regression of r 2 = 0.067 and a mean of 7.3 μg Al/L ( Zapatero et al., ). In contrast, tissue aluminium levels were not found to increase with age in 36 subjects from Denver, Colorado, U.S. or in 21 from Brisbane, Australia. However, the ages of the subjects were not reported ( Alfrey et al., ).

The concentration of 26 Al in the milk of rats that received daily s.c. injections of 26 Al from days 1 to 20 postpartum was greater than that in any of the tissues simultaneously collected from suckling rats ( Yumoto et al., ). There was about 0.2 to 0.4% of the injected 26 Al/g milk. The milk was obtained from the stomachs of the sacrificed suckling rats. As the authors did not report the amount of milk consumed or produced, one cannot determine the percentage of injected 26 Al that appeared in the milk.

Lactating rats were given daily s.c. injections of 26 Al from day 1 to day 20 postpartum. The concentration of 26 Al measured in kidney was higher than that in liver which, in turn, was higher than that in brain and blood of suckling offspring euthanized on days 9 and 15, demonstrating the transfer of aluminium to milk followed by its oral absorption and distribution in the suckling offspring ( Yumoto et al., ). Offspring of rats that were similarly treated were weaned on day 20 and sacrificed 40, 80, 160, 320 and 730 days postpartum. Blood, brain (cerebrum, cerebellum, and hippocampus), spinal cord, parietal bone, kidney and liver were obtained ( Yumoto et al., ). The amount of 26 Al/g tissue in the offspring as a % of the amount injected, on post-partum day 20, was ~ 0.02 in bone, 0.006 in liver, 0.004 in kidney, 3 × 10 -5 in brain cerebrum and 3 × 10 -6 in blood. The spinal cord had more 26 Al/g tissue than the 4 brain regions at postpartum day 20.

Aluminium distributes into milk. Milk aluminium concentration increased from 0.46 to 0.81 mg/L in cows receiving 114 mg Al/day as alum ( Archibald, ). Aluminium concentrations in the milk of rabbits receiving 0.4 or 0.8 mmole (10.8 or 21.6 mg) Al/kg s.c. injections 5 days weekly for 4 weeks increased ~ 2 and 5-fold ( Yokel, ; ). The increase of aluminium in milk peaked about 8 hr after i.v. and 12 to 24 hr after oral and s.c. administration in rabbits ( Yokel & McNamara, ). Prior to aluminium administration, the milk/serum aluminium ratio was 4.9. Approximately 2.4% of an i.v. dose of aluminium and 3.3% of the absorbed dose of aluminium following a s.c. injection were found in the milk ( Yokel & McNamara, ). Rats were given 10 mg aluminium, as the chloride, daily i.p. from postnatal days 1 to 12 ( Muller et al., ). Twenty-four hr after the last injection, the aluminium level in the milk of the aluminium-treated rats was 72-fold higher than that in rats not injected with aluminium, 2.02 compared to 0.03 mg/L wet weight. AUC in aluminium-treated rats was 0.3 mg/L wet weight. The results from both rabbit and rat showed a milk/blood ratio considerably > 1 suggesting that a process other than diffusion mediates the distribution of aluminium from blood to milk. These studies with 27 Al did not demonstrate an increase of aluminium in the tissue of suckling offspring.

Aluminium distributes into growing hair. Injection of aluminium lactate (s.c.) into the back of rabbits resulted in a considerable, dose-dependent, increase of the aluminium concentration above the pre-treatment average of ~ 1 mg Al/kg hair in the hair grown over and near the region of the injections ( Yokel, ). Due to the very large amount of aluminium injected (0.7 to 10.8 mg Al/kg 5 days/week for 4 weeks) and the route of administration, these results cannot be related to the human.

Aluminium distributes into the placenta and foetus. Injecting aluminium into rabbits during gestation resulted in higher aluminium concentrations in their placenta than in the tissues of 0 to 2 day old rabbits exposed in utero, which were elevated above non-aluminium-exposed offspring ( Yokel, ). Placental aluminium levels in mice not treated with aluminium were non-significantly higher than in maternal tissues. Injections (i.p.) and oral aluminium administration during gestation significantly increased placental aluminium concentrations above those seen in placenta of saline-control animals as well as the foetuses exposed to the aluminium ( Cranmer et al., ). Concentrations of aluminium in the placenta of guinea pigs that consumed a diet containing 47 mg Al/kg and in the brain, spinal cord and liver of their newborns were similar, ~ 0.005 mmole/kg (0.135 mg/kg) ( Golub et al., a ). Brain and spinal cord aluminium generally decreased from gestation day 30 to post-natal day 12 in the offspring.

Based on brain aluminium concentration in victims of Creutzfeld-Jakob disease, which is associated with widespread neuronal and glial pathology, that were not different from controls, it was concluded that brain damage alone does not result in elevated brain aluminium ( Traub et al., ). Brain aluminium was not elevated in 20 patients who died from liver disease or other complications of chronic alcoholism compared to 20 patients without a history of alcoholism ( Zumkley et al., ). Subsequent relevant studies included the intracerebroventricular injection of 0.2 mg aluminium gluconate which resulted in significantly more intraneuronal aluminium accumulation in the hippocampus and parietal and frontal cortex of rats than in those of controls ( Szerdahelyi & Kasa, ). The increase was greater in the hippocampus and parietal than frontal cortex. Injection of the cholinotoxin AF64A six days before intracerebroventricular aluminium gluconate injection resulted in significantly greater intraneuronal aluminium accumulation in the hippocampus compared to injection of aluminium gluconate alone, suggesting that neuronal toxicity enhanced aluminium uptake ( Szerdahelyi & Kasa, ). Aluminium uptake was enhanced in neurons exposed in culture to glutamate and calcium, suggesting that aluminium entered during cell degeneration ( Mattson et al., ). Synaptosomes prepared from rat brain cortex exposed to 11 μM aluminium, from aluminium chloride, took up ~ 2-fold more aluminium when exposed to increased lipid peroxidation induced by 0.8 mM ascorbic acid and 2.5 μM Fe 2+ ( Amador et al., ). Infection of rats with Japanese encephalitis virus resulted in an increased accumulation of aluminium in the brain ( Seko et al., ). These studies suggest stress (increased lipid peroxidation) and insult to the brain (induced by AF64A, glutamate and calcium and viral infection) can increase brain aluminium accumulation. Although the mechanism is unknown, it appears to be at the cellular level, since this effect was seen in cells in culture.

It does appear that Tf enhances uptake into neurons and that many different chemical species of aluminium can enter neurons and glial cells. However, if there are no available binding sites for aluminium on Tf in brain ECF, as suggested by Bradbury () , this mechanism may not be very important in vivo. The mechanisms of aluminium uptake by brain cells appear to include diffusion, TfR-ME and other, un-identified, carrier-mediated processes.

Astrocytes, another glial cell, did not take up aluminium ( Golub et al., ). In contrast, when 1 mM aluminium was added as the chloride, in the presence of 1 mM citrate and 1 mM calcium, the aluminium concentration in astrocytes was greater than in granule neurons isolated from the cerebellum and was even greater in astrocytes that had been co-cultured with neurons. Neuronal aluminium uptake was not affected by co-culture with astrocytes ( Suarez-Fernandez et al., ). However, the aluminium concentration in these cells was 30 to 50 times that seen in human brain. Aluminium accumulation in neuron- and astrocyte-like cells was significantly increased when introduced as aluminium fluoride and in astrocyte-like cells when introduced as aluminium chloride. Aluminium maltolate and aluminium lactate did not significantly increase aluminium in either cell type nor did aluminium chloride in neuron-like cells. Exposure to up to 1 mM aluminium maltolate resulted in concentration-dependent aluminium uptake that was generally greater in neuron- than astrocyte-like cells ( Lévesque et al., ). Uptake of aluminium into astrocytes from 0.1 mM aluminium associated with serine, glycine and glutamine was significantly increased after 24 hr, but not from aluminium glutamate or aluminium citrate exposure ( Aremu & Meshitsuka, ). Inhibition of glutathione (GSH) synthesis increased aluminium uptake from aluminium glutamate and from aluminium glycine but only after 8 hr. However, it did not increase aluminium from aluminium glutamine or serine. A non-specific inhibitor of glycine transporters (doxepin) and a selective blocker of the glycine transporter GlyT1 (sarcosine) increased aluminium uptake from aluminium glycine. A selective blocker (dihydrokainic acid) of the glutamine transporter GLT-1, also called EAAT2, increased aluminium uptake from aluminium glutamine. Neither a non-specific inhibitor of glutamate transporters (L-trans-pyrrolidine-2,4-dicarboxylic acid) nor an inhibitor of Na + /K + -ATPase (ouabain) affected aluminium uptake. The authors concluded that neither amino acid transporters nor Na + /K + -ATPase mediated aluminium uptake, which they suggest might be from diffusion and one or more other mechanisms.

When exposed to aluminium sulphate, rat glioma cells took up significantly more aluminium than did those of controls, whereas murine neuroblastoma cells did not ( Campbell et al., ). Oligodendrocytes, the glial-forming cells in the CNS, and neurons took up aluminium when introduced at 2.26 μM, as aluminium Tf, but not as aluminium chloride or citrate ( Golub et al., b ; Golub et al., ), consistent with the enhancement of aluminium uptake by Tf in neuroblastoma cells. Aluminium uptake into oligodendrocytes was much greater than into neurons.

Rat cerebellar cells in culture were exposed for a few minutes to aluminium, introduced as 5 mM aluminium citrate or as aluminium fluoride. Aluminium uptake was not seen in granule cells but was observed in GABAergic neurons, that were thought to be Purkinje cells, and flat glial cells, but not star-like (type 2) astrocytes, using synchrotron photoelectronic spectromicroscopy ( De Stasio et al., ; ).

Primary foetal rat hippocampal and human cortical neurons in culture took up aluminium introduced as the chloride (200 μM) in the presence of 1 mM EGTA. Exposure to a divalent cation ionophore (A) increased rat hippocampal intraneuronal aluminium concentration from ~ 3 to 20 mg/kg, and aluminium influx and accumulation in human cortical neurons in culture as well ( Mattson et al., ; Xie et al., ). Explants of rat cortical neurons took up significantly more aluminium, introduced as 340 μM aluminium lactate, aluminium lactate and 328 μM citric acid or aluminium lactate and 2 μM L-glutamic acid, than controls containing no aluminium ( Jones & Oorschot, ). There was no significant difference in intracellular aluminium amount from the aluminium forms. The aluminium was in the cytoplasm and/or cell nucleus.

Neuroblastoma cells, which model human neurons, have been used to study aluminium uptake. A human neuroblastoma cell line showed aluminium uptake with an equilibrium constant of 2.88 nM vs. 1.66 for iron and a similar t ½ , 3.8 min, for 50% cell internalization of the metal ( Morris et al., ). Mouse neuroblastoma cells took up aluminium when introduced as aluminium Tf, at pH 7 to 8. Addition of citrate or EDTA inhibited aluminium uptake ( Shi & Haug, ). Aluminium uptake from a medium containing 25 μM aluminium was saturated, achieving 5 nmole/mg cell protein. Although EDTA, citrate, tartrate, maltolate, fluoride and 8-hydroxyquinoline appeared to inhibit aluminium uptake at pH 6, they did not at pH 7.4. Conversely, although metabolic inhibitors had no effect on aluminium uptake at pH 6, they appeared to reduce uptake at pH 7.4. However, statistical significance was not shown ( Shi & Haug, ). Human neuroblastoma cells took up more aluminium when introduced as aluminium EDTA than as aluminium citrate or aluminium maltolate. Uptake was concentrative ( Guy et al., ). Tf enhanced aluminium uptake into neuroblastoma cells 2-fold more than citrate ( Abreo et al., ).

Brain aluminium concentrations in pregnant rats, given 0, 200 or 400 mg Al/kg/day during gestation days 1 to 20, were significantly lower than in non-pregnant rats, whereas those in liver, bone (only in non-aluminium treated rats), and kidney (only in rats that received 400 mg Al/kg/day) were significantly higher in the pregnant rats ( Bellés et al., ).

Brain aluminium concentration in mice consuming a commercial diet increased several fold from 1 week to 4 weeks of age, then remained fairly constant until declining several fold from 52 to 104 weeks of age ( Takahashi et al., ). The aluminium content of the diet was not described. In contrast, rat brain aluminium showed no consistent changes over the same time period ( Takahashi et al., ), suggesting no age-related changes in brain aluminium concentration.

There appears to be a mechanism to transport aluminium out of the brain. It has been suggested that citrate may enable aluminium transport out of the brain by a carrier-mediated process. When aluminium citrate was infused i.v. to produce constant brain and blood ECF aluminium concentrations, the brain ECF aluminium concentration was below that in blood ECF ( Allen et al., ). This suggests a mechanism at the BBB to reduce ECF brain aluminium by transporting it into blood. The concentration of Tf in CSF, and presumably ECF, is very low. It has been suggested that all Tf in brain ECF is iron saturated ( Bradbury, ) providing no ability of Tf to mediate neuronal aluminium uptake. However, the citrate concentration in brain ECF is higher than in plasma, suggesting that 90, 5, 4 and 1% of aluminium in CSF, and presumably brain ECF, is associated with citrate, hydroxide, Tf and phosphate, respectively, according to calculations conducted by Harris ( Yokel, ). It is therefore likely that aluminium citrate is the aluminium species transported out of the brain. Aluminium citrate transport across the BBB was assessed using microdialysis under conditions of aluminium equilibrium between blood and brain ECF. The brain to blood aluminium concentration ratio increased after addition to the dialysate of a metabolic inhibitor (2,4-dinitrophenol), pyruvate, a proton ionophore (p- (trifluoromethoxy)phenylhydrazone) or mersalyl acid and when proton availability was decreased by increasing dialysate pH. These results suggested the monocarboxylate-1 (MCT-1) transporter mediated aluminium citrate brain efflux ( Ackley & Yokel, ; ). However, the red blood cell, which expresses MCT-1 and the anion exchanger, did not take up aluminium citrate well, suggesting aluminium citrate is not a substrate for MCT-1 ( Yokel, ). Aluminium citrate uptake by an immortalized murine BBB endothelial cell line, in the presence of various inhibitors, was suggested to be ATP- but not Na/K-ATPase-dependent and not a substrate for a dicarboxylate carrier, but a substrate for an organic anion transporter ( Yokel et al., ). Using an immortalized rat BBB endothelial cell line, it was found, in a study focusing on the glutamate transporter, that aluminium citrate uptake was concentrative, temperature- and concentration-dependent, not sodium-dependent, and inhibited by ligands for the sodium-independent L-glutamate/L-cystine exchanger system Xc - . Loading the cells with these ligands enhanced aluminium citrate uptake, interpreted as a trans-stimulatory effect, leading the authors to conclude that system Xc - is a potential candidate for aluminium citrate uptake into the brain across the BBB ( Nagasawa et al., ).

S.c. injection of aluminium L-glutamate has been shown to result in elevated levels of aluminium in the brain of the rat ( Deloncle et al., ; ; ). This does not prove that the aluminium entered the brain as aluminium glutamate, as claimed by the authors. Speciation calculations suggest only ~ 0.5% of aluminium would be associated with glutamate in the human under extremely high aluminium concentrations ( Daydé et al., ). I.p. injection of magnesium D-aspartate with or without aluminium L-glutamate significantly decreased brain aluminium levels compared to the absence of magnesium D-aspartate ( Deloncle et al., ). Although the authors suggested that D-aspartate was acting as a chelator to reduce brain aluminium it is not clear why D-aspartate should produce an effect that is different from L-glutamate, as they have similar complexation constants ( Charlet et al., ), unless the isomers of the amino acid have differential effects.

Aluminium citrate was given i.v. at a rate that produced plasma concentrations in excess of the ability of Tf to bind the aluminium ( Allen et al., ). Under this condition aluminium citrate was presumably the predominant aluminium species in plasma. The appearance of aluminium in brain ECF was too rapid to be mediated by TfR-ME. This suggests a second mechanism, independent of Tf, which can transport aluminium citrate into the brain. Brain aluminium uptake, infused as aluminium citrate, was not influenced by a Tf receptor antibody in mice, nor was brain aluminium uptake in hypotransferrinemic mice different from that of controls ( Radunovic et al., ), providing further evidence of a Tf independent mechanism of brain aluminium entry. Decreased plasma protein binding, produced by uraemia or perhaps by decreased Tf metal binding capacity, should favour formation of aluminium citrate and other small molecular weight aluminium species. This was observed in partially nephrectomized rabbits ( Yokel & McNamara, ). This may increase brain aluminium distribution of non-protein bound aluminium species, such as aluminium citrate.

There appears to be more than one mechanism of aluminium distribution across the BBB into the brain though one has not been directly demonstrated. Evidence has been provided that Tf can mediate aluminium transport across the BBB by TfR-ME of the aluminium Tf complex ( Roskams & Connor, ). It is also assumed that TfR-ME mediates aluminium uptake into some peripheral tissues (see Toxicokinetics, Pharmacokinetic Modelling). The aluminium Tf complex is the predominant aluminium species in plasma. This process would presumably release free aluminium in brain ECF. Morris et al. () reported a positive correlation between aluminium concentration in neurons in the cortex and hippocampus and the density of Tf receptors. I.v. injection of 26 Al Tf resulted in brain 26 Al concentrations (~ 0.003 % of the injected dose/g brain) within 4 hr ( Yokel et al., a ). TfR-ME could account for this appearance of aluminium in the brain if the rate of aluminium transport is similar to that reported for iron. Results of interaction between the TfR and Tf bound to two aluminium atoms suggest that the affinity of the TfR for aluminium-saturated Tf is much lower than for iron-saturated Tf ( Hemadi et al., ).

Aluminium was taken up by hepatocytes to a greater extent when introduced as aluminium Tf than as aluminium citrate ( Abreo et al., ; ). p-Cresol, a compound that accumulates in uraemia, increased aluminium uptake from aluminium Tf, but not from aluminium citrate ( Abreo et al., ), whereas the anti-oxidants N-acetylcysteine, tetramethylpiperidine 1-oxyl, SOD, and catalase did not ( Abreo et al., ). Aluminium appears to enter hepatocytes by a Tf-receptor mediated process but can also enter more slowly by another mechanism(s).

To address the hypothesis that low levels of calcium and magnesium in the environment contributed to brain aluminium accumulation in the amyotrophic lateral sclerosis (ALS) and parkinsonism dementia disorders (see Toxicokinetics, Distribution (Including Compartmentalization), Human Studies, Tissue Aluminium Concentrations, Brain), cynomolgus monkeys were maintained for 41 to 46 months on a normal diet containing 1% calcium, a low calcium diet (0.32%), or a low calcium diet plus 150 mg aluminium and 50 mg manganese daily ( Garruto et al., ). Preliminary analysis of the spinal cord of one of the animals that received the aluminium-containing diet showed aluminium, but not manganese, accumulation. In another study, mice were fed a standard diet; a diet low in calcium and magnesium; a diet low in calcium and magnesium and high in aluminium; or a diet low in calcium and magnesium, high in aluminium and containing 1,25-(OH) 2 D 3 . Addition of aluminium to the diet increased the level of brain, kidney, liver and muscle aluminium. Addition of 1,25-(OH) 2 D 3 enhanced aluminium accumulation in these organs ( Yasui et al., b ). Rats fed a calcium- and magnesium-deficient diet had a non-significant increase of CNS aluminium, whereas rabbits fed a calcium- and magnesium-deficient diet with added aluminium, as the lactate, did not show an elevation of CNS aluminium compared to rabbits consuming the deficient diet without aluminium ( Yase, ). However, few details were reported for these two studies. In a study in rats, low amounts of calcium and magnesium significantly increased lumbar spinal and femoral bone aluminium levels. Addition of aluminium increased the aluminium concentration more, but the lack of a group given standard diet with aluminium for comparison does not allow determination whether or not calcium and magnesium deficiency increased nervous system aluminium accumulation in the presence of elevated aluminium in the diet ( Yasui et al., a ). Mice that consumed a low calcium, low magnesium diet or the same diet plus aluminium, as 15.6 g aluminium hydroxide/kg diet, for 11 to 31 months, had aluminium and calcium deposition in cortical and hippocampal neurons, shown by morin stain ( Kihira et al., ).

To determine if there might be genetic influences on aluminium accumulation, mice from 5 inbred strains were maintained on a control diet or one supplemented with 260 mg Al/kg diet for 28 days ( Fosmire et al., ). C3H mice were the only strain that showed significantly higher tibial aluminium due to aluminium in the diet, DBA the only strain that showed lower aluminium due to aluminium in the diet and the A/J the only strain showing significantly higher aluminium in the absence of aluminium in the diet. DBA strain mice were the only ones showing significantly more brain aluminium due to aluminium in the diet. The bases of the observed differences may be variation in the permeability of various barriers, such as the BBB, as speculated by the authors, but could also be due to other factors affecting aluminium distribution, such as absorption and elimination. No other studies were found that assessed the potential influence of genetics on aluminium kinetics.

Although it has been suggested that AlF 3 may play a role in aluminium toxicity, the fraction of intracellular aluminium as AlF 3 is < 1%, making this unlikely. Intracellular aluminium is more likely associated with phosphate, ATP and phosphorylated proteins. Concurrent gavage administration of aluminium, as 200 mg Al/kg, and folic acid in some rats, as 20 mg/kg, 5 days weekly for 8 weeks, resulted in significantly less aluminium in femur, brain and kidney, but not serum, in the rats that received the folic acid ( Bayder et al., ). It is not clear if folic acid reduced aluminium absorption or enhanced its elimination. Although the stability constant of the aluminium-folate complex is quite high, (log K = 15.15 ( Nayan & Dey, )), the low molar ratio of folate to aluminium of 0.006:1 suggests the results are not due to formation of an aluminium folate complex. Dietary supplementation with vitamin E (5, 15 or 29 mg/g chow) with i.p. injections of aluminium in the rat reduced plasma and brain aluminium compared to the absence of vitamin E supplements, although the effect was most pronounced with the lowest vitamin E concentration ( Abubakar et al., ). The authors speculated that the vitamin E effect could be due to preservation of cell membrane ion transport and membrane fluidity. However, an effect on aluminium excretion cannot be ruled out.

Some studies suggest that fluoride influences aluminium distribution. Addition of fluoride to s.c. injections of aluminium resulted in significantly higher aluminium levels in liver, spleen and adrenals than those from aluminium-alone injections and increased aluminium-induced behavioural toxicity, suggesting fluoride may alter aluminium distribution or some other aspect of the fate of aluminium ( Stevens et al., ). Addition of fluoride to the aluminium in the drinking water of rats reduced bone aluminium levels but appeared to exacerbate the osteomalacic lesion of aluminium-associated bone disease ( Ittel et al., b ). Pre-treating rabbits with 3 mg F/kg/day in their water for 9 days before intrathecal aluminium injection tended to lower brain aluminium levels, but only significantly in the cerebellum. On the other hand, intrathecal aluminium injection in rabbits followed by 3 mg F/kg/day in the drinking water produced no difference in brain aluminium levels compared to those in the controls ( Shore et al., ).

After 24 hr, retention of aluminium, administered as aluminium citrate, was greater in the liver, but less in the bone, kidney and spleen, of iron-deficient, than in those of control, rats ( Greger et al., ). In pregnant rats given a s.c. injection of 26 Al at day 15 or 16 of gestation, 0.09% of the dose was seen per gram liver in the dams and 0.% in foetal liver at gestational day 20 or 21 ( Yumoto et al., ; ). There was ~ 100-fold more aluminium in the maternal liver than in the brain of these rats, as well as in rats which were similarly injected in other studies (see below). Placental 26 Al concentrations were ~ 80 to 90% of liver concentrations. Of the injected dose, ~ 0.2% had transferred to the foetus and a comparable mass amount had been retained by the placenta. The liver contained ~ 5-fold more 26 Al than the placenta or foetus. Mice which drank water containing aluminium as aluminium chloride, dihydroxyaluminium sodium carbonate or aluminium hydroxide until they had consumed 700 mg aluminium, which took 159, 182 and 239 days, respectively, had significantly greater aluminium concentrations 48 hr after the last dose in the stomach, kidney, liver and tibia after consuming the aluminium chloride; but only in the stomach after consuming dihydroxyaluminium sodium carbonate and only in the tibia after consuming aluminium hydroxide ( Dlugaszek et al., ). These results show the influence of speciation on aluminium kinetics.

Ferritin isolated from the brain of rats that had received aluminium in their drinking water for 1 year had more aluminium than normal rats (115 vs. 42 mole of Al/mole of ferritin) whereas the molar ratio of aluminium to ferritin in the liver did not increase (4.3 vs. 4.6) ( Fleming & Joshi, ). Horse spleen ferritin bound up to 98 mole Al/mole ferritin after incubation exposure to aluminium citrate (30 mM) ( Cochran & Chawtur, ). Further procedures suggested that the aluminium was firmly bound to the ferritin, probably to the core. Horse spleen ferritin that was reconstituted in the presence of aluminium citrate contained an average of 120 mole Al/mole ferritin, whereas apoferritin and reconstituted ferrritin bound only 7.6 and 9.5 mole Al/mole ferritin, in an equilibrium dialysis study ( Dedman et al., a ). The authors concluded that aluminium can be incorporated into a growing iron core in ferritin, that this can be explained by non-specific binding and that, once the aluminium is bound, it is trapped and cannot dissociate freely, but that in the presence of aluminium-complexing ligands, such as citrate, ferritin will not sequester large amounts of aluminium. Ferritin isolated from the brain of rats that received repeated aluminium injections, where blood and brain aluminium were significantly increased, had 136 mole Al/mole ferritin compared to 3.6 in controls ( Sakamoto et al., ). Although the authors concluded that ferritin may act as an aluminium detoxicant, they found that the ferritin-associated aluminium corresponded to 5.9% of the total brain aluminium, suggesting it does not sequester a very large percentage of intracellular aluminium.

After repeated s.c. aluminium injections to rabbits that produced NFTs, the aluminium in the neurons was seen in the nucleus but not the cytoplasm ( Uemura, ). Similarly, aluminium was seen in the nucleus (nucleolus, interchromatin granules, euchromatin, and the heterochromatin) and cytoplasmic area (rough endoplasmic reticulum and free ribosomes) of rabbit neurons following administration of aluminium as the powder or chloride into the cisterna magnum or following i.v. injections of aluminium lactate ( Wen & Wisniewski, ). The intracellular distribution of aluminium in murine neuroblastoma cells that took up aluminium, introduced as aluminium chloride at pH 6, showed 20% to be associated with the nuclear pellet and cell debris, 70% in the supernatant fraction from endoplasmic reticulum, lyosomes and cytosol, and 11% with mitochondria ( Shi & Haug, ). Aluminium- ethylenediaminetetraacetic acid (EDTA) resulted in equal aluminium distribution in the cytosolic and crude nuclear fractions of human neuroblastoma cells. More aluminium was associated with protein than DNA in the nuclear fraction ( Dobson et al., ). In contrast, aluminium taken up by rat cerebral organotypic cultures exposed to aluminium chloride was only seen in lysosomes ( Schuurmans Stekhoven et al., ). A study of 26 Al uptake by human neuroblastoma cells exposed to aluminium-EDTA showed ~ 55% of the 26 Al in the nuclear fraction and the remainder in the cytoplasm. Within the nuclear fraction, ~ 81% was in the nuclear sap, 17% associated with nuclear protein, 1.2% with DNA and 0.5% with RNA ( King et al., ). In neuron- and astrocyte-like cells, aluminium maltolate exposure resulted in intranuclear and cytoplasmic vesicular aluminium accumulation, respectively. Aluminium accumulation in astrocyte-like cells after aluminium chloride, aluminium lactate and aluminium fluoride exposure was in small vesicles throughout the cytoplasm and nucleus ( Lévesque et al., ). When brain (cerebrum) was fractionated to obtain cell nuclei, ~ 27% of the 26 Al was seen in the nuclei of suckling, and 47% in those of weaned, rats ( Yumoto et al., ). Isolation of a nuclear fraction, and then chromatin and supernatant fractions from the nuclear fraction, showed that ~ 89% of the nuclear 26 Al was in the chromatin fraction ( Yumoto et al., ). Aluminium subcellular localization in many of these studies was similar to that seen in human brain (see Toxicokinetics, Distribution (Including Compartmentalization), Human Studies, Tissue Aluminium Concentrations, Brain), but some results are different, suggesting that in vitro exposure of cells to some aluminium chemical forms results in different cellular localization than occurs in vivo.

Studies of the sub-cellular localization of aluminium in rat liver cells showed considerably more in the nuclear fraction than in the mitochondrial or sub-microscopic fractions when aluminium was introduced as the ion at pH 7, suggesting selective nuclear aluminium uptake ( Kushelevsky et al., ). In contrast, rat hepatocytes took aluminium into the mitochondrial (~ 45 to 50%) and post-mitochondrial fraction (~ 40 to 45%) but only 6 to 7% into the nucleus. There were no differences when aluminium was introduced as the chloride, nitrate or lactate ( Muller & Wilhelm, ). In another study, daily i.v. injection for 50 days of 1.5 mg Al/kg, as the chloride, in piglets greatly increased serum and hepatic aluminium levels. Microanalysis with an energy dispersive x-ray spectrometer showed aluminium and phosphate in hepatocyte lysosomes, but aluminium was not seen in all lysosomes or in all hepatocytes ( Klein et al., ). Aluminium was seen in the lysosomes of kidney cells of rats given i.p. aluminium chloride ( Linss et al., ; ). The nucleus of Caco-2 cells appeared to selectively take up 26 Al, irrespective of the chemical species of 26 Al to which the cells were exposed ( Zhou & Yokel, ).

The percentage of aluminium bound to plasma proteins was reported to be 92 to 98% in the rat, at a serum aluminium concentration of to 10,000 μg Al/L following aluminium chloride injection ( Burnatowska-Hledin et al., ). Similarly, 98% of aluminium was found to be protein bound when rat serum aluminium concentrations were 110,000 to 440,000 μg Al/L ( Gupta et al., ). These aluminium concentrations greatly exceed those seen in humans and the capacity of Tf to bind aluminium. When aluminium, as the chloride, was added to rabbit serum to give a final aluminium concentration of 100 to 32,000 μg/L, the ultrafilterable percentage decreased as aluminium concentration increased in normal, but not renal-impaired, rabbits ( Yokel & McNamara, ).

The steady state serum to whole blood aluminium concentration ratios were ~ 0.9 to 1.1 in rats consuming aluminium in their diet ( Mayor et al., ). The aluminium concentration ratio in rabbit serum and plasma compared to whole blood was ~ 1.15 to 1.2, showing nearly equal distribution between plasma, serum and the formed elements of blood ( Yokel & McNamara, ). Over the range of 1 to 20 μg Al/mL, blood to plasma aluminium ratios were 0.8 to 1, also showing near equilibrium of aluminium between blood cells and plasma ( Pai & Melethil, ).

The above results suggest that the initial t ½ of aluminium elimination might be aluminium-dose/concentration dependent. The t ½ doubled with a 10-fold increase in the aluminium dose in the rat ( Pai & Melethil, ) and increased 1.8-fold with a doubling of the dose in the rabbit ( Yokel & McNamara, ). This could be due to greater formation of non-ultrafilterable aluminium species (see Toxicokinetics, Elimination and Excretion, Animal Studies, Elimination Rate).

Administration to dogs of aluminium, as alum, in a mixture of hashed lean beef, lard, cracker meal, bone ash and water or biscuit prepared from flour resulted in a measurable level of aluminium in the blood hours later, leading the author to conclude that the aluminium was absorbed and promptly entered the blood ( Steel, ). However, no results were reported for dogs that had not been treated with aluminium. Aluminium appeared in bile, lymph and urine within minutes following an i.v. injection ( Underhill et al., ). Most of the results of animal studies suggest an initial V d of aluminium consistent with blood volume. When samples were collected over longer periods, greater V d s became evident, although much less than seen with many xenobiotics. The V d after i.v. and oral administration of 8.1 mg Al/kg in rats and followed for 10 hr was 38 and 46 mL/kg ( Gupta et al., ). Following 0.1 mg aluminium (as the sulphate)/kg i.v. injection in the rat, V d s of 78, 47, and 42 mL/kg were seen ( Pai & Melethil, ; Xu et al., ; a ). After i.v. injection of aluminium lactate, the initial (central compartment) and steady-state V d s in the rabbit were reported to be 54 and 109 mL/kg after 40 μmoles Al/kg (1.1 mg/kg) and 44 and 100 mL/kg after 80 μmoles Al/kg (2.2 mg/kg) ( Yokel & McNamara, ). When sampling time was increased to 48 hr, initial and steady-state V d s in the normal rabbit after i.v. injection of 100 μmoles (2.7 mg) Al/kg as the lactate were reported to be 159 and mL/kg and 168 and 516 mL/kg in renally-impaired rabbits ( Yokel & McNamara, ). When blood aluminium samples were collected over 72 hr, the steady-state V d was found to be mL/kg ( Yokel & McNamara, - ). In the dog, the initial V d was estimated to be 50 mL/kg after 1 mg Al/kg as the chloride given i.v., when studied over a period of 2.5 hr ( Henry et al., ).

In contrast to aluminium citrate, administration of aluminium, as the lactate, chloride and perhaps some other species, may result in clearance of the aluminium by tissues, particularly by the reticuloendothelial organs, and sequestration, reducing renal clearance and increasing the body burden. Tissue aluminium concentrations in rabbits 1 week after completion of a series of 20 i.v. injections of aluminium citrate were considerably lower than after the same molar dose of aluminium lactate ( Yokel et al., a ). Similarly, addition of equimolar citrate to i.p. injections of aluminium chloride significantly reduced serum aluminium compared to the absence of citrate, whereas equimolar maltol significantly increased both serum and brain levels of aluminium in the rat ( Ogasawara et al., ).

It has been suggested that citrate can promote the redistribution and elimination of aluminium from plasma. This is dependent on the presence of a significant fraction of aluminium as aluminium citrate. In the presence of normal aluminium concentrations, Tf binds most of the aluminium in plasma (see Toxicokinetics, Distribution (Including Compartmentalization), Human Studies, Transport in Blood). Citrate promotion of aluminium distribution and excretion would be favoured in the presence of aluminium concentrations that exceed the Tf metal binding capacity. This very seldom occurs in the human, but has been produced in some of the experimental animal studies. Alternatively, citrate may promote aluminium distribution and excretion prior to association of the aluminium with Tf. The time course of aluminium complexation by Tf in vivo has not been determined; however, when aluminium lactate was incubated with Tf, the association of the aluminium with Tf was complete within 1 minute in vitro at 37 °C ( Yokel et al., a ). Exchange of aluminium from citrate to transferrrin at pH 7.2 to 8.9 and 25 °C occurred in three kinetic processes. The first, which might be formation of a ternary complex of Tf, aluminium and citrate, was nearly complete within 2 minutes ( Hemadi et al., ). A transition time for the change of plasma aluminium association from citrate to Tf of 4.2 minutes was tentatively used in a model of aluminium biokinetics ( Steinhausen et al., ) (see description in Toxicokinetics, Pharmacokinetic Modelling).

Aluminium levels generally decreased in guinea pigs from gestation day 30 to post-natal day 12 ( Golub et al., a ). Muscle aluminium was reported to increase with age from 2 to 6 to 12 months in rats, but to decrease at 24 months ( Kukhtina, ). Lung aluminium increased from a mean of 1.7 and 10 mg/kg (wet tissue) in guinea pigs and rats at 6 months of age to 32 and 52 mg/kg at 21 to 24 months, respectively ( Stone et al., ). Aluminium levels increased with age in liver and kidney of mice, did not change in the brain and heart, and decreased in femur and lung ( Massie et al., ). Bone and kidney aluminium increased with age in rats ( Greger & Radzanowski, ). The limited data available suggest that brain and blood aluminium concentrations increase with age. The age-related increase may be due to reduced aluminium clearance with age, as discussed below (see Toxicokinetics, Elimination and Excretion, Animal Studies, Elimination Rate), the large amount of aluminium in the diet of laboratory animals, as noted above (see Toxicokinetics, Absorption, Animal Studies, Oral Administration, Beverages and Foods) and the long t ½ of aluminium (as discussed below in Toxicokinetics, Elimination and Excretion, Animal Studies, Elimination Rate).

A woman who applied ~ 1 g of aluminium chlorohydrate-containing antiperspirant to each regularly-shaved underarm daily for 4 years was reported to have experienced bone pain and fatigue ( Guillard et al., ). Serum aluminium was 3.88 μM (105 μg/L) and 24 hr urinary aluminium excretion was ~ 1.75 μmoles (47 μg)/day, which is elevated, but not as high as would be expected with this serum aluminium concentration in the presence of normal renal function. Aluminium concentrations in serum and urine before antiperspirant use were not reported. After discontinuation of antiperspirant use, urine and serum aluminium concentrations decreased over 7 months, her bone pain nearly disappeared and her fatigue was less severe. Given the extensive world-wide use of aluminium-containing antiperspirants, the lack of other similar reports suggests that this patient was atypical, as speculated by Exley () , or that the samples were contaminated.

A study of 26 Al chlorohydrate absorption, a primary component of antiperspirants, which was applied once to both underarms of one male and one female subject, revealed an average excretion of 0.012% of the applied 26 Al in the urine over the subsequent 53 days ( Flarend et al., ). Daily application of tape to the underarm area to strip away dead skin and surface aluminium chlorohydrate followed by gentle wiping with a towelette for 6 days after its application removed 39% of the applied material. One might assume that the aluminium chlorohydrate that was not removed by the tape and washing represents the maximum amount of aluminium available for absorption. Based on this assumption and assuming that 85% of the aluminium that would eventually be excreted in the urine was excreted during the time course of this study, the results suggest that a maximum of 0.02% of the aluminium could eventually be absorbed. Given that 50 to 75 mg of Al might be applied daily in antiperspirants, even this very small absorption might be relevant. However, it cannot be assured that this absorption was not from inhalation of Al that flaked off of the application site and it is unknown if comparable aluminium absorption would occur following daily application of aluminium chlorohydrate. This might not occur because of formation of aluminium precipitate in the sweat gland that might impact on the potential for subsequently applied antiperspirant to be absorbed. This study provides the best estimate to date of percutaneous bioavailability of aluminium from antiperspirants.

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Utilizing both 27 Al and 26 Al in separate studies, greater aluminium absorption was seen in subjects with Down&#;s syndrome than in controls, 0.14 vs. 0.030% for 27 Al administered with citrate and 0.14 vs. 0.022% for 26 Al administered with orange juice ( Moore et al., ). However, these results are based on a single blood sample drawn 60 minutes after aluminium administration, a method noted above in Toxicokinetics, Absorption, Animal Studies, Oral Administration that may not very reliably estimate oral bioavailability. Down&#;s syndrome is associated with changes in neurodegeneration, particularly increased β-amyloid deposition, that resemble AD.

In a study of 20 AD subjects aged 65 to 76 (n=10) and 77 to 89 (n=10) blood aluminium levels were compared to those of 20 controls. Subjects and controls consumed ~ 4.5 mg/kg aluminium hydroxide and 3.3 to 6.5 g citrate (citrate:aluminium, 1.6:1 to 3.2:1) after an overnight fast ( Taylor et al., ). In the younger AD subjects, the blood aluminium was significantly greater at 60 minutes than in control subjects (104 vs. 38 μg/L). In the older subjects, the increase in blood aluminium levels was greater, but not statistically different, in the controls than in patients, in contrast to the younger subjects. Aluminium absorption was studied in AD subjects and compared to age-matched controls after consumption of a fruit drink containing 26 Al ( Moore et al., ). The percent of aluminium absorbed in subjects, estimated from single plasma samples obtained 1 hr after the oral aluminium consumption, was 164% of that seen in controls. The authors attributed these differences to absorption, although reduced renal aluminium clearance in the aged could also contribute to this difference. The lack of consistent overall differences as a function of age or dementia status makes it difficult to draw any general conclusion from this study. Zapatero et al. () found significantly higher serum aluminium concentrations in 17 AD subjects, compared to age-matched controls, but no difference between 15 subjects with senile dementias and controls. Based on greater serum and urine aluminium levels in 8 patients with dementia including the Alzheimer&#;s type who were 65 to 86 years old compared to 144 controls who were 30 to 65 years old (18 and 6 μg/L and 77 and 26 μg/L, respectively), Roberts et al. () claimed to have confirmed earlier findings that patients with dementia appear to absorb more aluminium from the diet than healthy subjects. However, the difference in the serum and urine aluminium levels could be due to factors other than dementia, such as the significant difference in the age of the subjects. AD appears to be associated with a higher serum aluminium concentration than seen in controls. Nothing can be concluded from these observations to elucidate the mechanism of this difference.

The information related to the affect of age on aluminium absorption is from adult and geriatric subjects. No published studies of children were found. A greater increase in blood aluminium was seen in subjects aged > 77 than in those aged < 77 (serum aluminium 101 vs. 38 μg/L at 1 hr), who consumed ~ 4.5 mg/kg aluminium hydroxide and 3.3 to 6.5 g citrate (citrate:aluminium, 1.6:1 to 3.2:1) after an overnight fast ( Taylor et al., ). Comparing oral aluminium bioavailability in the subjects < 59 with those > 59 years of age failed to reveal a difference ( Stauber et al., ). Taking these observations together with the results from animal studies, (see Toxicokinetics, Absorption, Animal Studies, Oral Administration, Factors Influencing Oral Aluminium Absorption, Urinary Excretion) there is a lack of consistent data to be able to conclude that there is a significant effect of age on aluminium absorption, distribution or retention.

The primary documented problems with aluminium as a toxicant to bone and the brain have occurred in persons with uraemia, who accumulate aluminium, due to their inability to excrete it, and may develop aluminium-induced toxicity ( Alfrey, ). There is evidence that uraemia may also enhance aluminium absorption. Ittel et al. (a) found greater serum aluminium levels in acute and chronic renal failure patients than those with normal renal function receiving the same daily dose of aluminium (1.18 g) as hydroxy-magnesium aluminate, greater daily urinary aluminium excretion in the chronic renal failure patients, and a significant negative correlation between renal aluminium excretion and creatinine clearance. They concluded that there was an enhancement of GI aluminium absorption in the presence of chronic renal failure. However, calculations using the biokinetic model, described in Toxicokinetics, Pharmacokinetic Modelling, failed to find evidence for increased oral aluminium absorption by humans with chronic renal failure ( Steinhausen et al., ).

Addition of calcium to aluminium hydroxide did not affect aluminium absorption in humans with normal renal function who presumably had normal calcium status ( Nolan et al., ). Based on ionic radii, it is more likely that aluminium would compete with magnesium than calcium. Although there is some evidence for aluminium-magnesium competition in vivo, this has not been well investigated.

Haemodialysis patients who had low or normal serum ferritin levels and were given aluminium hydroxide for 7 days had increased serum aluminium, whereas patients with high serum ferritin did not show an increase of serum aluminium concentration ( Cannata et al., ). Serum aluminium negatively correlated with serum iron, serum ferritin and Tf saturation in chronic haemodialysis patients ( Cannata et al., ; Huang et al., ). Similarly, there was a negative correlation between serum iron and aluminium absorption in dialysis patients ( Cannata et al., ). These results are consistent with those of animal studies showing enhanced aluminium absorption in the presence of iron deficiency (see Toxicokinetics, Absorption, Animal Studies, Oral Administration, Factors Influencing Oral Aluminium Absorption, Iron).

In fluoridated drinking water, decreased pH would favour formation of aluminium-fluoride complexes. In one survey, 19% of aluminium in treated water was complexed with fluoride, when 58 μM (~ 1 mg/L, 1 ppm) fluoride was added ( Driscoll & Letterman, ). Moderate concentrations of fluoride in drinking water were found to have a slight protective effect against aluminium-associated impaired mental function ( Forbes & Agwani, a ; b ; Forbes & Gentleman, ). However, there was no obvious benefit of 40 mg of fluoride given daily for 1 year to patients in the early stages of AD (D. Shore, personal communication, ). Although complexation of aluminium with fluoride can be important at the more acidic pHs found occasionally in water, there is not sufficient fluoride in plasma to form any significant amount of binary aluminium fluoride complexes (W.R. Harris, personal communication, ). It is not clear if fluoride significantly influences aluminium toxicokinetics.

Sodium silicate (100 μM) reduced the GI absorption of 26 Al (consumed in orange juice, a source of citrate) by 85% in fasted humans ( Edwardson et al., ). Taylor et al. () cited previous studies showing an inverse relationship between aluminium and silicon concentrations in drinking water. An earlier study showed an inverse relationship between renal function and plasma silicon but no correlation between serum aluminium and silicon in patients with chronic renal failure on regular haemodialysis ( Roberts & Williams, ). In a later study there appeared to be an inverse relationship between serum aluminium and silicon levels in a subset of haemodialysis patients ( Parry et al., ). Studies of the aluminium and silicon dioxide concentrations in drinking water suggested that moderate silicon concentration has a slight protective effect against aluminium-associated impaired mental function ( Forbes et al., ; Forbes & Gentleman, ). These results suggest that increasing dietary silicon may reduce aluminium absorption and facilitate excretion.

The primary humic substances in water and soil are humic and fulvic acids. One healthy person who took 1.75 g of aluminium hydroxide, adjusted to pH 2, and 1.25 gm of concentrated humic substances, excreted more aluminium in the urine over the subsequent 50 hr than when the aluminium was taken alone (1.4 v.s. 0.6% of the aluminium dose), suggesting humic substances can increase aluminium absorption ( Alexander et al., ).

Although citrate can increase aluminium absorption, it has not always been reported to increase tissue or cellular aluminium retention. Some animal studies have reported a citrate-induced increase of brain and aluminium (as described above in Toxicokinetics, Absorption, Animal Studies, Oral Administration, Factors Influencing Oral Aluminium Absorption, Carboxylic Acids), whereas other animal studies and one human study have not ( Sakhaee et al., ). Therefore, citrate may enhance oral aluminium absorption but may also enhance its distribution into and out of tissues as well as from the organism by renal elimination, in the presence of renal function, as suggested by Maitani et al. () , and discussed below (see Toxicokinetics, Elimination and Excretion, Animal Studies, Urinary Excretion).

The first study of oral aluminium absorption using 26 Al was conducted in one human subject who received aluminium citrate. The results suggested &#; 1% oral absorption ( Day et al., ), whereas two other studies involving 5 and 2 subjects led, respectively, to estimates of 0.015 ( Edwardson et al., ) and 0.52% ( Priest et al., ). However, there is a human study that failed to find an increase of aluminium absorption in the presence of citrate. This was conducted in subjects who received aluminium with their diet ( Stauber et al., ). Generally, increasing the amount of citrate consumed with aluminium hydroxide increased blood aluminium concentrations ( Taylor et al., ).

Administration of ranitidine, which increased gastric pH, reduced urinary aluminium excretion ( Rodger et al., ), consistent with an enhancement of aluminium absorption at lower gastric pH. Serum and urine aluminium levels increased in pre-surgery ulcer patients with normal renal function who had a mean gastric pH of 2.09 following administration of 30 mg/kg aluminium hydroxide, whereas the opposite was seen in post-surgery patients whose gastric pH averaged 5.78 ( Olaizola Ottonello et al., ). In contrast, limited observations in patients with chronic renal failure failed to show a correlation between gastric acid secretion and elevation of serum aluminium after oral aluminium consumption, suggesting gastric acid secretion may not play a critical role in aluminium absorption ( Beynon & Cassidy, ). There are insufficient reported results to draw a firm conclusion about any effect of gastric pH on oral aluminium absorption.

Studies in humans have also shown that oral aluminium absorption is dependent on many factors, although this has been less well studied than in animals. A summary of the reported factors affecting oral aluminium absorption in humans is shown in Table 18 . The following sections describe these effects in much more detail.

Oral aluminium bioavailability was estimated from 6-day urinary 26 Al output in 2 subjects ( Priest et al., ). Both subjects received intragastric dosing of 26 Al incorporated into aluminium hydroxide, 26 Al hydroxide in the presence of citrate, and 26 Al citrate. Oral aluminium bioavailability was estimated from urinary aluminium output, corrected for the fraction of aluminium administered intravenously that was found in the urine within 7 days, 0.72, as demonstrated by Talbot et al. () , and as used by Stauber et al. () above. Estimates of the percentage of 26 Al absorbed from 26 Al hydroxide in the absence and presence of citrate averaged 0.01 and 0.14%, respectively; aluminium bioavailability from 26 Al citrate was 0.52%. These limited results mirror many reports showing very low aluminium bioavailability from aluminium hydroxide (and sucralfate) and enhancement by citrate.

Oral aluminium bioavailability was estimated to be 0.006 and 0.007% from two studies of a commercial aluminium hydroxide product (Linc®); estimates were based on the increase above baseline of urinary aluminium excretion after consumption of 1, 4 or 8 tablets ( Haram et al., ; Weberg & Berstad, ). Weberg & Berstad () observed an inverse relationship between dose and oral aluminium bioavailability. They suggested that this was due to the ability of more tablets to produce a greater increase in the pH of the intragastric milieu, resulting in decreased solubility. However, if aluminium is primarily absorbed from the upper intestine, where the pH is about 6 or 7, this may not be the explanation. It is unknown if diet influenced these results, as this was not controlled or documented. Oral aluminium bioavailability from aluminium hydroxide, and aluminium glycinate taken with aspirin, was estimated to be 0.003 and 0.22%, respectively ( Meshitsuka & Inoue, ; Meshitsuka et al., ).

It was suggested that polyphenols in tea bind most of the aluminium, thus greatly reducing its oral bioavailability ( Flaten & Odegard, ). Collection of ileostomy effluent from a subject who had not consumed food orally for two weeks but had consumed tea suggested there was no breakdown of the polyphenols from the tea ( Powell et al., ). These results suggest that digestion does not change the major ligand that binds aluminium in tea.

Some studies found increased aluminium in the urine after tea consumption, suggesting absorption of aluminium from the tea. Urinary aluminium concentration increased in the 12 hr after tea consumption ( Koch et al., ). Equal volumes of coffee or water did not increase the urinary aluminium concentration. They did not report urine volume, or urinary aluminium output, so it is unknown if aluminium excretion increased. However, if urine volume was greater after consuming tea than water, as reported by Powell et al. () , urinary aluminium output would have been greater following tea consumption. In the 24 hr after consumption of 2 litres of tea, presumably containing a total of 218 μmoles of aluminium, by one subject, urinary aluminium output was 0.725 μmoles, compared to 0.14 μmoles after consumption of water by the same subject ( Powell et al., ). This would suggest 0.3% aluminium bioavailability. In contrast, tea, with or without lemon juice or milk, or mineral water was consumed one day with a defined diet, in a cross-over study. The tea contained 2.3 to 2.8 mg aluminium and comprised about 31% of the total daily dietary aluminium intake. Blood was obtained 11 times, from immediately before to 0.5 to 24 hr after dosing. No elevation of serum aluminium, above the pre-treatment mean concentration of 4.2 μg/L, was seen ( Drewitt et al., ). Four subjects who consumed 2 litres of tea containing ~ 4 mg Al/L eliminated an average of 0.003 mg aluminium within the subsequent 7 hr in their urine, or ~ 0.04% of the aluminium in the tea ( Gardner & Gunn, ). However, this is clearly an underestimate of the oral aluminium bioavailability because urinary aluminium excretion had not yet returned to the pre-treatment rate in most subjects, suggesting insufficient time to follow aluminium absorption and/or incomplete excretion of the absorbed aluminium.

Aluminium bioavailability was estimated based on 24 hr urinary aluminium excretion in subjects consuming a controlled diet that included tea and RSW water (which provided essentially no aluminium) ( Stauber et al., ). The ~ 3 mg Al/day provided by this diet is below typical dietary intake. Absorption of aluminium from food consumed prior to the study, which likely provided > 3 mg Al/day, may have contributed to the urinary aluminium excretion during the study. This would produce an over-estimation of aluminium bioavailability from the controlled diet. The estimate of oral aluminium bioavailability from food-plus-tea in this study was ~ 0.53%, assuming that 10% of the aluminium in the tea was available for absorption. Based on the assumption that 100% of the aluminium in the tea was available for absorption, oral aluminium bioavailability from food-plus-tea was estimated to be 0.28%. Therefore, the authors concluded that oral aluminium bioavailability from water and food is comparable. They claimed &#;&#; recent research suggesting that aluminium in food and aluminium in water have similar bioavailabilities&#;, citing Priest () . However, Priest does not make this statement or provide data to support, or refute, it.

The bioavailability of aluminium from a low aluminium diet was estimated to be 0.78%, compared to 0.09% when aluminium, as aluminium lactate, was added to the diet, ( Greger & Baier, ). These results are in the range of values obtained for aluminium from drinking water (see Toxicokinetics, Absorption, Studies in Humans, Oral Administration, Drinking Water). The results suggest an inverse relationship between aluminium dose and oral absorption. However different aluminium species were consumed under these two conditions.

Oral aluminium bioavailability from the diet was estimated to be 0.1 to 0.3% based on normal urinary aluminium excretion of 20 to 50 μg/day and a daily aluminium intake of 20 mg ( Ganrot, ). Daily aluminium intake is now believed to be less. Priest () estimated oral aluminium bioavailability from food to be ~ 0.1% based on a daily aluminium intake of 15 mg, a daily urinary excretion of 0.025 mg and 5% aluminium retention in the body. The same estimate was obtained by comparing an average daily urinary aluminium excretion of 0.004 to 0.012 mg to average daily aluminium intake from food of 5 to 10 mg ( Nieboer et al., ). Based on daily dietary aluminium intake of 10 mg, a terminal t ½ of aluminium of 50 years, and aluminium body burdens of 5 and 60 mg, oral aluminium bioavailability was estimated to be 0.14 and 1.6%, respectively ( Priest, ).

An error resulted in the introduction of 20 tons of 8% aluminium sulphate into a municipal water supply near Camelford, England. Some of the consumers reported that the water had an unpleasant metallic taste; others reported various symptoms ( Eastwood et al., ). Excessive aluminium, copper, lead and zinc were found in the water. Two of the affected individuals showed elevated urinary aluminium output. Bone biopsies showed the presence of elevated aluminium ( Eastwood et al., ) that was still elevated 6 and 7, but not 18, months later ( McMillan et al., ). These results suggest the possibility of elevated bone aluminium in humans with normal renal function after oral consumption of excessive amounts of aluminium. However, only two reports were found of elevated bone aluminium in humans with normal renal function after massive oral consumption of aluminium. One was a 49 year old male with a 25 year history of consumption of aluminium-containing antacids whose bone aluminium concentration, 24 mg/kg dry weight, was between that of three non-dialysis subjects at autopsy, which averaged 6.4 mg Al/kg, and that of 3 dialyzed subjects at autopsy, which averaged 125 mg Al/kg ( Recker et al., ). The other was a 39 year old female who consumed antacids containing a total of ~ 18 kg of elemental aluminium over 8 years. She had stainable aluminium on 27.6% of the bone surface ( Woodson, ).

Another study that modelled aluminium consumption from drinking water employed two subjects who consumed 26 Al added to water from a public supply ( Priest et al., ). Faeces and urine were collected for 7 days after 26 Al administration; these contained 97.6 and 100.4% of the 26 Al administered to the two subjects. These results suggest that little aluminium was absorbed. The results also illustrate the inadequacy of the balance method to determine oral aluminium bioavailability. The 26 Al in blood obtained 1, 4 and 24 hr after oral 26 Al dosing was multiplied by the estimated blood volume of each subject. The results suggested oral aluminium bioavailability of 0.027, 0.034 and 0.012%, based on these three sampling times. Cumulative urine excreted suggested oral aluminium bioavailability was 0.20 and 0.14%, for these two subjects. The authors corrected these values for the percentage of aluminium voided in the urine in the same time period after i.v. injection (72%) ( Talbot et al., ), as conducted by Stauber et al. () . This correction resulted in an estimate of 0.22% oral aluminium bioavailability. This is an order of magnitude greater than the results they obtained by estimating absorption from a single serum sample and the calculated volume of distribution, suggesting this latter method underestimates oral aluminium bioavailability.

A study of 2 humans who consumed 26 Al as aluminium chloride, Hohl et al. () produced an estimate of oral aluminium bioavailability of 0.1%. The authors collected urine for 4 days (although missing the collection of part of the sample from one of the two subjects on day 1). Their estimate of 0.1% oral aluminium bioavailability was not corrected by the aluminium that was retained by the subjects or excreted after the period of sample collection. The authors suggest this would not result in a large error.

A second study relevant to consumption of aluminium from drinking water involved 4 subjects who consumed a soft mineral water containing < 1 μg Al/L, the same water with 300 μg Al/L as Al 2 (SO 4 ) 3 , and deionized water containing 300 μg Al/L as Al 2 (SO 4 ) 3 ( Gardner & Gunn, ). Unfortunately, urine was collected only 7 hr after aluminium administration; urinary aluminium excretion rate would not have yet returned to the pre-aluminium-treatment rate in many cases. Therefore, the estimate of oral aluminium bioavailability, which was < 0.1%, is below the true value.

One of the few human studies of oral aluminium absorption that models drinking water is that reported by Stauber et al. () . The 21 subjects consumed a diet that provided a total intake of about 3 mg Al/day. They drank either 1.6 L daily of an ATW from a municipal treatment plant that they found contained 140 μg Al/L or reconstituted soft water (RSW) that had < 1 μg Al/L, with and without sodium citrate. The ATW provided 208 to 233 (in the absence of added sodium citrate) or 253 μg Al/day (when sodium citrate was added). The RSW provided < 1 μg Al/day (when no sodium citrate was added) or 46 μg Al/day (when sodium citrate was added). Oral bioavailability was estimated from the 24 hr urinary aluminium output times 2.2. The value 2.2 was used to correct for the estimated fraction of total urinary aluminium excretion that occurs within the first 24 hr and the fraction of absorbed aluminium that is retained (e.g., does not appear in the urine). This is based on the fraction of aluminium excreted in the urine over 24 hr compared to that excreted over 7 days, which was estimated to be 0.62 by ( Priest, ). It is also based on the fraction of aluminium administered intravenously that was found in the urine within 7 days by Talbot et al. () , 0.72, suggesting the balance of the aluminium was retained. They concluded that the oral bioavailability of aluminium from water was 0.39% in the absence, and 0.36% in the presence, of citrate. This was based on the increase in 24 hr urinary aluminium excretion when the subjects consumed ATW and a controlled diet compared to RSW and the same diet, and the increased aluminium in ATW compared to RSW. The controlled diet was given to all subjects in the same amounts for three meals, three snacks, tea and a banana daily, delivering calories and 2.9 mg aluminium. It contained standard amounts of specific food components, including meat, cereal, milk, tea, and cookies, each of which was analyzed to determine its aluminium concentration. Aluminium in ATW represented 6 to 7% of total aluminium intake. Its consumption raised urinary aluminium output approximately 9%. Therefore, the response seen was < 10% of background urinary aluminium excretion. A concern about this study is that one might expect the variability in the excretion of aluminium in the urine from food to mask any ability to see an increase in urinary aluminium output from the aluminium in water. The range of 24 hr urinary aluminium output in these subjects was 5-fold (1.8 to 9.3 μg). However, within-subject variability must have been considerably less for the results to produce a statistically significant difference in urinary aluminium output after consuming the ATW compared to RSW. This is indicated by the 95% confidence intervals (CI) that suggest considerably less variability than the 5-fold range of their subjects. The design of this study favoured the study objectives, to measure the amount of aluminium absorbed from water, above that contributed by food. Their study included within-subject comparisons and a defined diet containing a low amount of aluminium for the day before and the day of the study (3 mg vs. normal intake of 3 to 7 mg/day in Australia, according to the authors). Glynn et al. () stated that the concentration of aluminium in drinking water has to be extremely high in relation to food to ensure that aluminium from the water is a significant part of the total oral aluminium intake. Similar concern expressed was: &#;&#;biokinetic studies of injected or ingested aluminium in man and animals is complicated by the investigator&#;s inability to distinguish between aluminium from a test dose and that already present in the body. Most studies of stable aluminium are, thus, of poor sensitivity.&#; ( Priest, ). Apparently Stauber et al. () were able to overcome this reservation. The correction factors they used to estimate urinary aluminium output were based on two human studies conducted by other investigators in which 26 Al was used. These estimates may not accurately predict the fraction of aluminium excreted in urine in 1 day compared to that excreted to time infinity, and may not accurately predict the percentage retained, when that estimate is also based on 1 vs. 7 days of observations. Although these estimates may influence the absolute estimate of oral bioavailability, they are less likely to influence the relative estimates of aluminium bioavailability from water compared to that from food; this is discussed below.

The first human studies attempting to estimate oral aluminium bioavailability utilized 27 Al. These were balance studies, in which aluminium absorption was estimated from the difference between intake and faecal excretion. Aluminium retention was estimated from the difference between intake and faecal-plus-urinary excretion. However, it has become apparent that the percentage of aluminium that is orally absorbed is quite low (as noted in the animal studies above and more recent human studies, below). Therefore, studies using these methods are not considered reliable, as discussed above.

There are no good experimental data from which one can estimate aluminium bioavailability from atmospheric sources. A Standard Reference Material containing urban particulate material collected over more than 12 months near St. Louis, MO, that was thought to be representative of an atmospheric sample obtained from an industrialized urban area, was fractionated. Approximately 0.6% of the aluminium was in the exchangeable metal ion fraction ( Lum et al., ). About half was bound to iron-manganese oxides and half was organically-bound metal ions. Absorption of 3% of the aluminium in the lung to blood was adopted ( ICRP, ) according to Jones & Bennett () , but they note: &#;there is as yet no firm basis for this estimate&#;.

The absorption of aluminium from the lung can be estimated from a few studies of occupational aluminium exposure. Daily urinary aluminium excretion by 12 aluminium welders, whose lung aluminium burden may have been approaching a steady state, averaged 0.1 mg. Daily aluminium deposition into their lungs was estimated to be 4.2 mg. This would suggest absorption of ~ 2.4% of the aluminium ( Sjögren et al., ). The site of absorption cannot be ascertained from such data. Results from workers exposed to ~ 0.2 to 0.5 mg soluble Al/m 3 in the air (particle size not described) suggest ~ 2% absorption ( Pierre et al., ). Fractional absorption was similar in the workers in a second study ( Gitelman et al., ) who were exposed to a similar air aluminium concentration containing 25% respirable (< 10 μm diameter) aliminium. The urinary aluminium/creatinine ratio correlated better with respirable than total aluminium. However, fractional absorption was inversely related to air aluminium concentration (H.J. Gitelman, personal communication, ). These workers showed a better correlation between urinary aluminium excretion (which reflects absorbed aluminium) and respirable aluminium, than total aluminium ( Gitelman et al., ). These results suggest that the smallest aluminium particles that can distribute to the deepest part of the lung are best absorbed and suggest that absorption is from the pulmonary rather than GI route. The estimate of 26 Al absorption from inhalation of 26 Al oxide particles which had a MMAD of 1.2 μm by two subjects was 1.9% ( Priest, ).

One hundred and fifteen newly employed potroom workers, who had no previous history of work in an aluminium industry, were followed for 36 months. Monthly determinations of airborne aluminium in the first 18 months ranged from 0 to 2.145 mg/m 3 , with monthly medians ranging from 0.001 to 0.173 mg/m 3 . Forty-four percent of the total inhalable aluminium was in the respirable fraction, compared to previous determinations by this group of 52 and 87% in two potrooms of an established plant ( Rollin et al., ). Prior to employment in the potroom, workers&#; mean serum aluminium concentration was 3.37 μg/L. The serum aluminium level increased steadily during the first 12 months to a mean of 6.37 μg/L and did not appreciably increase further during the next 24 months. Smokers had higher serum aluminium levels than non-smokers. The mean urine aluminium level before employment was 24.2 μg/L; after 36 months of employment it was 49.1 μg/L.

Occupational exposure to aluminium fumes, dusts and flakes has been shown to produce elevated levels of urine aluminium and, less frequently, elevated levels of serum and bone aluminium. Workers involved in the electrolytic production of aluminium for an average of 3.8 years, the production of aluminium powder for 10.2 years, the production of aluminium sulphate for 7.4 years, and in aluminium welding for 10.7 years, and a group of patients with renal failure who were receiving dialysis, were compared with a referent group ( Sjögren et al., ). The dialysis patients had the highest plasma aluminium concentrations. All of the aluminium workers, except those involved in electrolytic aluminium production, had significantly higher serum aluminium levels than the referents. All aluminium workers had significantly higher urine aluminium than their referents. Serum and urine aluminium concentrations were positively correlated. Workers&#; plasma and urine aluminium concentrations were higher after a work shift compared to those before the shift and higher on a Friday than on a Monday ( Mussi et al., ). Plasma and urine aluminium levels increased more after exposure to comparable concentrations of fume than dust ( Mussi et al., ). Although the particle sizes were not reported, it is likely that those of the dust were larger than those of fume, the mass median diameter of which was ~ 0.4 μm ( Sjögren et al., ). End-of-shift urinary aluminium concentration correlated well with environmental aluminium concentration. The increase in urinary aluminium level was greater from inhalation of aluminium fumes than from the slightly lower concentrations of aluminium in dust. It is not known if inhalation exposure results in absorption across the lungs, from the GI tract after mucociliary clearance of material from lung to stomach, and/or via the olfactory tract. It is suggested above (see Toxicokinetics, Absorption, Animal Studies, Inhalation Exposure / Intranasal) that absorption from the GI or olfactory tracts is unlikely to account for aluminium absorption after inhalation exposure. Three previously unexposed volunteers and six welders were exposed to welding fumes containing ~ 39% aluminium, as aluminium oxide ( Sjögren et al., ). The industrial exposures varied from 0.3 to 10.2 mg Al/m 3 with a mean 8 hr TWA value of 2.4 mg Al/m 3 . The urinary aluminium level in one volunteer, who had no previous aluminium exposure and who was exposed to an 8 hr TWA of 7 mg Al/m 3 , showed an increase to ~ 50 μg Al/L, and then 375 μg Al/L, 12 and 24 hr, respectively, after initiation of inhalation. Urinary aluminium levels in the 3 volunteers increased from < 3 μg Al/L before, to > 100 μg Al/L after, exposure ( Sjögren & Elinder, ). The t ½ of the first phase of elimination was estimated to be ~ 8 hrs. One welder, who had been exposed for one month, had a urinary aluminium concentration of ~ 40 μg/L during a week of exposure to ~ 1.5 mg Al/m 3 ~ 7 hr daily. Another welder who had been exposed for 19 years had a urinary aluminium concentration of ~ 300 μg/L during a week of exposure to an 8 hr TWA of 0.5 mg Al/m 3 ( Sjögren & Elinder, ). These results suggested pulmonary absorption. The authors estimated that ~ 0.1 to 0.3% of the inhaled aluminium appeared in urine within a few days ( Sjögren et al., ). Twenty-five MIG welders exposed to a median of 1.1 mg Al/m 3 over periods of 0.3 to 21 years had a median urine aluminium concentration of 82 μg/L (54 mg/kg creatinine). After a period of 16 to 37 days of non-occupational aluminium exposure, the urine aluminium level was 29 μg/L (29 mg/kg creatinine) ( Sjögren et al., ). Comparison of urinary aluminium concentration in 23 of the welders before and after the exposure-free interval showed that it correlated with the aluminium exposure level before the exposure-free interval whereas, after the exposure-free interval, it related to duration of occupational exposure ( Sjögren et al., ). The bone aluminium concentration was 18 to 29 mg/kg in two welders after 20 and 21 years of exposure compared to 0.6 to 5 mg/kg in referents, illustrating retention of absorbed aluminium ( Elinder et al., ). The mean urine aluminium level of 15 workers in an aluminium fluoride plant exposed to a mean of 0.12 mg Al/m 3 was 12 μg/L, of 12 potroom workers in an aluminium smelter exposed to a mean of 0.49 mg Al/m 3 was 54 μg/L and of 7 foundry workers in the aluminium smelter exposed to a mean of 0.06 mg Al/m 3 was 32 μg/L; that for the 230 controls was 5 μg/L ( Drabløs et al., ). Due to inter-individual variability, these were not significant differences. However, there was a significant correlation between weekly mean aluminium concentration in air and weekly average urine aluminium excretion. Aluminium exposure in the aluminium fluoride plant was mainly from aluminium hydroxide and aluminium fluoride. Exposure in the smelter potroom was mainly from aluminium oxide and partly from aluminium fluoride and, in the foundry, from aluminium oxide and partly from oxidized aluminium metal fume. Although urine aluminium concentrations were poorly correlated with changes in serum aluminium, urinary aluminium and fluoride concentrations were significantly correlated in 8 cryolite workers ( Grandjean et al., ). Thirty-three foundry workers who worked as smelters, die casting operators, fettlers and sand casters were exposed for 1 to 17 (median 7) years to aluminium in dust and fumes. The exposure concentrations for the smelters, die casting operators and fettlers averaged 0.17, 0.027, and 0.58 mg/m 3 , respectively. These workers had a significantly higher mean serum aluminium than controls (16 compared to 11.3 μg/L) and non-significantly higher urine aluminium concentrations (18.93 vs.12.90 μg/L) ( Rollin et al., a ). However, the serum aluminium concentration in the control group was considerably greater than the concentration now considered to be normal, 1.6 μg/L ( Nieboer et al., ; Roider & Drasch, ).

There is one reported study that quantified aluminium absorption following i.m. injection. Flarend et al. () prepared 26 Al hydroxide and 26 Al phosphate adjuvants (which did not contain allergens) and 26 Al citrate. Two rabbits were given i.m. 26 Al hydroxide, 2 rabbits were given 26 Al phosphate adjuvant and 1 rabbit was given i.v. 26 Al citrate. In the first 2 days, 40% more 26 Al was absorbed from 26 Al hydroxide than from 26 Al phosphate. Within the first 28 days, 17% of the 26 Al from aluminium hydroxide and 51% of the 26 Al from aluminium phosphate was absorbed, when compared to the area-under-the-curve for the aluminium citrate. This is based on the assumption that the much greater (300-fold) peak blood aluminium seen after aluminium citrate injection than after adjuvant injections does not confound this interpretation. The authors suggested that all of the injected aluminium may eventually be absorbed. Therefore, 100% of aluminium may eventually be absorbed from muscle, even from insoluble aluminium species. Peak aluminium concentrations following absorption from the i.m. route are lower than from oral and inhalation of small particles due to the prolonged time course of i.m. aluminium absorption.

Rats exposed to lipophilic aluminium acetylacetonate under conditions designed to maximize inhalation via the nasal-olfactory system had elevated levels of aluminium in the brain ( Zatta et al., ). Aluminium was seen in the olfactory bulb, cortex, hippocampus, and entorhinal area, and also in the cerebellum, which is not within the olfactory pathway. Exposure to aluminium via deposition into the nasal cavity from which it might be absorbed may be relevant to environmental exposures, although such exposures are most likely to be from aluminium silicates in airborne dust, which contains very little aluminium in the exchangeable metal ion fraction, as noted below ( Lum et al., ). This exposure route may also be relevant to occupational settings, such as those of potroom workers, welders and of workers exposed to suspended aluminium particles. Although the study of aluminium chlorohydrate inhalation may involve a route of exposure and chemical species of aluminium relevant for the human, these studies do not model human exposure to typical aluminium species in the environment or workplace. Furthermore, these studies provide no information on the percentage of aluminium introduced into the nasal cavity that might, in turn, be taken up into the brain, which may be very small based on studies with manganese and cocaine ( Chow et al., ; Dorman et al., ).

In a second study designed to address the possibility that aluminium can enter the brain from the nasal cavity, rats were exposed by inhalation to 20.6 μg aluminium chlorohydrate/m 3 via nose-only exposure 6 hr/day for 12 days. The aluminium chlorohydrate was from a commercial source (Pfaltz & Bauer) and was delivered as aerosols generated by a venturi powder dispenser. Although particle size distribution was determined several times during the study, the results were not reported. The rats had a significantly greater aluminium concentration in the olfactory bulb, determined by PIXE, than in non-olfactory brain regions. Aluminium was not seen in the brain of rats that received similar non-aluminium exposures ( Divine et al., ). Four tissue samples from olfactory bulbs, with 8, 7, 13 and 7 aluminium sites, had average aluminium concentrations of 3.0, 3.8, 7.0, and 2.1 mg Al/kg, respectively. Four brain regions considered non-olfactory bulb associated, i.e., brain stem nuclei in the region of the substantia nigra, had 2, 1, 3 and 2 aluminium sites and average aluminium concentrations of 0.7, 0.5, 1.0, and 0.6 mg Al/kg, respectively. The average aluminium concentration and number of aluminium sites were shown to be significantly different by Student&#;s t test.

In the initial study to assess whether aluminium can enter the brain from the nasal cavity, Perl & Good () implanted Gelfoam® containing 0.5 mL of 15% aluminium lactate, 5% aluminium chloride, or 15% sodium lactate into the nasal recess of rabbits. The Gelfoam® remained in place for 1 month. Neuropathological changes and elevated aluminium were seen in the olfactory bulb, piriform cortex, hippocampus and cerebral cortex, but not in cerebellum, brainstem or spinal cord. However, this exposure protocol is not realistic with respect to potential human exposure. There is concern that Gelfoam® implants containing such a high aluminium concentration in the nasal cavity for 1 month could damage the nasal epithelia ( Lewis et al., ). Perl & Good () suggested that a defect in the normally effective olfactory mucosa/olfactory bulb barriers may lead to excessive aluminium exposure. Their experimental conditions may have produced such a defect, which may not be present or as prevalent in the normal condition. Although this study has been frequently cited, it has not been replicated.

An alternative route from the nasal passage has been proposed, that is exposure via the CSF. In this case, delivery would be from diffusion of the compound through the perineural fluid around the olfactory nerve through the cribriform plate. However, it is not clear if this pathway can mediate distribution from the nasal cavity into the brain as it has been primarily described as a route of drainage from the CSF compartment to the nasal lymphatics ( Jackson et al., ; Kida et al., ). If a compound could diffuse by this route from the nasal cavity into the CSF, it would be expected to initially distribute through the subarachnoid space and over the cortical surface.

The potential for delivery of compounds to the CNS from the nasal cavity via the olfactory neuron has been proposed. The strongest supporting data have been obtained with manganese (Mn) ( Tjälve et al., ). There is little evidence supporting similar transport of other metals, such as cadmium, nickel, and mercury. For a review see Tjälve & Henriksson () . Anatomically, the olfactory system as a route of delivery to the brain is intriguing as well as problematic for interpretation. The olfactory receptor neurons are the first-order neurons located within the nasal cavity in the olfactory epithelium. Their cell bodies lie in the basal two thirds of the epithelium. Several cilia extend from each cell into the mucous layer of the epithelium. These cells are separated and partially ensheathed by supporting cells of the olfactory epithelium. The axons of these neurons project via the olfactory nerve (the first cranial nerve) to the olfactory bulb and synaptically terminate on the mitral and tufted cells. These cells then relay via neurotransmitter synapses to higher order olfactory structures and to other brain systems. Such neurotransmitter target sites include the olfactory peduncle, the piriform cortex, the olfactory tubercle, the entorhinal cortex, and some amygdaloid nuclei. Projections are made from these primary olfactory cortical structures to other brain regions. While this distinct anatomical pathway exists, to serve as a direct route of exposure to the brain would require the axonal transport of the material of concern as well as the trans-synaptic transport from one neuron to the next within the pathway.

A few studies were conducted to assess aluminium absorption through the skin of mice. However, a number of concerns about these studies reduces confidence in the authors&#; interpretations. Anane et al. () applied 20 μL of a 0.025 or 0.1 μg aluminium chloride/mL solution to 4 cm 2 of skin (0.1 and 0.4 μg/day) on the dorsal shaved surface of mice for 130 days. The total aluminium applied during this time (0.5 to 2 mg/kg) is comparable to a one day aluminium exposure of humans using topical antiperspirants. Twenty-four hr urine samples were obtained starting 1 day after completion of aluminium dosing. Blood and brain samples were also obtained. A statistically significant increase was reported in urinary and serum aluminium concentrations after both aluminium exposures, compared to those for non-exposed mice of the same age. This suggests that a small fraction of the typical human use of a topical antiperspirant might produce a measurable increase in urine and tissue aluminium levels. Increases in brain aluminium levels were 19 to 124% over controls. The aluminium concentration in the hippocampus was reported to be 2 to 3 times the rest of the brain in controls and aluminium-exposed mice. This could be an artifact of aluminium contamination, which would be more pronounced in a smaller sample (hippocampus) than in the rest of the brain. Dermal exposure of mice pups from 2 to 22 days of age to 0.025, 0.05 or 0.1 μg aluminium chloride/cm 2 increased their brain aluminium levels by 5 to 24%. Using X-ray energy scanning electron microscopy, the authors reported 11 to 120-fold more aluminium in the hippocampus of treated mice than in those of controls, whereas atomic absorption spectrometric analysis of aluminium showed a 1.6 to 2.2-fold increase. Absorption of aluminium, applied as aluminium chloride, to mouse skin in vitro, was determined in a &#;static&#; culture system. Increased aluminium was observed in the compartment that modelled sub-dermal fluid. In a similar study, pregnant mice received dermal application of 0.4 μg aluminium chloride daily for 20 days ( Anane et al., ). Aluminium levels in maternal serum, amniotic fluid and foetal brain, kidney, and liver were all reported to be statistically increased, by 63, 21, 4.5, 5.0 and 15%, respectively, compared to controls. There is no mention in either report of methods to prevent absorption by non-transcutaneous routes. The aluminium solution was applied over a 4 cm 2 area on the back, which represents about 12% of the total body surface area of the mouse. It is quite possible that grooming produced oral aluminium exposure. A 20 g mouse receiving a total of 2 mg Al/kg would receive 0.04 mg of aluminium. Retention of 5 × 10 -5 of the administered aluminium by each gram of brain, as has been reported after i.v. aluminium injection (see Toxicokinetics, Distribution (Including Compartmentalization), Animal Studies, Central Nervous System), which corresponds to 100% bioavailability, would raise brain aluminium levels by 2 × 10 -3 mg Al/kg (2 ppm). The reported increase of brain aluminium was 18 × 10 -3 mg Al/kg, suggesting > 100 % bioavailability, and therefore casting further doubt on the validity of these findings. There is a low degree of confidence in the results and interpretation of this work.

Aluminium poorly penetrates the skin. In a study claimed to be the only report to that time on penetration of aluminium salts through excised skin, it was concluded that minimal aluminium reached the dermis following topical exposure. Abdominal and axillary human skin, 3 cm 2 , was exposed for up to 23 hr to 5 mL of 20% aluminium chlorohydrate, which would have contained ~ 280 mg aluminium. A 10 mm disk of the exposed skin contained &#; 7 μg aluminium. Removal of the stratum corneum (the outer layer of the skin that is 25 to 35 μm thick) by stripping with adhesive tape resulted in no greater aluminium penetration into the dermis. The authors noted that very little aluminium reached the dermis, the region of the sweat glands. They attributed the low penetration to binding of unknown aluminium complexes to the outer stratum corneum layers ( Blank et al., ). Stripping the stratum corneum with tape restored 50% of the function of sweat glands that had been inhibited by aluminium chlorohydrate, suggesting its site of action is quite shallow ( Quatrale et al., a ). More, ~ 2/3, of sweat gland function inhibited by aluminium zirconium chlorohydrate glycine complex was restored by stripping whereas removal of the stratum corneum did little to reverse the effects of aluminium chloride, suggesting it may have penetrated deeper into the sweat duct ( Quatrale et al., a ). TEM and morin stain techniques suggested that aluminium chlorohydrate collected in sweat ducts at the layer of the stratum corneum to completely fill the duct as an amorphous mass ( Quatrale et al., b ; Quatrale, ). Sorption, defined to include both adsorption (onto) and absorption (into) the stratum corneum, of unbuffered aqueous solutions of 50% aluminium chlorohydrate at pH 5 to 5.2, or aluminium chloride atomic absorption standard reference solution at pH 3.45 to 4.16, was rapid to guinea pig stratum corneum in vitro ( Putterman et al., ). Desorption of aluminium chloride was more rapid than aluminium chlorohydrate. The latter was essentially irreversibly bound to the stratum corneum, suggesting that aluminium might not be able to be absorbed through the skin. Hostynek et al. () concluded that the avid formation of aluminium complexes with skin proteins precludes all but very shallow penetration of the epidermis.

Aluminium salts are extensively used in antiperspirants because they suppress eccrine sweating more effectively than other metal salts ( Hostynek et al., ). They are thought to be effective because either they become neutralized in the sweat duct to form a gelatinous or flocculant hydroxide precipitate, or because they denature keratin in the cornified layer that surrounds the opening of the sweat duct. Both mechanisms predict that little aluminium would be absorbed through the sweat duct ( Hostynek et al., ).

Aluminium salts precipitate proteins and have astringent properties. This has led to their use to treat urinary bladder haemorrhage, diaper rash and prickly heat, insect stings and bites and athlete&#;s foot, and use in styptic pencils and products for dermatitis (Tinea pedis); in anti-diarrheal products and vaginal douches and as a keratolytic in anorectal preparations ( Allen et al., ; Knodel et al., ) (see also Sources of Human Exposure, Anthropogenic Sources, Uses and Table 6 ).

The chemical speciation of aluminium, consumed in beer, as it passes through the upper part of the GI tract was modelled by ( Sharpe et al., ). The citrate concentration in beer exceeded the aluminium concentration, resulting in the predominant aluminium species in lager, the mouth and stomach being aluminium citrate. In the duodenum and jejunum, where the pH is ~ 6.5, the predicted predominant species was aluminium phosphate. This is the primary site of aluminium absorption. At pH 7, neutral aluminium species exceeded charged and &#;solid&#; (insoluble) aluminium species at total aluminium concentrations below μg Al/L, which is well above the median aluminium concentration in the beers studied (100 μg Al/L).

Lower serum aluminium concentrations resulted from portal vein than from i.v. injections of the same aluminium dose, as the sulfate, to rats, indicating significant first-pass pre-systemic clearance of aluminium by the liver ( Xu et al., a ). These results suggest that determination of aluminium absorption based on area-under-the-curve calculations from multiple blood/serum aluminium determinations over time might underestimate absorbed aluminium, although this method estimates the aluminium that reaches systemic circulation and is available for distribution to organs such as the brain.

Tf addition to the medium vascularly perfusing an intestinal preparation increased aluminium uptake, suggesting it facilitated entry of aluminium, introduced as the chloride, into blood, perhaps from intestinal cells ( Jäger et al., ). It has been suggested that Tf mediates aluminium release from mucosal cells into blood ( Greger & Sutherland, ). There is no single unifying explanation for these results. It is probable that there is more than one mechanism of aluminium uptake, which might be aluminium species-, pH- and intestinal region-dependent. Multiple mechanisms would account for the lack of ability of manipulations to totally block aluminium uptake, and perhaps the significant results obtained by some, but not other, investigators.

Some evidence suggests a role for sodium transport processes. Low sodium and amiloride, a sodium uptake blocker, increased the uptake t ½ of aluminium ( Provan & Yokel, a ). In contrast, Van der Voet & de Wolff (a) found a negative interaction between sodium and aluminium uptake. Further study by Van der Voet & De Wolff () showed that the presence of calcium, but not sodium, reduced aluminium uptake. The presence of both calcium and sodium attenuated the calcium effect, leading the authors to speculate: &#;&#; aluminium attempts to mimic calcium in its Na-related intestinal passage&#;.

It has been suggested that citrate facilitates aluminium absorption by opening the tight junctions between GI mucosal cells, by chelating calcium, which is required for tight junction integrity, and that the aluminium is absorbed as aluminium citrate ( Froment et al., b ). This mechanism of enhanced aluminium absorption was favoured by Taylor et al. () . However, they found peak serum citrate concentrations 31 to 32 minutes after aluminium citrate consumption, whereas aluminium concentrations peaked at 77 to 108 minutes, suggesting that aluminium was not absorbed as aluminium citrate due to the faster absorption of citrate and was not released into blood as aluminium citrate ( Taylor et al., ).

Aluminium, like most substances, is better absorbed from the upper intestine than from the stomach. The stomach is lined by a thick, mucus-covered membrane. It has a much smaller surface area than the intestine. The primary function of the stomach is digestive, whereas that of the intestine in absorptive. Ionized molecules are usually unable to penetrate the lipid bilayer of cell membranes due to their low lipid solubility ( Benet et al., ). As aluminium would be expected to be present primarily as the free ion, with associated waters of hydration, at the low pH of the stomach, non-carrier-mediated absorption would not be predicted from the stomach. Studies with in vivo isolated duodenal segments suggested aluminium uptake at pH 2 was due to both an aluminium-concentration-dependent non-saturable process and a saturable process that is at least partially vitamin D dependent, suggesting that aluminium may compete with calcium ( Adler & Berlyne, ). Uptake of aluminium from the citrate into stomach sacs was much less than into small bowel and colon ( Whitehead et al., ). Plasma aluminium concentrations peaked 45 minutes after oral citrate intake by rats ( Froment et al., a ; b ). They observed a simultaneous peak of plasma aluminium and glucose and concluded that the site of aluminium absorption is probably the proximal small intestine ( Froment et al., b ). The lower pH of the proximal duodenum would be expected to result in greater aluminium absorption than more distal intestinal segments ( Greger & Sutherland, ).

The most ambitious study of the influence of beverages and foods on oral aluminium absorption was conducted by Walton et al. () . This is a non-peer reviewed report of a study in which large sample sizes were not used. However, an issue that has not been well investigated was addressed. They exposed anesthetized rats to 2 mL of water containing no aluminium, or 8 mg aluminium as aluminium sulphate and/or various beverages and foods by gastric administration. Blood was obtained from the tail, prior to and 1, 2, 3 and 4 hr after, dosing. Urine was obtained, at the same times after dosing, by needle aspiration from the bladder. Considering the short period of observation (4 hr), serum aluminium is probably a better indicator of absorbed aluminium than is aluminium excreted in the urine. Administration of 8 mg aluminium in water increased peak serum aluminium about 4.5-fold and produced a urinary aluminium concentration of 2.6 μg/L. Co-administration of orange juice, coffee and wine with the aluminium significantly increased peak serum aluminium levels, compared to administration of aluminium alone, approximately 17-, 2.5-, and 1.9-fold, respectively. Serum aluminium peaked at 1 hr when given alone. The time of peak serum aluminium in the presence of co-administered foods was not reported. Therefore, it is not known if the rates of aluminium absorption are similar and, as a result, if the 4 blood samples obtained represent similar time profiles of the aluminium absorbed. Urinary aluminium concentration increased approximately 10.5-, 1.3- and 1.8-fold when these three beverages were co-administered with aluminium. Meat and Vita Wheat® biscuits (a carbohydrate/cereal product) significantly attenuated the elevation in serum aluminium caused by aluminium dosing to 62 and 65%, when compared to administration of aluminium alone. Urinary aluminium was attenuated by these two foods to 45 and 57%. These foods were available for 36 hr prior to their co-administration with the aluminium, to &#;load the gastrointestinal tract with the single food and its breakdown products.&#; In contrast, no food was available for 36 hr prior to aluminium alone or beverage (plus aluminium) dosing. In preliminary studies, the investigators found food in the stomach 24 hr after removal of food access, so they went to 36-hr food deprivation. They did not verify the lack of stomach contents after 36-hr food deprivation. As noted above, this does not assure the lack of stomach contents. Co-administration of beer, Coca-Cola®, tea, apple, broccoli, butter and margarine produced non-significant effects. Co-administration of both orange juice and Vita Wheat® with aluminium resulted in an increase of serum aluminium levels of 9.1-fold, an attenuation of the result seen with orange juice alone, but urine aluminium concentration was not attenuated by the addition of Vita Wheat® to the aluminium plus orange juice administration. No definitive conclusions can be made from this study. The results from co-administration of coffee and wine, which slightly increased serum and urine aluminium levels, and meat and the cereal product, which decreased serum and urine aluminium levels, suggest that co-administration of certain foods with drugs or foods that contain significant amounts of aluminium warrants further study.

In contrast to the above hypothesis, Reiber et al. () suggested that a substantial portion of aluminium, regardless of the form consumed, will be solubilized to monomeric aluminium in the stomach. They based this on studies showing solubilization of aluminium from particulate and colloidal sources within 2 hr at pH 1 to 2 and the average residence time in the human stomach, which has a pH of 1.5 to 2, of 1 to 4 hr. They concluded: &#;&#;the often raised issue of the relative bioavailability of the aluminium source would seem to be a moot point&#;, because &#;Regardless of the consumptive form, the bulk of aluminium will be converted to monomolecular species in the stomach&#; As they claimed that the stomach is impervious to charged species, they concluded: &#;In a healthy stomach, however, it is unlikely that any free or complexed aluminium can be absorbed across the stomach wall.&#; They claimed that the pH of stomach contents rapidly rises to 6.2 when in the duodenum, and then to pH 7.3 after leaving the duodenum. Because the nadir of aluminium solubility, due to aluminium hydroxide formation, is at pH 6.2 ( Harris et al., ), they suggested: &#;&#;more than 99.9 percent of the consumed aluminium should ultimately be excreted in the stool as an aluminium hydroxide precipitate, leaving less than 0.1 percent available for uptake&#;, explaining why only a small percentage of oral aluminium is absorbed ( Reiber et al., ). They recognized that this scenario is simplistic. However, at the pH of the human intestine, ~ 6.8, the major aluminium hydroxide species which would be formed in the absence of other ligands to associate with aluminium would be the soluble Al(OH) 4 - ( Harris et al., ), suggesting a lower percentage of precipitated aluminium than stated by Reiber et al. () . If studies utilizing large doses of 27 Al are not considered, there is very little data relevant to comparative oral aluminium bioavailability for different aluminium forms to test the suggestion of Reiber et al. () .

In a subsequent study, rats drank water containing 0, 10, 50 or 500 mg Al/L, introduced as the chloride, for 9 weeks while consuming a diet containing 5 mg Al/kg ( Glynn et al., ). Bone aluminium increased above control concentrations in the rats drinking the waters containing the higher two aluminium concentrations. In vivo fractionation of the stomach contents of these rats showed an increase of dissolved aluminium as water aluminium concentration increased, up to 50 mg Al/L, and the appearance of measurable quickly reacting aluminium species in those exposed to 500 mg Al/L. The authors interpreted their results as supportive of their hypothesis that aluminium absorption will increase when the aluminium-binding capacity of food in the stomach has been saturated. When compared to typical drinking water aluminium concentrations of 50 to 100 μg Al/L, these results suggest that aluminium would not be absorbed when stomach contents are present, as the aluminium binding capacity would not be saturated. This is not supported by several studies utilizing 26 Al in much lower aluminium doses than employed by Glynn et al. () . These studies found oral aluminium absorption in the presence of stomach contents ( Drüeke et al., ; Jouhanneau et al., a ; Yokel et al., b ).

It has been suggested that the chemical species of aluminium in drinking water in the absence of fluoride would be primarily labile, monomolecular Al(H 2 O) 6 below pH 5 and Al(OH) 1 to 4 +2 to -1 at higher pHs ( Lazerte et al., ). In the presence of fluoride (1 ppm; 53 μM), AlF 2 + and AlF 3 would be expected at pH < 6.5. At higher, pHs mixed Al(OH) x F y complexes or Al(OH) 4 - would be expected ( Nieboer et al., ). It is thought that these species would favour aluminium absorption from drinking water compared with that from food ( Martyn et al., ) in which aluminium is presumed to be bound to phosphorus-rich compounds such as phytates and casein, a phosphoprotein ( Glynn et al., ). Glynn et al. () determined soluble and quickly reacting aluminium species (presumably species that might be absorbed) in the presence of 4 mg Al/L, the chloride, added to simulated gastric contents containing 40% rat feed. Less than 50% of the added aluminium was in the soluble fraction. As nearly 100% would be expected to be labile species (Al +3 , monomeric hydroxo and sulphato complexes) under these conditions, the authors concluded that the labile aluminium rapidly complexed to components of food. They hypothesized that foods may alter aluminium absorption. The presence of food may change the pH. It has been suggested that food may bind aluminium, hence reducing its bioavailability. Therefore, it has been suggested that enhanced aluminium absorption may occur in the presence of an empty stomach, especially during periods of fasting. This has been discussed in Toxicokinetics, Absorption, Animal Studies, Oral Administration, Factors Influencing Oral Aluminium Absorption, Foods and Dietary Components. There is no strong evidence to support this notion.

The chemical form in which aluminium is administered can affect its absorption ( Cunat et al., ; Deng et al., ; Froment et al., b ; Schönholzer et al., ; Yokel & McNamara, ). As noted above in Toxicokinetics, Absorption, Animal Studies, Oral Administration, Factors Influencing Oral Aluminium Absorption, Carboxylic Acids, addition of citrate, which is believed to solubilize aluminium and perhaps open the paracellular pathway, increased oral aluminium bioavailability in many studies. Consumption by rats of diets for 18 days containing ~ 200 to 260 mg Al/kg diet as aluminium hydroxide, palmatate, lactate or phosphate, or aluminium hydroxide as a reagent grade chemical, or 2 different sources of desiccated gel, resulted in some significant differences in brain, bone and kidney aluminium concentrations ( Greger, ). For example, aluminium hydroxide raised brain aluminium more than aluminium palmitate and one form of aluminium hydroxide gel raised kidney aluminium levels more than another form but resulted in lower aluminium levels in the tibia. Using the in situ rat gut technique, significantly more aluminium appeared in the plasma after perfusion with the citrate, lactate, tartrate and gluconate forms of aluminium, whereas plasma aluminium was not elevated after perfusion with the chloride, nitrate, sulphate and glutamate forms ( Cunat et al., ).

Overall, results suggesting that food composition of the presence of food in the stomach significantly affects oral aluminium bioavailability have been obtained in a few studies ( Walton et al., ; Drüeke et al., ; Yokel & Florence, ) whereas another study did not find a significant effect of water quality or the presence of food in the stomach on oral aluminium bioavailability ( Yokel et al., b ).

It was speculated that the species of aluminium in the GI tract, which may be present as insoluble or soluble forms and associated with various ligands and, perhaps more importantly, the form of mucus and interaction of aluminium with mucus, vary as a function of time since food consumption and, perhaps, composition of the diet. This may result in variable amounts and composition of absorbable aluminium species, contributing to the variable results in relation to the effect of stomach contents on oral aluminium absorption.

It has been assumed that the presence of food in the stomach inhibits aluminium absorption, due to aluminium association with organic ligands in food. Only a few studies have directly addressed this hypothesis. The results do not consistently show an influence of food on aluminium absorption. Some of the studies of oral aluminium bioavailability that model aluminium exposure from drinking water restricted food access, whereas others did not. Rodents and rabbits recycle their faeces to increase essential nutrient absorption and usually have stomach contents 24 to 36 hr after food removal. Therefore, simply depriving the animal of food does not guarantee that there will be no stomach contents. In some studies, rats were dosed after a 16 or 24 hr fast ( Drüeke et al., ; Schönholzer et al., ), whereas in others free access to food was allowed ( Drüeke et al., ). Oral aluminium bioavailability in these studies ranged from 0.06 to 0.36%. The oral bioavailability of 26 Al, given in the absence of ligand, in rats that were deprived of food for 24 hr was 0.94% ( Drüeke et al., ). As stomach contents were found in rats deprived of food for &#; 24 hr, as noted above, it cannot be assured that there were no stomach contents in the rats in this study. In contrast, Yokel et al. (b) did not find a difference in oral 26 Al bioavailability, when the Al was given in the absence of ligands, in rats exposed to a procedure that resulted in no stomach contents compared to rats that did have chow in their stomachs. Similarly, the addition of calcium and magnesium carbonates, designed to simulate hard water, did not affect oral aluminium bioavailability ( Yokel et al., b ). Walton et al. () conducted an ambitious study to assess the influence of beverages and foods on the oral absorption of aluminium given as the sulphate, to produce alum in solution. Their results show increased peak serum aluminium concentrations and urinary aluminium excretion after co-administration of orange juice and, to a much smaller extent, coffee and wine. Meat and carbohydrate/cereal products decreased aluminium absorption. However, neither the blood nor urine samples obtained hourly for 4 hr after dosing enable determination of oral aluminium bioavailability.

It is unclear from animal studies whether age influences aluminium absorption. Comparison of blood and urine aluminium in weanling and growing rats after oral aluminium hydroxide administration led Olaizola et al. () to conclude that there is an inverse relationship between aluminium absorption and age. Rat brain aluminium concentration inversely correlated with age in control rats that were 21 days, 8 months and 16 months old ( Domingo et al., ), in contrast to most observations in the human (see Toxicokinetics, Distribution (Including Compartmentalization), Human Studies, Tissue Aluminium Concentrations, Brain). After consuming aluminium and citrate in drinking water for 6.5 months, elderly rats generally had higher concentrations of aluminium in liver, kidney, spleen, bone and testis than the young rats ( Gómez et al., ). In contrast, the brain aluminium concentrations were significantly lower in old than young rats ( Domingo et al., ). The results of these studies are not consistent. Furthermore, none of these studies directly addressed absorption. The differences seen could be due to distribution or elimination.

The results of one of two studies suggest that ethanol can affect the toxicokinetics of aluminium, but the mechanism is not known. Rats were given saline, 10% ethanol in drinking water, 25 mg Al/kg, as aluminium nitrate, by gastric intubation (i.g.) or 10% ethanol in drinking water and 25 mg Al/kg i.g. for 6 days/week for 6 weeks ( Flora et al., ). After the 6 weeks, aluminium concentrations were significantly higher in blood and liver (24 and 76%, respectively), and non-significantly higher in kidney and brain (28 and 31%), in the ethanol-and-aluminium-treated group compared to the group treated only with aluminium. The amount of ethanol consumed was not reported. If fluid consumption was typical for the rat, it would have been 10 to 12 mL/100 g/day. The ethanol-and- aluminium-treated group also showed significant differences from the aluminium-only-treated group with respect to δ-aminolevulinic acid dehydratase, zinc protoporphyrin, and glutamic oxaloacetic transaminase in blood; glutamic pyruvic transaminase in liver; δ-aminolevulinic acid in urine; and dopamine and homovanillic acid in brain. These effects were generally an accentuation of the aluminium effects. However, it is not known if the elevation of blood and liver aluminium levels was due to ethanol alteration of aluminium absorption, distribution or excretion. It is also not known if ethanol increased aluminium toxicity or if these effects were the result of the combined toxicity of these two agents. It has been noted that chronic ethanol ingestion compromises GI tract integrity ( Davis, ). The author speculated that it may increase aluminium absorption. Results of the combined administration of ethanol and aluminium in rats suggested that ethanol enhances the effects of aluminium, introduced as the chloride, but no information was provided to indicate if ethanol affected aluminium toxicokinetics ( Rajasekaran, ). However, daily gavage with a 30% v/v ethanol solution delivering 3 g/kg and 91.8 mg aluminium lactate/kg for 90 days did not significantly affect serum aluminium, compared to aluminium alone ( Kohila et al., ). There are no reports that assess directly the influence of ethanol on aluminium absorption, distribution or elimination.

Like iron, calcium (Ca) status impacts on aluminium absorption and accumulation. Dietary calcium deficiency increased the rate and extent of aluminium absorption, when introduced as the chloride, tissue aluminium accumulation, and aluminium-induced neuropathology in rats ( Provan & Yokel, ; Taneda, ). Increased calcium decreased aluminium uptake and its appearance in plasma in studies that used the rat everted gut sac and in situ rat gut technique, suggesting a common uptake mechanism for aluminium, introduced as the chloride, and calcium ( Cunat et al., ; Feinroth et al., ). Based on ionic radii, it is more likely that aluminium would compete with magnesium than with calcium. Although there is some evidence for aluminium-magnesium competition in vivo, this has not been well investigated.

It has been suggested, based on the very low concentrations of silicon in biological fluids, that it is very doubtful that a monomeric aluminium silicate species plays any significant role in the biological chemistry of aluminium, after the aluminium has been absorbed ( Harris et al., ).

There is evidence suggesting that increased dietary intake of silicon (Si)-containing compounds may reduce aluminium absorption and facilitate aluminium excretion. There are also studies that did not find an effect of silicon-containing compounds on aluminium absorption. Silicon is absorbed in the animal GI tract as monomeric silicic acid. It can react with aluminium to form hydroxyaluminosilicate species and slowly, but eventually, amorphous solids ( Birchall et al., ). This was thought to reduce aluminium bioavailability, as shown by reduced systemic aluminium absorption in fish ( Birchall & Chappell, ) and reduced oral aluminium absorption in humans (see Toxicokinetics, Absorption, Studies in Humans, Oral Administration, Factors Influencing Oral Aluminium Absorption, Silicon-Containing Compounds). Addition of sodium metasilicate to the diet was reported to reduce brain hippocampal aluminium accumulation in 28, but not 23, month-old rats ( Carlisle & Curran, ). The basis for the age difference is unknown. These results have not been independently replicated and are not considered reliable. Addition of 0.5 mM silicic acid to water from 5 days before to 4 hr after aluminium citrate dosing by oral gavage reduced aluminium in most tissues of rats ( Quartley et al., ). Rats drinking water containing 59 or 118 mg Si/L (as sodium silicate with 27% SiO 2 ) and receiving 450 mg aluminium nitrate nonahydrate injections 5 days weekly had less brain, liver, bone, spleen and kidney aluminium than rats not consuming silicon, suggesting that silicon-containing compounds may have reduced aluminium absorption and/or enhanced its elimination ( Bellés et al., ). However, as the molar dose of silicon consumed was considerably less than the dose of aluminium administered, the mechanism does not seem to be simply aluminium complexation by silicon. Drüeke et al. () did not find an effect of co-administered silicon dioxide and 26 Al on absorption of 26 Al given with citrate to rats after eating. It is possible that there was insufficient silicon in the presence of the food to compete with the citrate and interact with the aluminium to influence its bioavailability.

Aluminium can form a complex with the dietary long chain mono-unsaturated FA, oleic acid, but the stability of this complex has apparently not been described ( Krasnukhina et al., ; Lesnikovich et al., ). It appears aluminium does not complex with the saturated long chain FA stearate ( Ross & Takacs, ). No information was found on aluminium complexation with the dietary saturated long chain FA, palmitic acid, the long chain poly-unsaturated FAs, α-linolenic and arachidonic acids, and the long chain branched chlorophyll degradation products, phytonic and pristonic acids. Aluminium can form a 1:1 complex with phytic acid but the reaction is slower and less favoured thermodynamically than phytic acid complexation with divalent cations ( Evans & Martin, ). Insoluble aluminium-phytate complexes form at higher aluminium:phytate mole ratios ( Evans & Martin, ).

Ultrafilterable species may redistribute within the organism, particularly in the presence of reduced renal function. Quartley et al. () gave rats a single oral dose of aluminium citrate; 2, 4 and 24 hr later they found elevated aluminium in all tissues but the brain. The aluminium concentration decreased in most tissues from 2 to 24 hr, except for the bone, in which it increased. Citrate may have enabled redistribution of the aluminium into bone.

Citrate may enhance oral absorption and may also enhance distribution into and out of tissues as well as from the organism by renal elimination, in the presence of renal function, as suggested by ( Maitani et al., ). Citrate inhibited or produced only a small increase of aluminium uptake into neuroblastoma and human erythroleukemia cells ( Guy et al., ; McGregor et al., ; Shi & Haug, ).

Concurrent acute administration of 2 mmole aluminium with 2 mmole citric, gallic, chlorogenic, caffeic or protocatechuic acids resulted in a significant increase in rat blood aluminium 2 hr later only with citric acid. There was no effect on liver aluminium from any ligand, an increase of kidney aluminium with citric and chlorogenic acid, and an increase in tibial aluminium with all but chlorogenic acid ( Deng et al., ). Consumption by rats of a diet containing 16 mmole/kg of aluminium chloride and carboxylic acid resulted in no significant differences of aluminium in blood, liver, kidney or tibia; but an increase of aluminium in brain after citric and chlorogenic acids ( Deng et al., ). The very high aluminium concentrations reported in blood and tissues in the control subjects reduce confidence in these results.

Citrate may enhance oral aluminium absorption if there is sufficient citrate present to compete with other binding ligands for aluminium in the GI tract. Speciation calculations indicated that citrate would solubilize ~ 97% of aluminium in the stomach ( Glynn et al., ). Citrate is the major small molecular weight ligand for aluminium in plasma. Formation of aluminium citrate also enables the distribution of aluminium out of plasma, and may enhance aluminium elimination by the kidney in the presence of renal function. However, in the absence of renal function, citrate can significantly increase aluminium-induced toxicity, presumably by enhancing aluminium distribution out of the blood and the resultant tissue aluminium accumulation. However, the enhanced solubility of aluminium by citrate did not completely account for enhanced aluminium absorption ( Froment et al., b ). It has been suggested that aluminium citrate is sufficiently lipid soluble from pH 2.5 to 8 to be absorbed by diffusion ( Partridge et al., ). Taylor et al. () argued that the alkaline environment of the upper intestine could produce insoluble aluminium species, as the aluminium citrate species would not predominate at neutral and higher pHs. However, the typical pH of the human duodenum/jejunum ranges from 4.5 to 6.8, which is not alkaline. Furthermore, in the presence of equimolar aluminium and citrate, aluminium citrate-hydroxide complexes would predominate (W.R. Harris, personal communication, ). Alternatively, enhanced aluminium absorption may require sufficient citrate to activate another mechanism of aluminium absorption. Other hypotheses to explain the enhancement of aluminium absorption by citrate are the transport of aluminium citrate into mucosal cells, and citrate opening the tight junctions of the intestinal cells, as discussed in Toxicokinetics, Absorption, Animal Studies, Oral Administration, The Site and Mechanisms of Oral Aluminium Absorption.

The chemistry of aluminium interaction with citrate has been quite extensively studied ( Harris et al., ) (see also Identity, Physical and Chemical Properties, Analytical Methods, Physical and Chemical Properties, Properties of Aluminium Compounds). Citrate can complex aluminium, forming an electrically neutral 1:1 citrate:aluminium complex at pH 2 to 5 in the absence of great excess of citrate. At higher pHs, this complex deprotonates, with a pKa of ~ 4, to a complex with one negative charge held by a carboxylate group that is not involved in the aluminium citrate:complex ( Lakatos et al., ). More complex chemical species slowly form at higher concentrations ( Harris et al., ).

The chemical speciation of aluminium is known to be greatly influenced by pH ( Harris et al., ). The bioavailability of aluminium, to some extent, is influenced by the aluminium species. However, Reiber et al. () suggested that the human GI tract acts as a series of reactors. They predicted that, in the stomach, all aluminium would be converted to small molecular weight soluble species due to the predominance of the hydrated aluminium ion at pH 1 to 2. They suggested that, when the stomach contents enter the duodenum/jejunum where the pH increases to 4.5 to 6.8, all aluminium would be converted to hydroxides. They predicted uniform oral bioavailability of aluminium, independent of the chemical species of the aluminium consumed. However, this ignores the presence of ligands to compete with hydroxide to associate with aluminium at the site of absorption. Using the in situ rat intestine preparation with systemic and portal blood sampling, Van der Voet & de Wolff (-) found aluminium absorption to be higher at pH 4 than at pH 7, presumably due to generation of more soluble aluminium species. However, the predicted aluminium species at acidic pHs, in the absence of binding ligands, are Al(H 2 O) 6 3+ and Al(OH) 2+ ( Harris et al., ), which would not be expected to permeate the gut wall by diffusion. This is consistent with the assumed primary site of GI aluminium absorption, the upper intestine, discussed below (see Toxicokinetics, Absorption, Animal Studies, Oral Administration, The Site and Mechanisms of Oral Aluminium Absorption).

There is evidence of greater aluminium absorption from more soluble aluminium species. Aluminium borate, glycinate, hydroxide and sucralfate are much less soluble in water than aluminium chloride, lactate, nitrate and citrate and were generally less well absorbed (0.27, 0.39, 0.45 and 0.60 vs. 0.57, 0.63, 1.16 and 2.18%, respectively ( Yokel & McNamara, ). Similarly, aluminium hydroxide and sucralfate are less soluble at pH 3, 6 and 7 than aluminium lactate and chloride and were also less well absorbed (0.015 vs. 0.037%), based on urinary aluminium excretion ( Froment et al., a ).

Cefali et al. () studied aluminium absorption from Zeolite A ® , an aluminium silicate product, in dogs; they observed highly variable plasma aluminium levels during the control phase and a small increase of plasma aluminium as a result of the treatments. They did not use baseline-corrected data in their determination of aluminium pharmacokinetics. Therefore, one cannot have much confidence in these results.

The absorption of aluminium from aluminium citrate is greater than from aluminium hydroxide: 2.18 vs. 0.45% in the rabbit ( Yokel & McNamara, ), 1.49 vs. 0.015% and 1 vs. 0.1% in the rat ( Froment et al., a ; Schönholzer et al., ). Sucralfate, which, like aluminium hydroxide, is insoluble in water but soluble in acid and base, exhibits oral bioavailability comparable to that of aluminium hydroxide and lower than that of soluble aluminium species. Aluminium bioavailability from sucralfate in the rabbit was 0.6%, and was 0.63% from aluminium lactate, compared with 0.57 to 1.16% from aluminium chloride and nitrate ( Yokel & McNamara, ). In the rat, oral aluminium bioavailability was 0.015% from aluminium hydroxide and sucralfate, 0.037% from aluminium lactate and aluminium chloride, and 1.49% from aluminium citrate ( Froment et al., a ).

The bioavailability of aluminium from ingested aluminium hydroxide appears to be less than from the aluminium ion, based on studies using 27 Al. In the rabbit, 0.45% of aluminium as the hydroxide was absorbed compared with 0.57 to 1.16% from aluminium chloride and nitrate ( Yokel & McNamara, ). In the rat, 0.01% of aluminium from the hydroxide was absorbed compared with 0.037% from the chloride ( Froment et al., a ). Wilhelm et al. () could not detect aluminium absorption after an oral dose of 1 mg Al/kg, as aluminium lactate, illustrating the necessity of using large doses in bolus 27 Al dosing studies. Their estimate of 1% oral bioavailability, based on bone aluminium 17 days after oral aluminium dosing, would be an underestimate if any bone aluminium were eliminated within that time, although there may not have been significant bone aluminium elimination (see Toxicokinetics, Elimination and Excretion, Animal Studies, Elimination Rate).

Relevant published data on the oral bioavailability of aluminium species from drugs include the use of aluminium hydroxide as an antacid and phosphate binder; sucralfate as an antacid; aluminium lactate as a component in dental products for sensitive teeth; an aluminium silicate product, Zeolite A, which is an inducer of osteoblast proliferation; and aluminium in the presence of citrate. Some of the earlier work, conducted with 27 Al, was reviewed by Wilhelm & Ohnesorge () . Because of its poor absorption, use of large doses of aluminium was necessitated in studies of bolus 27 Al dosing to determine oral aluminium bioavailability. The chemical species of the aluminium, when given in large doses, particularly when the aluminium species has good buffering capacity, such as aluminium hydroxide, would not be expected to be totally affected by the normal chemical reactions in the gut. It is less likely that the series of chemical reactions in the gut that might produce comparable aluminium species irrespective of aluminium species ingested, as proposed by Reiber et al. () , would be relevant. Therefore, these studies might more closely reflect the absorption of the aluminium species introduced, albeit after very high doses, assuming there is no saturation of uptake processes.

The bioavailability of aluminium from selected foods has been estimated in the rat. 26 Al was incorporated into the synthesis of acidic SALP, used as a leavening agent in baked goods, and then incorporated into a biscuit. Basic SALP, used as an emulsifier in cheese, was incorporated into a processed cheese ( Yokel et al., ). When rats, that had no stomach contents, ate the biscuit containing acidic SALP, it was estimated that oral aluminium bioavailability was ~ 0.1%, significantly less than from water ( Yokel & Florence, ). Oral Al bioavailability from the cheese containing basic SALP was ~0.1 to 0.3% (Yokel et al., unpublished results). Comparison of oral Al bioavailability from these representative foods to that obtained from water (~0.3%) times the contributions of food and drinking water to the typical human&#;s daily Al intake (~5 to 10 mg from food and 0.1 mg from water, respectively) suggests food provides ~25-fold more Al to systemic circulation, and potential Al body burden, than does drinking water.

There are sufficient studies with reasonably similar results to estimate the oral bioavailability of aluminium from water. Those who suggest water may be a significant contributor of the aluminium body burden assume that aluminium in water is more bioavailable than the aluminium in food. Some recent data support this assumption, as presented in the next paragraph ( Yokel & Florence, ). Diet provides most of the human&#;s daily aluminium intake. Those who wish to allay any concern about drinking water as a source of aluminium suggest that the oral bioavailability of aluminium from food and water are similar ( Reiber et al., ) and have provided some data to support this conclusion ( Stauber et al., ).

Weanling rats fed 1 to 2.7 gm of Al/kg diet, added as aluminium hydroxide in the absence and presence of added sodium citrate dehydrate, were estimated to absorb 0.01 to 0.04% of the aluminium ( Greger & Powers, ). The percentage of aluminium absorbed was lower with the higher dietary concentration of aluminium as the citrate, in contrast to above studies, thereby showing a positive correlation between aluminium dose and fraction absorbed.

In an ambitious but not definitive study, Walton et al. () orally administered various beverages and foods to anaesthetized rats, in the absence of aluminium-treated water. Tail blood and urine, withdrawn by needle aspiration of the bladder, were obtained prior to, and 1, 2, 3 and 4 hr after, dosing. Considering the short period of observation (4 hr) serum aluminium is probably a better indicator of absorbed aluminium than is urinary excretion. Margarine and 8 mg of aluminium, as aluminium sulphate, increased serum aluminium levels. The aluminium content of the margarine was not determined. The other beverages and foods tested, beer, Coca Cola®, coffee, orange juice, tea, wine, apple, broccoli, butter, meat and Vita Wheat®, did not appreciably increase serum aluminium levels when administered alone. This is not surprising as the aluminium dose provided by these beverages and foods, which ranged from 0.005 to 8.6 μg, was &#; 0.1% of the 8 mg of aluminium in the 1 mL of water which produced an elevation of serum aluminium of 4 to 5-fold. Determination of relative oral bioavailability of aluminium from food and water was not the objective of this study. Little can be learned from these results concerning the oral bioavailability of aluminium from foods.

No increases in blood or liver aluminium concentrations were seen in rats which consumed tea as the only source of fluid for 28 days ( Fairweather-Tait et al., ). In one study, it was reported that increased tissue aluminium concentrations were attributed to the intake of aluminium in food. Guinea pigs that ate a test diet of sponge cake three times weekly for 3 weeks providing a total of 40 mg of aluminium, as acidic sodium aluminium phosphate (SALP) showed a significant elevation in bone aluminium concentrations compared with those that ate only guinea pig chow, which provided a total of 3 mg aluminium ( Owen et al., ).

It has been suggested that the aluminium in tea leaves has low oral bioavailability ( Glynn, ). In tea, 91 to 100% of aluminium is in organic complexes with a M r > 20,000. Even at pH 2, ~ 83% remained bound to the organic matter ( French et al., ; Gardner & Gunn, ). For example, a much lower percentage (15%) of the aluminium in tea was found to be in chemically labile species, compared with that in drinking water (61 to 75%) ( Stauber et al., ). Approximately 50% of aluminium in tea infusions was as soluble species, ~ 50% as non-labile monomeric aluminium species and a small fraction as labile monomeric aluminium, whereas > 90% of aluminium in tap waters was labile monomeric aluminium ( Chen et al., ). A large fraction of the aluminium in tea infusions was very strongly bound to unidentified ligands ( Alberti et al., ). Kralj et al. () found that ~ 10 to 35% of the aluminium in tea was negatively charged aluminium citrate. They thought the remainder was bound to phenolic compounds. Addition of citrate increased the negatively charged aluminium citrate species by up to 40% of total aluminium, whereas milk complexed most of the aluminium that was not associated with citrate to protein, mainly casein. The authors suggested that addition of citrate and milk protein would enhance aluminium absorption. Reiber et al. () suggested that a substantial portion of aluminium, regardless of the form consumed, will be solubilized to monomeric aluminium in the stomach and subsequently converted to poorly soluble aluminium species in the near neutral pH of the upper intestine. As the stomach is not an important site of aluminium absorption, this implies that oral aluminium bioavailability should be aluminium species independent. Citrate and other ligands influence aluminium absorption, suggesting that this hypothesis is an oversimplification.

Although food comprises the primary source (> 90%) of aluminium for the typical human (see Human Exposure, General Population Exposures, Food and Beverages), there are very few data on oral aluminium bioavailability from foods, or beverages other than water. The difficulties in estimating aluminium bioavailability from water using 27 Al, discussed above, apply to food. It has generally been assumed that oral aluminium bioavailability from food is less than that from water due to the aluminium being incorporated in high molecular weight, relatively insoluble, complexes ( Glynn et al., ).

There is some evidence that fractional absorption of aluminium is dose dependent in the fasted animal. Oral aluminium bioavailability in the rabbit dosed with 108 or 540 mg Al/kg, as aluminium lactate, was 0.7 and 1.9% ( Yokel & McNamara, ). Although not significantly different, these results suggest a positive correlation between aluminium dose and bioavailability. On the other hand, absorption of aluminium into rat blood and tissues after perfusion of the gut with 48 or 64 mM aluminium chloride at pH 3 was not concentration dependent ( Arnich et al., ).

The average daily intake of aluminium from drinking water for a 70 kg person is approximately 160 μg, or about 2.3 μg/kg b.w./day. Studies that best model oral aluminium bioavailability from drinking water meet two criteria. They use aluminium doses ~ 2 μg Al/kg b.w./day, which reasonably compares with daily oral aluminium intake from water by adult humans of ~ 2.3 μg Al/kg b.w./day, (see Human Exposure, Total Human Uptake from All Environmental Pathways (Combined Exposure) and Evaluation of Human Health Risks, Health Effects, Exposure Characterization) and they introduce the aluminium either as a chemical species that might be found in drinking water, that is, as the chloride, sulphate or hydroxide, which have the ability to release the free aluminium ion in solution, or they use water from municipal water supplies. As noted above, by necessity, all studies with 27 Al use aluminium doses much greater than 2 μg Al/kg. The use of 26 Al enables determination of oral aluminium bioavailability after administration of &#; 2 μg Al/kg.

In summary, there are sufficient studies in which 27 Al was utilized by many different research groups to investigate neurobehavioural endpoints or in which blood, urine and/or tissue aluminium levels were studied following controlled administration of 27 Al or 26 Al, to show that aluminium can be absorbed after oral administration. These studies also show that this route of exposure has the potential to produce toxicity. However, many of the studies with 27 Al were conducted utilizing supra-physiological exposures or doses of aluminium. This has led to the controversy of whether or not aluminium exposure, under normal conditions, has the potential to produce toxicity.

Application of accelerator mass spectrometry to quantify 26 Al has enabled study of aluminium toxicokinetics under physiological conditions. This method has been used since ~ . For example, in one study, 2 rats were given a single gastric administration of 26 Al in the absence of ligand during access to a normal diet; 2 rats did not receive 26 Al. Seven days later the 26 Al-treated rats had higher brain 26 Al levels than the controls ( Fink et al., ). In a second study by this group, using conditions that simulate drinking water, 8 rats were given a single gastric administration of 26 Al in the absence of ligand after 30 hr of no access to food; 2 rats did not receive 26 Al. Two weeks later, brain 26 Al concentrations of 2 of the 26 Al-dosed rats were comparable to those of controls (3 × 10 -9 of the 26 Al dose), whereas brain 26 Al in the other 6 26 Al-dosed rats ranged up to 100 times higher ( Walton et al., ). The large variability is disconcerting. These results were frequently cited as evidence supporting the hypothesis that aluminium in drinking water contributes to brain aluminium accumulation. Assuming that a comparable fraction of orally consumed aluminium reaches and is permanently retained by the human brain, Walton et al. () concluded that humans drinking alum-treated water (ATW) over seven to eight decades would have ~ 1 mg Al/kg wet brain. This is greater than normal levels of aluminium in the brain. On the other hand, these results could support the hypothesis that aluminium in drinking water does not contribute to brain aluminium accumulation if one uses the lowest brain aluminium level obtained after 26 Al dosing, or if aluminium is not permanently retained by the brain. Subsequent studies utilizing 26 Al, reviewed below, have clarified this issue.

In light of the evidence for oral absorption of aluminium presented in the paragraph immediately above, it must be assumed that there was insufficient aluminium absorbed in the studies described in the previous paragraph. Contributing to the lack of a significant increase of aluminium could be endogenous aluminium in the organism, contamination, and variability in the aluminium assay. The negative studies cannot be taken as proof of lack of oral absorption or as support for the null hypothesis that aluminium is not absorbed after oral administration.

On the other hand, in many studies, increased blood or tissue aluminium levels were not found after oral 27 Al administration. For example, rats consuming approximately 0, 0.01, 0.2 or 5.5 mg Al/kg/day in their drinking water, as aluminium chloride, in the absence or presence of acetate or citrate, failed to show an increase of aluminium in bone or brain ( Fulton et al., ). Consumption of 0.112 mg Al/day for 20 days by one baboon did not result in increased serum aluminium compared to a 10-day period of 0.06 mg Al/day consumption in the same animal ( Turnquest & Hallenbeck, ). This exposure level and duration were much smaller than in most other studies, so the negative result from this one animal is not informative. Prior to their report of 0.03% oral aluminium absorption from Zeolite A, Cefali et al. ( ; ) did not find significant aluminium absorption from Zeolite A, sodium aluminosilicate or aluminium hydroxide, containing 3.36, 0.90 and 27.8 mg Al/kg, respectively. Rats consuming drinking water containing 3.8 mg Al/L (as the chloride) for 10 weeks, and a diet containing 4 to 5 mg Al/kg, had no elevation of brain, bone or liver aluminium compared to those drinking water containing 0.05 mg Al/L ( Glynn et al., ). Tissue aluminium concentrations significantly decreased from 0 to 10 weeks after consumption of this diet, perhaps due to consumption of a diet containing more aluminium prior to the study, which might have masked any changes due to the consumption of aluminium in drinking water during the study. At the pHs of these drinking waters, 4.3 to 4.6, speciation calculations suggested 99% of the aluminium should be labile species, and therefore available for absorption ( Glynn et al., ).

In addition to elevations of serum or urine aluminium levels, numerous studies have shown increased levels of aluminium in the brain after oral 27 Al exposure, demonstrating oral aluminium absorption. Some examples follow. Rats and dogs were fed 300 or mg aluminium hydroxide daily in their food for 5 months. These animals exhibited a significant elevation of brain aluminium concentrations, compared to those not receiving the aluminium hydroxide ( Arieff et al., ). A significant elevation of brain aluminium was claimed after a single administration of oral aluminium hydroxide to mice ( Cutrufo et al., ), although these authors did not report their actual results. Rat bone, but not brain, aluminium was significantly elevated after consumption for 8 weeks of a diet containing 570 mg sucralfate/kg. Sucralfate is a sucrose aluminium sulphate complex. The consumption of aluminium was approximately 4 mg/kg/day ( Burnatowska-Hledin & Mayor, ). Consumption, by rabbits, of distilled water containing 0, 100 or 500 mg Al/L, introduced as aluminium chloride, for 12 weeks produced a positive correlation between aluminium exposure and aluminium in bone, stomach, intestine and kidney, but not in brain ( Fulton & Jeffery, ). Brain aluminium was significantly increased in rats after 90 daily oral doses of 30 or 100 mg/kg of aluminium chloride ( Bilkei-Gorzó, ). Consumption by mice of drinking water containing 400 mg Al/L (as aluminium lactate) for 6 months increased aluminium in brain and other tissues ( Anghileri et al., ). Mice consuming ~20 μg Al/day as aluminium hydroxide gel in their drinking water for 105 days were reported to have 30, 60 and 340% increases in kidney, liver and brain aluminium concentrations, respectively ( Sahin et al., ).

It is clear that aluminium can be orally absorbed. This has been shown by studies in which neurobehavioural changes and elevations of serum, urine and tissue aluminium following oral aluminium dosing of animals and humans have been reported. This corrects misinformation in stating: &#;&#; Large doses of soluble [Al] compounds taken orally will produce &#; no systemic effects&#; and &#;No entity &#;chronic aluminium poisoning&#; has been identified in human beings&#; ( Maynard, ).

Comparison of areas under the &#;plasma aluminium concentration (AUC) × time curve&#; after oral vs. i.v. dosing is the method generally accepted for determining the oral bioavailability of most substances ( Rowland & Tozer, ). This method requires repeated blood sampling, which is a disadvantage. The use of 26 Al and this method were employed by Zafar et al. () who compared the AUC after oral, to i.p., not i.v., systemic injection, and by Yokel () who compared the AUCs, or their equivalent, after oral administration of 26 Al and i.v. administration of 27 Al.

The use of the product of &#;tissue aluminium concentrations × tissue weights&#; to determine aluminium bioavailability assumes no aluminium elimination from the sampled tissues. If all tissues are not sampled, this method results in an underestimate of bioavailability. This method was employed by Wilhelm et al. () who used bone and Zafar et al. () who used liver, kidney, spleen, femur, brain, pancreas and blood. Some other studies estimated oral bioavailability from the sum of urinary aluminium excretion and levels of aluminium in bone (and liver and brain) tissue, thereby partially overcoming one of the limitations of using urinary aluminium excretion only to estimate bioavailability ( Drüeke et al., ; Jouhanneau et al., ; a ).

Estimation of absorption from a single serum sample and the calculated volume of distribution would be expected to underestimate bioavailability because this approach does not account for aluminium that has not yet been absorbed, has distributed out of the vascular compartment, or has been excreted. It does not assure that peak serum aluminium was sampled unless independently determined. Underestimation of bioavailability by this method was shown by Hohl et al. () who found that peak serum 26 Al suggested 0.01% bioavailability, whereas cumulative urine 26 Al estimated it to be 0.1%. Similarly, an approximate 10-fold greater estimate of bioavailability was obtained based on urinary aluminium excretion compared with that derived from a single (1, 4 or 24 hr) blood sample ( Priest et al., ; ). The authors concluded: &#;&#;bioavailability cannot be accurately determined from blood 26 Al or 27 Al levels at a single time after administration&#; ( Priest et al., ). Furthermore, an accurate estimate of volume of distribution assumes an accurate estimate of the t ½ of elimination.

Estimating aluminium bioavailability based on urinary excretion compared to intake has been the method most commonly used to determine aluminium bioavailability. This method has many advantages. Collection of urine is less invasive than the sample collection requirements for most other methods that estimate oral bioavailability, which typically include blood and/or tissue. However, in the single dose, non-steady-state study, collection of all urine, or at least urine collection for a sufficient duration to ensure that nearly all of the urinary aluminium output from the dose has been obtained, is required. This is difficult when 27 Al has been used as the aluminium dose because it is necessary to distinguish urinary excretion of the aluminium administered in the test dose from that ingested prior to the study or from other sources during the study. The requirement for total urine collection is also a compliance issue for the human subject. In the steady-state study, a sample collection period representing normal urinary aluminium output should be sufficient to reduce the compliance issue. Calculation of bioavailability assumes that all absorbed aluminium is excreted in the urine. This method may underestimate bioavailability due to the aluminium eliminated in bile, although this is only ~ 1%, (see 5.3.1.2 below), and the aluminium retained during the duration of the study. In a human study, Stauber et al. () utilized two correction factors to estimate oral aluminium bioavailability. They collected urine for 24 hr and multiplied the amount of aluminium excreted by 2.2 to correct for the percentage of i.v. injected aluminium found in the urine after 7 days (72%), and the percentage of total aluminium excreted in 7 days that was excreted in the first day (62%).

Bioavailability (fractional absorption) is the amount of a substance absorbed compared to the amount administered. With respect to the toxicokinetics of aluminium, systemic bioavailability, the fraction that ultimately reaches systemic circulation from where it has access to the brain and bone, the target organs for its toxicity, is most relevant. Oral aluminium bioavailability has been determined using several methods. Each of the methods has strengths and weaknesses. One of the first used was the balance study in which absorption was estimated based on the difference between intake and faecal, or urinary-plus- faecal, excretion. Estimating aluminium absorption based on the difference between intake and faecal excretion is not accurate for aluminium, for which oral bioavailability is very low. This approach assumes the difference between aluminium intake and faecal excretion is that which is absorbed and retained or excreted in the urine, which is the major route of elimination of absorbed aluminium. Small errors in determination of aluminium in faeces can significantly influence the estimate of bioavailability. As oral aluminium absorption is 1% or less under most conditions, with the balance passing through the GI tract unabsorbed, it would be very difficult to accurately determine the 1% loss of aluminium due to absorption based on the difference between oral intake and faecal excretion. This was acknowledged by Cam et al. () . Therefore, the results of studies that utilized this method ( Allen & Fontenot, ; Cam et al., ; Clarkson et al., ) are not considered to be reliable estimates of oral aluminium absorption. Balance studies that estimate retention based on the difference between intake and urinary-plus-faecal excretion tend to overestimate the bioavailability of aluminium because aluminium can be retained on the gut wall and then be eventually excreted in faeces, but not absorbed. Therefore, the results of a study that utilized this method ( Gorsky et al., ) are not considered a reliable estimate of oral aluminium absorption.

There has been considerable research on aluminium pharmacokinetics, including its oral absorption. However, most of this research, including all of that carried out prior to , has been conducted using 27 Al. To determine oral aluminium bioavailability, which is very low, and to see a significant increase of aluminium in blood, urine or tissue above the endogenous aluminium concentration, it was necessary to give very large doses of 27 Al. More recently, studies have been conducted to estimate oral aluminium bioavailability using 26 Al.

Deposition of ~ 2 to 12% of fly ash into the lungs of rats was observed in three studies. Lung and pulmonary deposition of aluminium were 9.8 and 7.9% for spherical monodisperse aluminosilicate particles having a diameter of 2.2 μm ( Raabe et al., ). Aluminium deposition into rat lung after 7 days of exposure to power plant fly ash with a mass median aerodynamic diameter (MMAD) of ~ 2 μm was 11.8% ( Raabe et al., ). In another study, the percentage of aluminium in fly ash that deposited in the lung was calculated from the amount of aluminium in the lung of rats after exposure to 73 mg fly ash/m 3 for 23 hr/day, 5 days/week for 1 month ( Tanaka et al., ). The deposition fraction was 1.8%. Similar exposure of rats to a fly ash that was 9.7% aluminium and had a MMAD of 3 μm at 10.4 mg/m 3 for 7 hr/day, 5 days/week for 1 month resulted in a deposition fraction of 5.1% ( Matsuno et al., ). The authors attributed the differences to particle diameter, noting a smaller apparent deposition fraction with larger particles. Rabbits exposed to a mean concentration of 0.56 mg aluminium oxide/m 3 for 8 hr/day, 5 days/week for 5 months showed significant increases in aluminium concentrations in the brain, lung, and bone that were, respectively, 247, 15,800 and 122% of the values for the controls, whereas aluminium levels in the heart were significantly lower (70% those of controls) ( Rollin et al., b ). Serum aluminium levels increased during this study, although not consistently over time.

Aluminium chlorohydrate is present in many aerosol anti-perspirants. Rats and guinea pigs were exposed to aerosolized aluminium chlorohydrate, 0.25, 2.5, or 25 mg/m 3 , 6 hr/day, 5 days/week, for up to 21 months (guinea pigs) or 24 months (rats). Neither animal species showed appreciable aluminium accumulation in the brain, heart, spleen, kidney, liver or serum, whereas significant increases in aluminium concentrations were seen in the lung of both species, adrenal glands of rats, and peri-bronchial lymph nodes of the guinea pigs ( Stone et al., ).

The only data from which one can estimate the percentage of aluminium absorbed from inhalation exposure is from exposures in the occupational environment (see 5.1.2.1 below). As the percentage of aluminium estimated to be absorbed during inhalation exposure is greater than from oral aluminium intake (see 5.1.2.2 below), it seems unlikely that absorption from the GI tract accounts for the absorption of all inhaled aluminium. There has been no estimate of the percentage of aluminium absorbed via the intra-nasal route, so its role in relation to pulmonary absorption cannot be delineated.

The size of the inhaled particles is expected to have a profound effect on the deposition and absorption of aluminium in the lung. Dust comprises particles from < 1 to > 100 μm in diameter; inhalable particles are those with diameters up to 10 μm. Particles having diameters up to 10 and 2.5 μm are now classified as PM 10 and PM 2.5 respectively (for more details on these aerosol fractions see Identity, Physical and Chemical Properties, Analytical Methods, Physical and Chemical Properties, Chemical and Morphological Speciation). Ultrafine particles have diameters < 0.1 μm. Particles can be removed from the respiratory tract by mucociliary clearance, the movement of mucous that covers the respiratory epithelium by cilia projecting from cells lining the respiratory tract. The mucous is moved up and out of the respiratory tract into the upper GI tract. This process has the potential to contribute to the oral route of exposure for substances initially deposited in the respiratory tract. Experimental studies have not isolated the pulmonary from other absorption sites ( Rollin et al., b ).

EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

Intratracheal/intrapleural exposure

Intratracheal instillation of aluminium compounds in laboratory animals has been used as a simple and relatively inexpensive method for screening aluminium for fibrogenicity or other types of pulmonary toxicity, including carcinogenesis. Experimental studies to evaluate fibrogenic potential in rats i.e., the ability to induce pulmonary fibrosis of 4 different types of aluminium fibres including alpha (uncalcined form) and gamma alumina (calcined form) following single intratracheal injections, were performed by Dalbey & Pulkowski (). Six months after dosing, pulmonary function tests (functional residual capacity, deflation pressure-volume curves, maximal forced deflation, single breath carbon monoxide diffusion capacity, and pulmonary resistance) and histopathological evaluation were performed. Rales were noted during the first week of instillation in aluminium treated groups, but not in the groups given glass beads or quartz. Standard lung volume and maximal forced exhalation parameters were decreased at 6 months after instillation in aluminium treated groups as compared to animals injected with saline and glass beads (controls). Single-breath carbon monoxide diffusing capacity was significantly decreased in aluminium treated animals compared to both types of controls which indicated the presence of a physical barrier between the air in the alveoli and the blood. The weight of the postcaval lung lobe was significantly increased for all groups administered aluminas, and the most marked increase was seen in the quartz group. The histopathological changes were similar in all treated groups and consisted of areas of granulomatous inflammation with early collagenization (fibrosis). The presence of multinuclear giant cells and the infiltration of macrophages were suggestive of a foreign body type reaction. Interstitial fibrosis was also apparent and was characterized by a thickening of alveolar walls with collagen. Both groups treated with uncalcined aluminas tended to have a higher incidence and severity of granulomas with fibrosis. Although minor pulmonary changes were noted in the aluminium treated groups, these effects were significantly less pronounced than the changes induced by the instillation of the positive control (quartz). Results are consistent with previously published work (Ess et al., ; King et al., ; Stacy et al., ) and point to the variation in responses to material within the class of alumina compounds. In interpreting these results, it must be considered that large doses were instilled with the intent of overloading normal clearance mechanisms in the lung to exaggerate any reaction that might occur. The dose of 50 mg is equivalent to about 30 mg/g lung, well above the 1 mg/g generally associated with the onset of overloading during long-term studies (Oberdorster et al., ). Influx of alveolar macrophages (AM), accumulation of particles, inflammation, and fibrosis are changes which would be expected following the administration of a large dose of relatively insoluble particles producing low toxicity to rats. The main goal of these instillations was to rank several alumina samples for their general potential to induce pulmonary fibrosis.

Lindenschimdt et al. () examined the effects of aluminium on the development of pulmonary fibrosis and histological changes/inflammatory responses in the lungs of rats instilled with 1 or 5 mg Al2O3/100 g body weight. A dose-dependent minimal and generally transient increase in inflammatory responses was measured in the bronchoalveolar lavage fluid (BALF) including; activity of lactate dehydrogenase (LDH) an index of cell membrane damage; beta-glucurnidase and N-acetylglucosaminidase, markers of macrophage/polymorphonuclear membrane damage; and levels of total protein, an index of potential fibrotic activity and/or vascular damage. Increase in total cells at this dose was primarily due to elevation in neutrophils and lymphocytes. At low dose, the only significant change was an increase of neutrophils on day 1 which returned to the control level by day 7. The changes observed at high doses returned slowly to normal values during the 2-month study period. Although intratracheal instillation is not the normal route of exposure, the minimal and generally transient changes induced by Al203 are consistent with the lack of significant lung toxicity found in both humans and animals. Significant pathologic response at high doses might be due to the overload phenomenon of aluminium oxide dust (~9.1 mg/g lung tissue). Morrow () showed that deposition of large amounts of inert dust in the lungs (> 1-2 mg/g lung tissue) resulted in inhibition of phagocytic removal of dust, leading to a delayed clearance from the lung.

Tornling et al. () administered intratracheal instillations of aluminium oxide (primary alumina), aluminium oxide with adsorbed fluorides (secondary alumina), and saline to three different groups of rats. The alumina dust (40 mg) was suspended in saline. BALF was obtained and histological examination of the lungs was performed 1, 4, and 12 months after exposure. No signs of fibrosis were found in any of the animals. No significant changes in alveolar cell concentrations were noted for the group treated with primary aluminium; however the secondary aluminium group exhibited increased concentrations of macrophages and neutrophils one month and one year after exposure. This suggests that fluoride plays an important role in early changes to alveolar cell populations. One year after exposure both the aluminium treated groups exhibited significantly raised concentrations of fibronectin, which indicates that alumina, not fluoride, is essential for this observed effect. The biochemical properties of fibronectin support the formation of an extracellular matrix network, and therefore fibronectin may be an early marker of fibrosis. Due to the administration of aluminium by intratracheal instillation, which is not a physiological route, the results observed in this study need to be confirmed by further investigations in which inhalation is used as a route of exposure. Instillation may have led to pulmonary overload which could have contributed to the development of the observed effects.

Pigott & Ishmael () assessed the effects of a single intrapleural injection (0.2 mL suspension/20 mg suspended solids) of refractory alumina fibres (Saffil fibres) obtained immediately after manufacturing or, later, after extensive thermal ageing. The potential for these fibres, which had different diameters, to result in the development of mesotheliomas in groups of rats was examined. No mesothelioma was detected in any of the rats dosed with the Saffil fibres, or in the negative controls. Malignant mesothelioma was diagnosed in 7 rats in the asbestos group (positive control) and in 3 rats in one of the aluminosilicate groups. However, it must be considered that intra-cavity injections result in a high deposition of the test material directly on the target tissue. This does not reflect inhalation exposures in which the fibres must first be deposited in the alveolar region of the lung and penetrate lung tissue before it reaches the pleural space. The increased mesothelioma proliferation and malignant mesotheliomas detected in the aluminosilicate B group as compared to the aluminosilicate A group is likely a reflection of the size of the fibres. Coarse fibres were found to be more irritating than fine fibres. The results of this study suggest that Saffil alumina fibres are inert and are not associated with mesothelioma induction. This study supports the results from a previously conducted inhalation study (Pigott et al., ).

After a single intrapleural instillation of Al(OH)3 at a dose of 0.3 g/mL saline to rats there was an increase in chest wall elastic properties and viscoelastic pressure accompanied by pleural inflammation after 7 days (Albuquerque et al., ). The pleural adherence was associated with a marked increase in the type I/type III collagen ratio after 30 days. Histological examination demonstrated no significant differences in lung parenchyma in the aluminium hydroxide treated and control groups.

In vitro studies

Gusev et al. () and Warshawsky et al. () conducted in vitro studies to examine the effects of aluminium on lung cell related functions. Gusev et al. () showed that phagocytosis of alumina dust by rabbit AM did not produce exogenous generation of superoxide radicals and hydrogen peroxide as measured by nitroblue tetrazolium reduction in resting and stimulated cells when compared to quartz dust. Alumina dust exerted no effect on hydrogen peroxide generation and substantially decreased the level of superoxide radical generation by human granulocytes. Warshawsky et al. () also conducted a study to assess the role of AM after exposure to aluminium oxide. The cytotoxicity of aluminium oxide particles (median size was equal or less than 0.36 μm and surface area 198.4 m2/g) to hamster and rat AM in vitro was measured at 0.1-0.5 mg/L ×106 cells at 24 and 48 hr using trypan blue exclusion procedures. The viability of the hamster AM in the presence of aluminium oxide up to the highest concentration was similar to control. After 24 and 48 hr, the viability of the AM was approximately 80 and 70%, respectively. Results demonstrated that aluminium oxide showed no changes in AM viability under in vitro conditions.

Oral exposure

As discussed in Toxicokinetics, Absorption, Animal Studies, Oral Administration, the oral bioavailability of silicon and aluminium from Zeolite A (30 mg/kg), sodium aluminosilicate (16 mg/kg), magnesium trisilicate (20 mg/kg), and aluminium hydroxide (675 mg) in dogs was examined by Cefali et al. (). Twelve female dogs received a single oral dose of each compound at one-week intervals. One of the 12 dogs receiving aluminium hydroxide displayed frothy emesis, and two dogs excreted soft stool.

Intracellular binding of aluminium was examined in the mucosa of the stomach, duodenum, jejunum and ileum of adult rats following a single oral administration (300 mg/kg) of aluminium hydroxide (More et al., ). A second group of rats received a daily oral administration of Al(OH)3 (300 mg/kg) for 5 days. No marked differences in body weight and no microscopic lesions in the GI tract (body and antrum of the stomach, duodenum, jejunum and ileum) were observed in either group of animals. Six hr after single Al(OH)3 administration, aluminium deposits were observed in the gastric lumen, in the duodenum, and in the lumen of both the jejunum and ileum. After repeated administration, the presence of aluminium-reactive deposits was noted only in the lumen of the stomach (at the bottom of the antral glands) and in the lumen of the intestine from day 3 to day 7. Other data (discussed in Toxicokinetics, Absorption, Animal Studies, Oral Administration, The Site and Mechanisms of Oral Aluminium Absorption) have demonstrated that aluminium absorption occurs in the small intestine by a paracellular pathway process via the tight junctions (Garbossa et al., b; Provan & Yokel a). The results also suggest that after repeated administration of large oral doses, aluminium accumulates in the antral mucosa of the stomach and is released slowly in the digestive tract.

Dermal exposure

The comparative irritancy of several aluminium salts was assessed by Lansdown () in three different species. Groups of 5 mice, 3 rabbits and 2 pigs were treated daily for 5 consecutive days with applications of 10 % w/v aluminium chloride, aluminium nitrate, aluminium chlorhydrate, aluminium sulphate, aluminium hydroxide (the pH of the solution was highest at 7.2 among these chemical species of Al tested) or basic aluminium acetate. Twenty-four hr after the final treatment with aluminium hydroxide, signs of erythema, thickening, scaling hyperkeratosis, acanthosis, microabsecesses and the presence of aluminium in keratin were not observed. After single dermal application of aluminium hydroxide (10%) on mouse, rabbit and pig skin no signs of dermal irritation or inflammation were found (Lansdown, ).

Repeated Exposure

Inhalation/intratrachael exposure

The fibrogenic potential of very fine metallic aluminium powder was investigated by Gross et al. (). Three different types of aluminium powder were tested. Pyro powder and flaked powder were composed of flake-like particles, and the atomized powder consisted of atomized spherical particles. Aluminium oxide dust was used as a negative control. Two chambers, containing 30 rats and 30 hamsters each, were held at dust concentrations of 100 mg/m3 of the pyro powder and the atomized metal powder respectively, two additional chambers were held 50 mg/m3 of the respective powders. Six chambers, each containing 30 rats and 15 guinea pigs, were maintained at dust concentrations of 15 and 30 mg/m3 respectively, for each of the three types of metallic aluminium powders. The animals were exposed for 6 hr daily, 5 days each week, for 6 months for the 50 and 100 mg/m3 groups, and for 12 months for all other animals. An additional group of 30 rats and 30 hamsters was exposed to aluminium oxide dust at an average concentration of 75 mg/m3 for 6 months, and 30 rats and 12 guinea pigs were exposed to aluminium oxide at a concentration of 30 mg/m3 for one year. Intratracheal injection of the aluminium powders at different dose levels was also conducted. Pulmonary fibrosis was not apparent following inhalation of the aluminium powders in hamsters and guinea pigs; however scattered small scars resulted from foci of lipid pneumonitis in rats. All three species of animals developed alveolar proteinosis, the severity and extent of which were not consistently or clearly related either to the type of aluminium powder or to the severity of the dust exposure. The alveolar proteinosis resolved spontaneously and the accumulated dust deposits cleared rapidly from the lungs after cessation of exposure. Intratracheal injection of large doses of aluminium powders into rats produced focal pulmonary fibrosis; no fibrosis occurred in the lungs of hamsters following intratracheal injection. The results of this experiment indicate that inhalation of fine metallic aluminium powders does not produce fibrogenic effects, and that intratracheal injection of these powders is likely an artefact of the injection itself.

Christie et al. () examined the pulmonary effects of aluminium in rats and hamsters (see also Effects on Laboratory Mammals and In Vitro Test Systems, Irritation, Inhalation Exposure). Inhalation exposure to 100 mg/hr aluminium, in the form of powder, or 92 mg Al/per 2 hr, as a fume, each day for 9-13 months showed a significant retention of aluminium in the lungs of both groups of animals. The aluminium retention in the lungs in rats and hamsters exposed to fume was much greater than when exposed to powder. Following exposure to fresh air, aluminium oxide was cleared rapidly from the lungs of the both powder and fume groups. Weight of wet lung, ash and aluminium oxide content of lungs in exposed animals increased. The initial pulmonary tissue response was proliferation of macrophages within alveolar spaces as well as lipoid pneumonia. The focal aggregates of macrophages were located around the small bronchioles and small pulmonary arterioles; lymphoid hyperplasia was observed. After chronic exposure to aluminium powder, rats showed focal deposits of hyaline in alveolar walls, and focal areas of lipoid pneumonia developed in hamsters.

The pulmonary reaction to inhalation exposure of refractory alumina fibre (Saffil fibres), either as manufactured or in a thermally aged form, was assessed in rats (Pigott et al., ). Animals were exposed to the fibres 5 days a week, for a 6 hr period, for a duration of 86 weeks. Pulmonary reaction to both forms of alumina fibre was minimal. Focal necrosis and regeneration of olfactory epithelium was seen in the nasal cavity in 2 Saffil fibre treated animals, and the appearance of aluminium fibres in the mediastinal lymph nodes indicated that fibres and particles may also have been transported via macrophages into the lymphatic system. Benign and malignant pulmonary tumours were confined to the rats in the positive control group which were dosed with asbestos. The results of this study indicate that inhalation of refractory alumina fibres is not associated with an increase in pulmonary or other tumours.

Ess et al. () studied the fibrogenic effect of intratracheal instillation of 7 alumina samples in rats. Five of the samples were used for aluminium production, one sample was a chemical grade form of alumina characterized by small particle diameter and high chemical purity, and the last sample was a laboratory-produced alumina. Quartz was used as a positive control because of its well-known fibrogenic activity. The alumina samples were administered at a total dose of 50 mg by 5 injections given over a period of 2 weeks. Groups of 5 animals were sacrificed at 60, 90, 180, or 360 days after exposure. Histopathological examinations were carried out on all animals and bronchoalveolar lavage was performed to assess inflammatory reactions. Fibrogenic potential was not detected for any of the 5 aluminas used for primary aluminium production, while it was reported that the other 2 samples induced fibrotic lesions. A correlation between cytological and biochemical parameters studied in BALF and the fibrosis determined by histology was not noted for the alumina-treated animals. A persistent inflammatory alveolar reaction was seen in the animals instilled with the alumina samples, which was less severe than the reaction produced by the instillation of quartz. The route of administration needs to be considered in interpreting these results. Intratracheal instillation may have overloaded clearance mechanisms; however this cannot account for differences of intensity between samples which were administered at the same dose.

There are a number of limitations in these studies. First, most studies do not demonstrate a dose-response relationship. Few data are available concerning exposure conditions and the size of the ambient aerosol. Some studies were of relatively short duration compared with the life-span of the animals employed; consequently, although no adverse effects were reported in nearly all cases, it is not possible to assess how much, if any, of the compound was deposited in the lungs and whether the time-span of the experiment may have been too short to demonstrate delayed effects.

Oral exposure

Several repeated dose toxicity studies have been conducted in order to assess the effects of oral exposure to aluminium hydroxide on clinical signs, food and water consumption, growth, haematology and serum chemistries, tissue and plasma concentrations of aluminium, and histopathology.

In a study conducted by Hicks et al. () there were no treatment-related effects in rats fed up to 288 mg Al/kg b.w./day as aluminium hydroxide in the diet for 28 days.

Berlyne et al. (a) investigated the effects of repeated oral, s.c., and i.p. aluminium hydroxide administration in normal and uraemic rats. Groups of nephrectomised rats were administered 1 or 2% AlCl3 or Al2(SO4)3 in the drinking-water or oral Al(OH)3 (150 mg of elemental aluminium/kg/day) by gavage. Groups of non-nephroctomised rats received the same treatments. The duration of the treatment was not indicated. Groups of nephrectomized and normal rats also received i.p. and s.c. injections of Al(OH)3. The clinical signs of intoxication in nephrectomized animals observed following i.p. administration (90 mg/kg b.w.) included periorbital bleeding, lethargy, anorexia and death. Plasma, liver, muscle, heart, brain, and bone levels of aluminium were markedly elevated in the i.p.-treated group. S.c. injection was apparently less toxic, resulting in no mortality, but periorbital bleeding occurred in nephrectomized animals. Aluminium levels were elevated in all tissues, the highest concentration being in the brain. Administration of high doses of aluminium chloride (180 mg/kg b.w.) and aluminium sulphate (300 mg/kg b.w.) in drinking water to nephroectomized rats produced periorbital bleeding and 100% death in treated animals. Periorbital bleeding was noted for the rats which received drinking water supplemented with Al(OH)3. In normal rats only aluminium sulphate produced periorbital bleeding in 3 of 5 rats, but no mortality.

Thurston et al. () examined aluminium deposition in the tissues of rats following dietary aluminium hydroxide exposure in order to assess whether the toxicity of this compound was modified when hypophosphatemia was prevented. Weanling rats (6 per group) were assigned to either a whole meal diet; a whole meal diet with aluminium hydroxide (3.2 g/kg) added; or a whole meal diet with added aluminium hydroxide (3.2 g/kg) plus 10 g/kg disodium hydrogen phosphate. An additional group underwent partial nephrectomy and was assigned to the whole meal diet with added aluminium hydroxide.

The duration of the experiment was 4 weeks; after the treatment the animals were sacrificed, blood samples were taken and a complete post-mortem examination was conducted. Animals in the aluminium hydroxide group exhibited a significant impairment of growth, while animals receiving both aluminium hydroxide and the phosphate supplement showed a normal rate of growth. The adverse effects on growth were more severe in uraemic rats but the pattern was the same for aluminium hydroxide treated and untreated animals. Skeletal aluminium content was raised in the normal animals given aluminium hydroxide or aluminium hydroxide and phosphate; however, the uraemic animals showed the most marked increase in skeletal aluminium levels. These results suggested that some aluminium accumulation is seen following oral exposure but that adverse effects are not exhibited if hypophosphatemia is avoided.

The accumulation of aluminium in bone and various regions of the CNS in rats treated with aluminium hydroxide (100 mg/kg b.w./day) or aluminium citrate (100 mg/kg b.w./day) i.g. for either 4 or 9 weeks (6 times a week) was studied by Slanina et al. (). However, a decrease in weight gain was observed after 4 weeks of aluminium hydroxide treatment indicating the presence of subacute adverse effect.

Subchronic oral administration (18 days) of aluminium hydroxide (271.3 μg Al/g diet) resulted in significantly increased tibia weight compared to rats fed aluminium phosphate (272 μg/g), aluminium lactate (262 μg/g), or aluminium palmitate (268 μg/g) (Greger et al., ).

Body weight of weanling and adult rats was not affected after repeated oral exposure to high doses of aluminium hydroxide mixed with sucrose in the diet ( ppm for 67 days) (Sugawara et al., ). Rats were fed test diets that had been supplemented with aluminium hydroxide at levels of 989 and μg Al/g diet. An additional group of rats was fed a control diet containing 26 μg Al/g. No aluminium-induced anaemia or hypophosphatemia was observed in young or adult rats and serum aluminium did not exceed the normal level. Aluminium concentration in the intestinal tract mucosal membrane increased significantly but no effect on inflammatory infiltration or necrosis was noted in the intestine. Serum and hepatic triglyceride levels and adipose weight were decreased significantly in young rats, but neither serum cholesterol nor phospholipid levels was affected by aluminium ingestion. In the adult group, aluminium hydroxide produced a decrease in only hepatic glycogen content (Sugawara et al., ).

The body burden of aluminium in weanling rats fed one of 4 diets for 29 days was assessed by Greger & Powers (). Rats were assigned to receive a diet containing 40 μmol Al/g diet with or without citrate, a diet containing 100 μmol Al/g diet with citrate, or a control diet containing 0.39 μmol Al/g diet. Rats were injected with DFO or buffer 24 hr prior to sacrifice. Rats fed Al-supplemented diets accumulated significantly more metal in their tissues than rats fed the basal diet, the accumulation was greatest in the rats fed aluminium with citrate. Haematocrit levels following oral aluminium exposure were inversely correlated to tissue aluminium concentrations. It was expected that DFO might mobilize aluminium from tissues subsequently increasing serum and urinary aluminium levels proportionately to bone aluminium concentrations. However, the changes induced by DFO were small and the elevated serum and urine aluminium concentrations were not more correlated to the body load of Al, as indicated by tibia aluminium concentrations. It was estimated that approximately 0.01 to 0.04% dietary aluminium was absorbed. Aluminium hydroxide added to the diet (0.05%) of rats during the 30 days did not affect vitamin A bioavailability (Favaro et al., ). Hicks et al. () found no treatment related effects in rats fed up to 302 mg Al/kg bw as aluminium hydroxide for 28 days.

Oral administration of high doses of aluminium hydroxide (, or mg/kg) in rats for 30 days did not produce any clinical signs or gross symptoms of intoxication, or any significant differences in body weight and food intake. However, in treated animals, behavioural changes (memory and learning ability disturbances) associated with elevated brain aluminium content were observed (Thorne et al., ).

Dlugaszek et al. () examined the effects of long term exposure to aluminium in drinking water, including the distribution of the ingested aluminium and changes in the tissue levels of essential elements. Aluminium was administered in drinking water as aluminium chloride, dihydroxy aluminium sodium carbonate, or aluminium hydroxide. Animals in the Al(OH)3-treated group exhibited an increase in Mg concentration in bones, a decreased Fe concentration in the stomach, and a decline of copper in the kidneys and liver. The group which received AlCl3 exhibited the highest elevation of aluminium in the tissues following oral exposure.

Bilkei-Gorzo () investigated neurotoxic effects following daily oral administration (90 days) of insoluble aluminium hydroxide (300 mg/kg Al(OH)3), water soluble AlCl3 (30 or 100 mg/kg) and chelated aluminium hydroxide (100 mg Al(OH)3/kg + 30 mg citric acid/kg) in rats. The ability to learn (determined by the number of runs necessary to learn the labyrinth) was affected in all aluminium treated groups; the learned performance was altered to a greater extent in the Al(OH)3 and AlCl3 treatment groups. The aluminium content of the brain was elevated in each treatment group; however, the elevation was highest in the groups treated with soluble aluminium compounds. Similarly, all treatments resulted in elevated acetylcholinesterase activity, with significant increases in the AlCl3 group, and in Al(OH)3 chelated to citric acid. No relevant differences in body weights, general conditions, or water and food intake were noted between control and treated groups. These results suggested that, although water-soluble aluminium compounds exhibit greater neurotoxicity, the highly insoluble aluminium hydroxide compound appeared to be absorbed subsequently producing some effect on nervous system functions.

Ecelbarger et al. (b) conducted a study to assess the impact of chronic exposure to dietary aluminium on aging rats. Male rats were fed diets containing 0.4 or 36.8 μmol Al/g diet in the form of aluminium hydroxide for 8 months until they reached 23 months of age. One day prior to sacrifice, one-half of the rats in both treatments were i.p. injected with DFO, and the remaining rats were injected with saline in order to investigate the usefulness of DFO for estimating body burden of Al. The rats exhibited little evidence of aluminium toxicity as body weight, feed intake, or changes in the relative size of tissues did not appear to be affected by the treatments.

The possible relation between aluminium intake, levels of aluminium in the brain, and dementia was investigated in rats and dogs following chronic oral aluminium hydroxide exposure (Arieff et al., ). Clinical signs of intoxication were not apparent in rats with normal renal function (n=10) or rats with chronic renal failure (n=14) exposed to an oral daily dose of 300 mg aluminium hydroxide, for 5 months. Brain Al3+ was significantly greater than normal for both groups of rats, the most marked increase being in the group with renal failure. The effects of aluminium were also investigated in two groups of mongrel dogs. One group of dogs received a diet which included 3 g of added aluminium hydroxide daily for 5 months, while the other group received the same diet without Al. In the aluminium loaded dogs the content of Al3+ in the cerebral cortex was significantly greater than in that of the controls. Electroencephalograms (EEG) were conducted in the exposed dogs and the results for the aluminium treated dogs were within the normal range. It must be considered that the number of animals in each treatment group was not clearly reported.

A significant increase in tubular phosphate reabsorption with an increase in the apparent velocity of maximal tubular transport was reported in rats following aluminium i.v. administration (Mahieu et al., ). Proximal tubule damage was reported in rats (Ebina et al., ) and rabbits (Bertholf et al., ) following i.v. administration of aluminium. Rats consuming a high aluminium diet (36.8 μmol Al/g diet) for 8 months excreted significantly more protein in urine which is indicative of renal damage (Ecelbarger et al., b).

Studies on the effects of oral administration of aluminium on pregnant animals and their offspring are presented in Effects on Laboratory Mammals and In Vitro Test Systems, Reproductive and Developmental Toxicity.

Protective treatments on aluminium-induced developmental effects

Albina et al. () conducted a study to determine if a chelating agent, deferiprone, could protect against aluminium-induced maternal and developmental toxicity in mice. Pregnant mice were randomly divided into 5 groups. One group was administered 1,327 mg/kg b.w. of aluminium nitrate nonahydrate by gavage on gestation day 12, a second group was given 24 mg/kg b.w./day of deferiprone on days 12-15 of gestation, and a third group was given 1,327 mg/kg b.w. of aluminium nitrate nonahydrate on gestation day 12 followed by deferiprone (24 mg/kg b.w. at 2, 24, 48 and 72 hr following aluminium exposure. The controls received sodium nitrate or deionised water. Administration of deferiprone alone did not produce any apparent signs of developmental toxicity. Aluminium-induced maternal toxicity included significant reductions in body weight gain, absolute liver weight and food consumption compared to controls. Administration of deferiprone did not offer protection against these aluminium induced maternal effects. In contrast, deferiprone administration following aluminium exposure resulted in a more pronounced decrease in maternal weight gain and corrected body weight change. Developmental toxicity was manifested by delayed ossification of a number of bones in the aluminium treated groups compared to controls. The group treated with aluminium nitrate and deferiprone exhibited a higher number of litters with foetuses showing skeletal deficiencies. These results suggested that deferiprone is not an effective agent to protect against aluminium-induced developmental toxicity and might increase the severity of aluminium-induced maternal and developmental adverse effects in mice.

Silicon-containing compounds were shown to limit absorption of ingested aluminium (Edwardson et al., ). Therefore, it was proposed as exerting a protective effect against aluminium-induced toxicity (see also Toxicokinetics, Absorption, Animal Studies, Oral Administration, Factors Influencing Oral Aluminium Absorption, Silicon-Containing Compounds). Bellés et al. () conducted a study to test this hypothesis. Aluminium nitrate monohydrate was administered to three groups of pregnant mice by gavage (398 mg/kg b.w./day) on gestation days 6-15. These animals received silicon in drinking water at concentrations of 0, 118 or 236 g/L on days 7-18 of gestation. Three additional groups of pregnant mice received 270.6 mg/kg of sodium nitrate and the same concentrations of silicon in drinking water as the aluminium-treated groups. The percentage of aluminium-induced deaths, abortions and early deliveries was significantly reduced in the group administered 236 mg/L silicon. However, no significant differences were noted at 118 or 236 mg/L silicon on aluminium induced foetotoxicity.

In vivo models

Neuropathology

The pathology of DAE patients provides insight into potential mechanisms of aluminium neurotoxicity and its transport into the nervous system. As discussed above, Reusche et al. () noted an abundance of intracellular argentophyllic (silver binding) granules in the brains of DAE patients, which are most commonly ovid, intracellular, and lysosomal in appearance. LAMMA revealed high concentrations of aluminium in the cytoplasm of cells exhibiting these structures. One of the major carriers of aluminium in the serum and interstitial fluids is Tf (see Toxicokinetics, Distribution (Including Compartmentalization), Human Studies, Transport in Blood). At physiological pH, aluminium in serum is bound to transferrrin, although less tightly than Fe would be bound. In CSF, higher concentrations of citrate result in significant re-speciation to aluminium citrate (Yokel, ). Uptake of Tf by neural cells involves receptor-mediated endocytosis via the Tf receptor. Indeed, in the CNS, Tf-mediated uptake has recently been used as a molecular means of introducing novel compounds or proteins into the brain. Importantly, receptor-mediated endocytosis would be expected to deliver material to the endosomal and then lysosomal compartments. Hence, in DAE patient, the subcellular distribution of aluminium in neural cells (neurons and cells of the choroid plexus) is consistent with a mode of exposure that involves Tf-mediated delivery to the nervous system. The extent to which aluminium citrate is taken up by neural cells is unclear.

Rodent models of aluminium toxicity by direct injection

To bypass limitations of absorption, some investigators have directly i.p. injected aluminium-salts. Esparza et al. () injected rats with aluminium lactate at concentrations of 5 mg/kg/day and 10 mg/kg/day for 8 weeks (5 injections per week) and then assessed markers of oxidative stress and cognitive function (see below). The estimated exposure would be > times normal. Levels of aluminium in cortex, hippocampus, cerebellum and liver were measured, with only cerebellum and liver showing significant accumulations of aluminium. Levels of aluminium in serum were not reported. Significant reductions in the levels of manganese and copper were found in brain, with no change in Fe in any organ. In this model, the hippocampus showed the largest number of changes indicative of oxidative stress, including increased GSH, increased measures of lipid peroxidation (thiobarbituric acid reactive substances (TBARS)), increased levels of oxidized glutathione (GSSG), and increased SOD levels. In the liver, the levels of GSH were similarly increased, however, paradoxically, the levels of lipid peroxidation were lower than control. Importantly, the magnitude of the changes in these markers never approached the level of 2-fold and most were less then 50%.

A follow up study by these investigators (Gómez et al., ) utilized a similar paradigm of 7 mg/kg/day i.p. injections of aluminium lactate into rats for 11 weeks (5 injections per week), focusing on oxidative markers in the hippocampus. The most robust evidence of general toxicity included 30% reductions in body weight. The levels of aluminium in hippocampus increased ~5-fold, to 22 μg/g. While this study reported a similar elevation in TBARS (~ 2-fold), increases in GSSG were not detected. Slight elevations (~50%) in mitochondrial superoxide dismutase (SOD) mRNA, an important antioxidant enzyme that is induced by oxidative stress, were noted.

Platt et al. () examined the impact of aluminium on CNS integrity by direct intracerebroventricular injection, via cannula, of 5.4 μg of aluminium chloride for 5 consecutive days; followed by either 7 days or 6 weeks of no treatment before sacrifice. Interpretation of the study is somewhat confounded by damage to the brain resulting from instillation of the cannula and from disruption of the BBB, however several findings were revealing. Aluminium was found to distribute readily along white matter tracts and resulted in activation of both astrocytes and microglia at sites distal to the injection site. Although not a mimic of chronic exposure from drinking water or food sources, these data suggest that acute exposure of neural tissues to aluminium salts elicits responses indicative of neurotoxicity. Overall, however, the reported increases in markers of oxidative stress were of a relatively low magnitude.

In another example of acute toxicity, Sreekumaran et al. () examined several parameters of neuronal morphology following a one-time injection of 8 mg/kg aluminium chloride into CSF, via the cisterna magna of rats. Following a 30 day survival, animals were sacrificed and tissues were prepared for Golgi impregnation to reveal dendritic and axonal structure. Significant reductions (averaging 30 to 40%) in axonal length and dendritic branching were noted in the treated group.

Yang et al. () reported evidence of apoptotic cell death in the CNS of rats given a single injection of aluminium maltolate (100 μl of 500 μM solution). In a small number of animals (n = 4), 5 days after injection, TUNEL positive cells were detected in hippocampus along with biochemical evidence of DNA fragmentation. Biochemical evidence of caspase activation (caspase 3 and 12) was also reported. The study did not identify which type of cell(s) in the hippocampus were affected.

Dramatic evidence of aluminium toxicity in retina of rats was reported by Lu et al. (). Chronic i.p. injection of 12 mg of aluminium chloride for 16 weeks resulted in severe atrophy of the retina with losses of photoreceptors. Interestingly, in this model, the location of accumulated aluminium mimicked that seen in DAE patients. Aluminium was concentrated in cytoplasmic granules that resemble lysosomes. There was no report of neurofibrillary pathology or discussion of mechanisms of cell death.

Miu et al. () studied rats given i.p. injections of aluminium gluconate 85 ug/100 g body weight 3 times a week for 6 months. At sacrifice, the authors showed evidence of reductions in neuronal density in the hippocampus, intracellular accumulations of aluminium in dense granules, and thickening of meningeal blood vessels. Serum levels of aluminium were measured at 3 intervals, recording levels of 86.8, 38.9, and 69.7 μg/100 mL of serum (mean values for n=12). These levels were roughly 5 to 40-fold higher than controls. The average level of aluminium in human serum ranges from 1-2 μg/L. Hence the levels in these rats were about 3 to 8-fold the normal human level.

In a parallel study, using the same method of dosing and concentration of aluminium gluconate for 12 weeks, Miu et al. () reported finding similar lesions in addition to changes in myelin structure and evidence of mitochondrial swelling in hippocampal neurons. None of these pathologies was quantified however.

A key issue in the foregoing studies, however, relates to the speciation of aluminium and mechanisms of uptake by neural cells. The pathologic distribution of aluminium in DAE patients, and in some of the animal studies described above, are consistent with Tf-receptor-mediated endocytosis. Free-flow endocytosis of aluminium citrate could produce a similar pattern. Indeed, the pattern of aluminium accumulation in patients suffering from DAE, membrane delineated lysosomal-like structures, is consistent with an endocytic mechanism of uptake. It is unclear as to whether acute exposure to high levels of aluminium salts by direct injection into CNS reasonably simulates the exposures which result from long-term low level intakes via the oral route. In some of the acute exposure studies, aspects of human neurogenerative disease are produced. However, as described above, pathologic analyses of DAE patients do not reveal the pathologies found in AD and other neurodegenerative diseases, including neurofibrillary pathology, symptoms of motor neuron disease (as occurs in rabbits), or senile plaques. Overall, the connection between aluminium exposure and neuropathologic features of human disease is not particularly strong, though some resports of positive associations continue to foster debate.

Rodent models of aluminium toxicity by oral exposure

Aluminium has been implicated in the aetiology of ALS in Kii peninsula of Japan and the islands of Guam. In these environments, the levels of aluminium and manganese in drinking water are high while the levels of calcium and magnesium are low (for review see Garruto, ). Kihira et al. () reported that mice feed diets high in aluminium (1.56 g/100 g) and low in Ca/Mg (50% reduction from control diet) developed pathologic features of human disease (Kihira et al., ), including neuronal accumulation of tau immunoreactivity in a pattern resembling pre-tangles of AD. Reductions in the density of cortical neurons were also noted in mice on low calcium/magnesium diets and in mice on the aluminium + low Ca/Mg diet. Mice given high doses of aluminium alone showed no evidence of neuronal loss. No symptoms of motor neuron disease were noted and animals exhibited near normal lifespans. Lowering Ca and Mg in diet induced a greater number of abnormalities in general health and appearance than Al laced diets (with or without manipulation of calcium/magnesium levels). Intracellular accumulations of aluminium were noted. Although it is possible that the levels of other minerals in the diet could influence the toxicity of aluminium, the most informative outcome of this study was that chronically high doses of aluminium did not result in obvious neurodegeneration, profound neuropathology, or clinical symptoms relevant to motor neuron disease. The average 25g mouse consumes about 5 g of food per day (formulated to contain 15.60 mg/g of aluminium). Therefore, the estimated consumption of aluminium by these animals would be about 3 g/kg/day, a dose nearly unattainable in humans. Despite this extremely high dose for a prolonged period, these animals developed relatively few phenotypes related to human neurological disease.

In a study of chronic exposure to aluminium in diet (rats fed 32 mg aluminium sulphate per day for 5 weeks), no evidence of apoptotic cells (TUNEL positive) was noted in cerebral cortex (Rodella et al., ). Similarly, the relative density of neurons in cortex was not obviously diminished. The authors did report that the density of NADPH-diaphorase positive neurons in cortex was diminished by 50%, but a better validation of such a reduction could be made by unbiased stereological assessments of these neurons (Gundersen et al., ).

Swegert et al. () examined the effects of aluminium exposure on oxidative metabolism in rats given diets supplemented with aluminium chloride at an estimated dose of 20 mg/kg/day, which is approximately 20 times higher than the maximum amount normally consumed by humans from food. Animals were treated for 90-120 days at which time tissues were harvested and mitochondria were isolated for further study. Thirty to forty percent reductions in mitochondrial respiration rates were noted in brain mitochondria, with a paradoxical increase (~2-fold) in respiration rates in heart.

Flora et al. () reported similar changes in oxidative markers in rats given aluminium nitrate in water at a concentration of 0.2% (2 g/l) for 8 months. Levels of aluminium in blood increased from ~3 μg/dL to >20 μg/dL. In brain, the levels increased from ~8 μg/dL to ~16 μg/dL. Indices of lipid peroxidation (TBARS) and the levels of GSSG were increased in brain. Again, however, the magnitude of changes in these measures was less than 2-fold with only very modest increases in the levels of GSSG.

Golub et al. () fed mice defined diets containing μg/g of aluminium lactate from conception to sacrifice at 24 months of age (~ dose 100 mg/kg/day). Several parameters were analyzed (see below for discussion of cognitive behaviour), but relevant to this section was an absence of evidence for oxidative stress (no increase in TBARS). Surprisingly, however, despite the high dose of aluminium in the diet, the levels of accumulated aluminium in the brain were not significantly greater than that of controls.

Collectively, these studies establish that dietary aluminium intake can lead to accumulation of aluminium (speciation uncertain) in the brain of rats and mice. Modest increases in measures of oxidative stress have been noted, but evidence of significant neuropathology related to aluminium intake was not consistently noted. The level of sustained oxidative injury that is required to produce neuropsychological abnormalities is unknown, few of the oxidative markers measured in the foregoing studies increased as much as 2-fold.

Behavioural studies of laboratory animals exposed to aluminium

Before reviewing the literature concerning the cognitive behaviour of laboratory animals exposed to aluminium, it is worth noting that there are detailed longitudinal studies of humans exposed to elevated levels of aluminium in the workplace. Buchta et al. () examined a battery of neuropsychological and motor skills in a large cohort of auto manufacturing workers. They recorded average urine levels of aluminium of 70 μg/L, which compares with 1-2 μg/L in most individuals (Buchta et al., ). Individuals who had experienced at least 6 years of exposure were selected for analysis and their results were compared with those of co-workers of similar age, gender, and education who worked in other areas of manufacturing. The only measure by which the workers exposed to aluminium could be distinguished was a small reduction in reaction time (speed to respond to a question or perform a motor task). In all other cognitive measures including intelligence quotient (IQ), verbal intelligence, and the European Neurobehavioral Evaluation System, workers exposed to aluminium were no different from control populations (Buchta et al., ). Thus in humans, exposure to significant levels of aluminium does not lead to robust changes in cognitive function. However, the above study did not assess the levels of aluminium in blood, which would indicate absorption. Though there are clearly too few human studies, much of the data from studies in adult animals also suggests aluminium exposure does not lead to significant reductions in cognitive function.

As mentioned above, a lifelong exposure of Swiss Webster and C57BL/6J mice to high doses of aluminium (~100 mg/kg/day in feed) was utilized as a paradigm by Golub et al. (). With the caveat that brain levels of aluminium were not elevated in the treated mice, suggesting poor absorption, there were little or no deleterious effects of the aluminium-laced diet on several behavioural measures, including grip strength (slight reduction ~10%), temperature sensitivity (slight increase), and spatial reference memory. In the latter task, data from the C57Bl/6J mice are most informative where no adverse impact on acquisition or retention of memory was noted. A prior study by Golub et al. () fed Swiss Webster mice food supplemented with either 500 μg or μg/g aluminium lactate (calculated dose 200 mg/kg/day) from conception to sacrifice at 150-170 days of age. In several measures of cognitive function, mice fed the aluminium laced diet performed as well as controls. However, 10 to 15% reductions in fore and hindlimb grip strength were noted.

Similarly, although Esparza et al. () reported increased levels of several oxidative markers in the brains of rats given high doses of aluminium (5 and 10 mg/kg/day by i.p. injection), no changes in performance in a passive avoidance task were noted in animals treated with either dose. The classic passive avoidance task involves an electric shock deterrent in which rats are required to remember that the more preferred location (a dark enclosure next to the lighted open space) is associated with shock. Retention of the memory is usually tested 24 hr after conditioning. Hence the task is a measure of memory function.

In contrast to the results of the study by Esparza et al. (), Zhang et al. () reported dramatic reductions in performance in passive avoidance in rats exposed to aluminium through drinking water. In the latter paradigm, aluminium chloride was provided through drinking water at a concentration of 3 mg/mL for 90 days. Serum levels of aluminium were not reported. Interestingly, in this study, an extract of Dispsacus asper (a herbal medicine) and vitamin E were shown to alleviate the memory deficits. The authors suggested that the anti-inflammatory and/or anti-oxidant properties of these drugs contributed to the improvements.

Domingo et al. () examined passive avoidance in rats provided drinking water containing aluminium nitrate at concentrations that would equate to doses predicted to be 50 and 100 mg/kg/day for 6.5 months. No effects of the high aluminium exposure on measures of spontaneous motor activity or learning in passive avoidance tasks were noted.

Struys-Ponsor et al. () studied rats given i.p. injections of 667 μg of aluminium gluconate 3 times per week for 60 days prior to assessment of spatial memory in a radial water maze task. Although a slowing of reaction time was noted, there were no statistically significant deficits in the ability of the aluminium-injected animals to perform the task.

Two studies by Miu et al. (; ), the pathological findings of which are described above, also assessed neuropsychiatric parameters. The work reported slight reductions in performance in a passive-avoidance memory task and in a spatial reference memory task. The latter work () reported changes in behaviour in open fields which were interpreted as reductions in spontaneous activity and emotional responses.

Overall, the data on neuropsychological measures in rodents given high doses of aluminium by oral routes are not suggestive of profound toxicity. However, none of these animal studies is able to reproduce life-time exposures that could occur over the life-span of humans. It is clear that humans with compromised renal function develop neuropsychological symptoms upon exposure to elevated levels of aluminium. However, from the study of individuals exposed occupationally to aluminium fumes, humans with normal kidney function seem to tolerate high levels of exposure relatively well (see above). The degree to which the chemical form of aluminium, the route of exposure, and the age/health of the individual could modulate the neurotoxicity of aluminium is uncertain and has not been extensively modeled in animals.

Effects on Bone

The bone constitutes a primary site for the deposition of aluminium (Mahieu et al., ) (see also Toxicokinetics, Distribution (Including Compartmentalization), Animal Studies, Bone). Elevated aluminium levels in humans, primarily in individuals with impaired renal function, have been associated with several bone disorders including osteomalacia (excess unmineralized osteoid) and aplastic bone disease which is characterized by normal or decreased osteoid (Firling et al., ). The mechanism by which aluminium exerts its effects on bone tissue has not been fully elucidated (Cointry et al., ). Experimental evidence in a number of different animal models has led to a variety of proposed ways in which aluminium might influence new bone development. It has been suggested that aluminium may directly interfere with osteoblast activity thereby influencing the production or mineralization of osteoid (Firling et al., ). Bone formation may be impaired due to aluminium induced reductions in the total number of osteoblasts (Sedman et al., ). Direct physiochemical inhibition of mineralization sites has also been proposed as a potential mechanism (Firling et al., ). Aluminium-induced alterations in the PTH-calcium axis have also been extensively investigated with respect to aluminium-induced bone toxicity (Mahieu et al., ). One of the functions of the PTH is to stimulate bone resorption by increasing osteoblast activity (Quarles, ). It has been proposed that aluminium impairs the secretion of this hormone from parathyroid glands (Morrisey et al., ). Numerous studies, using a variety of animal models, have been conducted to investigate the effects of aluminium on bone. In interpreting the results of these studies, it is important to consider the difference in bone remodelling physiology between species. It is thought that larger animals such as the dog and pig approximate the bone physiology of humans more closely than rats and mice (Quarles, ). The route of aluminium administration and the duration of the study period may also have had significant impacts on the overall results of these studies. It should also be noted that the use of large doses of aluminium in some of these experimental studies may have resulted in a generalized toxicity to the animals, which could complicate the interpretation of aluminium-induced bone toxicity endpoints (Quarles et al., ). Some of the in vitro and animal studies investigating the effects of aluminium and bone have been reviewed and are summarized below.

PTH is considered to enhance osteoblast-directed osteoclast activity, and it has been proposed that aluminium may inhibit the production or secretion of this hormone (Jeffery et al., ). Morrissey et al. () used dispersed bovine parathyroid cells to determine if aluminium directly affects PTH secretion. Digested bovine parathyroid glands were placed in media containing varying concentrations of aluminium, ranging from 0.5 to 2.0 mM. The incubations were terminated after 2 hr and the amount of hormone secreted into the medium was determined by radioimmunoassay. The secretion of PTH decreased with increasing amounts of aluminium. Hormone secretion decreased by an average of 68% in cells incubated with 2.0 mM aluminium compared to the cells incubated in the absence of aluminium. To examine if there was an irreversible toxic effect of aluminium with respect to PTH secretion, the cells were incubated for 1 or 6 hr with 2.0 mM aluminium, washed with low calcium buffer, and re-incubated in media without aluminium. Hormone secretion appeared to be restored and was comparable to that of cells which had not been incubated with aluminium. Cells were also incubated with radio-labelled leucine to examine the effect of aluminium on the biosynthesis of proparathyroid hormone, PTH, and parathyroid secretory protein. Examination of the incorporation of this radio-labelled amino acid into these proteins revealed that the biosynthesis of these compounds was not affected by aluminium incubation. Therefore, the results of this study suggest that aluminium directly affects the secretion of protein from parathyroid cells.

Ellis et al. () investigated the effects of aluminium on bone toxicity in a group of 20 rats given daily i.p. injections of aluminium chloride for periods of up to three months. Sixteen rats received daily i.p. injections of 0.27 mg Al/day (as aluminium chloride), increasing gradually to a dose of up to 2.7 mg Al/day. The periods for the injections ranged from 48 to 85 days and, in 5 animals, no further injections were given after 63 or 84 days of treatment until sacrifice, 27 or 49 days later. The total dose of aluminium ranged from 38 mg to 109 mg. Four controls were i.p. injected with saline. The whole femur bone aluminium content was higher in the 16 rats given aluminium chloride (176 ± 8.2 ppm/ash compared with the controls (15.4 ± 4.7 appm). A mineralization defect of bone was detected in the rats after 53 days of aluminium treatment, and this increased in severity as the injections were continued. This was marked by an excess of osteoid on the surface of normally mineralized cartilage at the usual site of endochondral ossification. The excess osteoid was typical of osteomalacia with abnormally wide seams and no calcification front. Endochondral ossification was restored to normal, but osteomalacia persisted for up to 49 days after the cessation of treatment.

Chan et al. () investigated the effects of i.p. aluminium chloride (1.5 mg/kg/day) for a duration of 9 weeks in normal (n=16) and uraemic (n=23) rats. Eight rats in the nonuraemic group and 10 rats in the uraemic group received the aluminium treatment, while no injections were given to the remaining control animals. At the end of the treatment period, the rats were euthanized and tissue aluminium, serum vitamin D metabolites, and quantitative bone histology were measured. Bone aluminium concentrations were higher in uraemic rats (121 ± 27 mg/kg) than in normal rats (47 ± 4 mg/kg), and liver aluminium values were higher in the normal group (175 ± 47 mg/kg) than in the uraemic rats (100 ± 36 mg/kg). Aluminium did not appear to have an effect on the levels of any vitamin D metabolites; however, serum concentrations of 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D were reduced as a direct result of uraemia. The nonuraemic aluminium treated animals did not exhibit any significant skeletal changes as compared to the controls. Marrow fibrosis and osteomalacia developed in some of the uraemic, non-aluminium treated animals. However, osteomalacia as defined by (1) an increase in osteoid area (29 ± 13% uraemia + aluminium vs. 3 ± 6% uraemia, no aluminium), (2) an increase in osteoid surface (42 ± 16% vs. 7 ± 11%), and (3) an abnormal pattern of tetracycline uptake at the calcification front, was more severe in uraemic animals treated with aluminium than in untreated uraemic animals.

Robertson et al. () conducted a study to investigate the effects of aluminium on bone histology and PTH levels, and to determine if chronic renal failure accentuates aluminium toxicity. Male Wistar rats were divided into 5 groups. The first group (n=5) received a low dose of aluminium (i.p. injection 0.1 mg aluminium as aluminium chloride 5days/week), the second group (n=5) received a high dose of aluminium (i.p. injection of 1.0 mg aluminium as aluminium chloride 5 days/week); the control group (n=4) was administered an i.p injection of an equal volume of diluent over the same injection schedule. One group (n=6) of rats underwent partial nephrectomy and received an i.p injection of diluent, and another group (n=5) underwent partial nephrectomy and received an i.p. injection of 1.0 mg aluminium as aluminium chloride 5 days/week. The treatment lasted for 120 days for the control and low dose aluminium group, but for a shorter period (between 90-100 days) for the other three groups due to the need for early sacrifice as a result of high attrition in these groups. The trabecular bone of the ischium and the iliac wing was obtained from each animal and examined histologically; the bone mineralization process was evaluated by double tetracycline labelling. There were no differences in bone parameters between the low dose aluminium group and the controls. In the other three groups, the relative osteoid volume (p < 0.02) and the osteoid seam width (p < 0.001) were significantly increased as compared to the controls. These parameters are indicators of osteomalacia. The number of osteoclasts/mm2 increased in nephrectomized rats not exposed to aluminium (p < 0.02) and decreased (p < 0.05) in rats with normal renal function exposed to high doses of aluminium. The number of osteoclasts/mm2 was not significantly different from that of the control level for the aluminium treated nephrectomized rats. Animals with normal renal function given the high dose were the only group to exhibit a decrease in PTH level, which may explain the reduced osteoclast numbers in this group. However, the increase in osteoclasts/mm2, as compared to controls (8.13 ± 2.92 vs. 3.93 ± 100 osteoclasts/mm2), in the non-exposed renal failure group, compared to the reduction of osteoclasts in the exposed renal failure group (2.34 ± 1.38 osteoclasts/mm2 vs. 3.93 ± 100 osteoclasts/mm2), indicates that aluminium may have a direct toxic effect on osteoclastic activity.

Cortical bone growth was measured in rats given aluminium to study the early effects of aluminium on bone (Goodman, ). Thirty weanling male rats were assigned to one of three groups: control (n=10), experimental (n=10), or basal (n=10). Rats in the experimental group were given i.p. injections of aluminium chloride (2 mg aluminium, 5 days per week); animals in the control group received an injection of saline vehicle at the same frequency, and the basal animals did not receive any treatment. The treatment period lasted for 44 days. Bone growth was assessed over two consecutive periods of 28 and 16 days in the control and experimental rats, using tetracycline labelling of bone. Rats in the basal group were sacrificed on the first day of the experimental period. Histological measurements in sections of bone obtained from the basal group were interpreted to represent the status of the bone at the beginning of the bone-labelling period in rats from the control and experimental groups. Bone (0.017 ± 0.004 mm3/day) and matrix formation (0.017 ± 0.004mm3/day) in the experimental group remained at control levels (bone formation: 0.020 ± 0.004, matrix formation 0.02 ± 0.004 mm3/day) during the first period of assessment (28 days after treatment initiation); however, both these measurements were significantly lower (p <0.01) than control values at the end of the entire 44 day study (bone formation: 0.014 ± 0.003 mm3/day vs. 0.022 ± 0.003mm3/day, matrix formation:0.014 ± 0.003mm3/day vs. 0.022 ± 0.003mm3/day). Bone and matrix apposition at the periosteum in aluminium treated animals was significantly reduced (p < 0.) from control levels at the end of the 44 day treatment period, but was not significantly different at the assessment following 28 days of treatment. Aluminium treatment did not induce a state of osteomalacia as no significant effect on the osteoid width or the mineralization front width was apparent. The results of this study indicate that aluminium reduces bone and matrix formation early in the course of aluminium exposure, prior to the development of histologically apparent osteomalacia. Aluminium may affect matrix synthesis by reducing the total number of active osteoblasts or diminishing the cellular activity of individual osteoblasts.

Goodman et al. (a) examined the effect of short-term (4 week exposure) aluminium administration on bone growth and histology, and evaluated the role of renal insufficiency in mediating the skeletal effects of aluminium. Thirty rats underwent partial nephrectomy and were assigned to one of three groups: control, aluminium-treated, or basal control. Thirty additional rats with intact renal function were divided into the same treatment assignments. Aluminium treated rats received i.p. injections of aluminium chloride (AlCl3) in saline 5 days/wk for 4 weeks; the aluminium dose was 2 mg/day. Control rats received injections of saline only, according to the same treatment schedule. Bone growth, bone formation, mineralization, and resorption were measured using double tetracycline labelling of bone. Total bone and matrix formation and periosteal bone and matrix formation were reduced in both nephrectomized and normal renal function rats treated with aluminium as compared to the respective controls. Periosteal bone and matrix formation were similarly reduced in both groups. There was no difference in bone parameters between the control rats of the nephrectomized group as compared to the normal renal function control rats; however, total bone, total matrix, periosteal bone, and periosteal matrix formations were all less in the nephrectomized aluminium treated rats as compared to the non-nephrectomized aluminium treated rats. Resorption surface was greater in both aluminium- (1.70 ± 0.41mm vs. 1.33 ± 0.34 mm) and nephrectomized-aluminium-treated (1.87 ± 0.6 mm vs. 165 ± 0.43 mm) rats compared to the respective controls, and resorptive activity at the endosteum was greater (p < 0.05) in the nephrectomized aluminium treated group (12.2 ± 6.3 μm/d) than in the controls (7.9 ± 4.9 μm/d). Serum calcium and phosphorus concentrations were similar in aluminium-treated and control animals, suggesting that PTH secretion was not substantially affected by aluminium administration. Osteomalacia was not detected, but it should be considered that the duration of this study may not have been of sufficient length for this condition to develop. The results of this study suggest that aluminium exerts is toxic effects on bone by acting directly to reduce new bone and matrix synthesis. In addition, it appears that aluminium may act to increase bone resorption. The enhanced effect of aluminium in nephrectomized rats may be a result of increased aluminium accumulation due to an impaired ability to excrete the metal; however, aluminium in bone was not quantified in this study.

In order to investigate the effects of aluminium on the vitamin D-dependent mineralization process, aluminium chloride (1 mg/kg) was administered i.v. 3 times per week for 3 weeks to normal (n=5) and vitamin D-deficient (n=5) beagle puppies (Quarles et al., ). Vitamin deficiency was induced in the 5 dogs by providing a diet deficient in vitamin D and calcium for a period of 15 weeks before treatment initiation. Bone biopsies and plasma were obtained before and after the 3 week treatment period in each group. In the next phase of this study, aluminium chloride administration was continued at a lower dose (1 mg/kg twice a week) and both groups received the diet fortified with calcium and vitamin D. This phase of the study lasted for 11 weeks. The vitamin D deficient dogs displayed biochemical and bone biopsy evidence of osteomalacia before administration of aluminium. Plasma phosphorus, PTH, and 25-hydroxyvitamin D concentrations did not appear to be affected by the 3 weeks of aluminium administration in either group. However, bone aluminium content increased to a greater extent in the vitamin D-deficient dogs (390 ± 24.3 μg/g) than in the normal dogs (73.6 ± 10.6 μg/g). After 3 weeks of aluminium treatment, the bone histology in both groups revealed changes consistent only with aging. Provision of a calcium/vitamin D replete diet to the deficient dogs, and reduction of aluminium dosage for 11 weeks resulted normalization of their plasma biochemistry and healing of the osteomalacia. The bone aluminium content of the non-vitamin D deficient dogs increased during the additional 11 weeks of aluminium exposure to 151.0 ± 11.3 μg/g as compared to a bone aluminium content of 73.6 ± 10.6 μg/g after 3weeks of exposure. In contrast, the bone aluminium content in the vitamin D deficient dogs decreased from 390 ± 24.3 μg/g to 173.5 ± 5.6 μg/g at the end of the additional 11 weeks of exposure. Histochemical staining for bone aluminium revealed no apparent aluminium in the normal group and, in the vitamin-D deficient group, there was identifiable aluminium at the mineralization fronts after the 3 weeks of treatment. At the end of the 11 weeks of additional exposure staining for aluminium was detectable only in the cement lines, indicating that mineralization occurred over the previous sites of aluminium deposition. The results of this investigation indicate that aluminium accumulates preferentially in pre-existent osteomalacic bone and localizes at the calcification front (osteoid-bone interface). The presence of aluminium at the calcification front did not impair vitamin D-dependent mineralization as remineralization occurred in the bones of the osteomalacic pups following vitamin-D repletion. Osteomalacia did not occur in the normal pups; however, this does not eliminate the possibility that aluminium administration at higher doses or for prolonged periods might cause bone toxicity in these animals. Therefore, although aluminium may have the potential to cause osteomalacia, its presence at mineralization fronts does not appear to be the mechanism through which this occurs.

Alfrey et al. () studied aluminium compartmentalization in rats with an induced state of uraemia or hypoparathyroidism. Seventy four male rats were divided into two main study groups. The first group consisted of 10 animals that underwent selective PTX, 10 animals were rendered uraemic by uninephrectomy, 11 animals underwent both nephroctomy and PTX, and 8 animals served as controls. 1,25(OH)2D3 was administered to normalize serum calcium levels. All animals received 1.5 mg/kg aluminium (as AlCl3) by i.p. injection 5 days/wk for 79 days. There was a significantly greater (p < 0.001) trabecular bone osteoid area (percent total bone area) in the PTX uraemic group than in the uraemic group (45 ± 9.7% compared to 13.4 ± 10.6%). Plasma calcium levels were significantly higher in the uraemic PTX group (10.7 ± 0.9 mg/dL) and lower in the control PTX group (9.0 ± 0.5 mg/L) than in their respective controls (9.9 ± 0.6 g/L: uraemic group; 9.8 ± 0.3 mg/L: control group), and phosphorus levels were significantly higher in both the PTX uraemic group (9.3 ± 1.5 mg/L) and PTX control group (8.1 ± 0.6mg/L) as compared to the controls (5.9 ± 0.3mg/L). The second study group was comprised of 35 uraemic rats; 8 of these rats had previously undergone selective PTX and were given 1,25(OH)2D3. The uraemic PTX animals and 8 of the uaremic animals received 1.5 mg AlCl3/kg by i.p. injection 5 days/week for 35 days, and were killed at the end of this treatment period. Aluminium injections were discontinued in the remaining animals, and nine underwent selective PTX at this time. These animals were followed for an additional 30 days. Bone aluminium levels in the animals killed after 35 days were lower (p < 0.05) in the PTX uraemic group than in the uraemic control group (37 ± 7.6 and 47 ± 7.6 mg/kg, respectively). The bone aluminium levels in the uraemic group that underwent PTX after aluminium loading (53 ± 8 mg/kg) and in the uraemic group (48 ± 5.7 mg/kg) 30 days after aluminium discontinuation were not significantly different. The results of this study suggest that PTX affects the compartmentalization of aluminium in bone, especially in animals in a uraemic state. It also appears that PTX may intensify aluminium-induced osteomalacia as the PTX group had significantly greater bone osteoid area than the uraemic group of rats.

Galceran et al. () conducted a study to further characterize the mechanism of aluminium induced osteomalacia. One group of dogs (n=7) was treated i.v. with 0.75 mg aluminium, 5 days a week for 3 months; 7 additional dogs served as controls. At the end of the treatment period, the dogs were killed, and the tibiae were obtained and perfused in vitro. PTH and methylxanthine (an inhibitor of phosphodiesterase) were added to the perfusate. The serum aluminium level was 20.4 ± 2.3 μg/L before treatment, and rose significantly to 206.2 ± 28.3 (p < 0.01) after aluminium administration. No significant difference in PTH levels was detected before and after aluminium treatment. Because PTH acts to stimulate cAMP release from bone, cAMP levels were measured in both groups before and after PTH administration to examine the effect of aluminium on this process. Although the basal cAMP secretion was the same in both groups of dogs, cAMP increased to a peak of 188.2 ± 30.6 pmol/min in the normal dogs vs. 113 ± 8.15 pmol/min in the aluminium treated dogs after PTH was added to the perfusate (p < 0.05). Examination of bone biopsies taken before and after aluminium administration revealed that the number of osteoblasts had decreased 8-fold (p < 0.01) following aluminium treatment. Aluminium treatment led to an increase in the percent total osteoid surface (44.3 ± 4.7% vs. 22.1 ± 4.1%), decreased mineral apposition rate (0.5 ± 0.4 μm/day vs. 1.3 ± 0.2 μm/day), and aluminium deposition at the mineralization front. Despite the decrease in osteoblast number, the histological features of the post aluminium treatment biopsies indicated that aluminium stimulated osteoblastic activity at some point during its administration. This was apparent from the presentation of new woven bone formation in two dogs, and a layer of newly deposited lamellar bone covering all trabecular surfaces in another. Aluminium also appeared to stimulate the activity of fibroblasts as indicated by the presence of extensive marrow fibrosis in five of the treated dogs. These data support the possibility that aluminium is capable of both stimulating and suppressing matrix synthesis at different times throughout the exposure period. Although the levels of PTH were similar in the aluminium exposed and control animals, the decreased generation of cAMP following the addition of PTH to the perfused bones of the aluminium treated group suggests that aluminium may cause bones to be resistant to the effects of PTH.

Sedman et al. () examined the effects of i.v. aluminium injections for a duration of 8 weeks on various bone parameters in growing piglets. Four piglets were administered 1.5 mg AlCl3/kg/day parenterally, and 4 control piglets received daily injections of deionised water for the same period. Quantitative bone histology and measurements of bone formation were assessed at three skeletal sites (two in the proximal tibia and one in the distal femur) in both the experimental and control groups. Bone aluminium was significantly higher (p < 0.001) in experimental animals (241 ± 40 mg/kg) as compared to the controls (1.6 ± 0.9 mg/kg). Osteomalacia, as defined by histological criteria, was documented in all aluminium-treated animals. The rate of mineralized bone formation was also lower in the aluminium-treated group compared to that in the controls at all three sites. However, it was found that, at sites of continued osteoblastic activity, total osteoid production did not differ between the two groups. These results suggest that bone mineralization is inhibited by aluminium via a decrease in the number of active osteoblasts rather than by an inhibition of the calcification of osteoid.

Ott et al. () conducted a study to investigate the development and reversibility of aluminium-induced bone toxicity in weanling and adult rats. Four groups of weanling rats and one group of adult rats were used in this study. Each group consisted of 18 rats. Half the rats in each group received daily i.p. injections 10mg Al/kg as aluminium chloride. The other half of the group was given normal saline solution. Weanling rats were sacrificed after 3, 6, or 9 weeks of treatment. The remaining group of weanling rats received injections for 9 weeks, and was allowed to recover for 3 weeks. The adult group received aluminium treatment for 9 weeks. The effects of aluminium on blood serum levels of various compounds, and on aluminium bone content, and rate of bone formation were assessed after intervals of 3, 6, and 9 weeks. The calcium, phosphate, creatinine, and PTH levels were similar in aluminium-treated rats and controls. Aluminium was detectable by histochemical stain after 6 weeks in the aluminium treated animals; however, other bone parameters did not differ significantly at this time between the treated animals and the controls. A decrease in bone formation (measured by tetracycline labelling) on trabecular and endosteal surfaces was apparent by 9 weeks in the aluminium exposed groups. The weanling rats had a bone formation rate of (0.15 ± 0.2 mm2/100 days vs. 0.46 ± 0.14 mm2/100 days) which was significantly lower (p < 0.02) than the rate in the controls, while the adult rats had a rate of (0.04 ± 0.06 mm2/100 days) vs. (0.23 ± 0.12 mm2/100 days) in the controls. One group of rats was allowed to recover for 3 weeks without any aluminium administration. The bone formation rate in the younger group was similar to that of the controls after 3 weeks of recovery. Adult rats showed signs of early osteomalacia as evidenced by an increase in the length (4.75 ± 2.3 vs. 2.15 ± 1.5% surface) and width (18.4 ± 9.7 vs. 4.8 ± 1.3 μm) of the trabecular osteoid as compared to the controls. In this study it appeared that aluminium administration led to decreased rates of bone formation in rats despite normal calcium and parathyroid levels, and normal renal function. It is possible that aluminium induced decreased bone formation by inhibiting osteoblast formation or activity.

Quarles et al. () conducted a study to define the primary effects of aluminium on bone in the mammalian species, and to examine the dose/time-dependent actions of aluminium on bone. Two year-old beagles were assigned to one of three treatment regimens. The first group (n=6) received 0.75 mg Al/kg as aluminium chloride i.v. three times per week, the second group (n=6) received 1.20 mg Al/kg at the same dosing schedule, and the third group (n=6) received sodium chloride i.v. and served as controls. The treatment period lasted for 16 weeks. Transcortical bone biopsies were taken from each group after 8 weeks and 16 weeks. In both the low and high dose aluminium groups, serum aluminium levels were significantly elevated compared with those of controls, but calcium, or PTH levels were not altered by treatment. Bone biopsies taken at 8 weeks in the low dose group displayed characteristics of a low turnover state, as marked by a reduction of bone resorption (2.6 ± 0.63% vs. 4.5 ± 0.39%) and osteoblast&#;covered bone surfaces (2.02 ± 0.51% vs. 7.64 ± 1.86%) as compared to the controls. The mineralized bone formation rate was also found to be significantly decreased. Biopsies taken at week 16 of aluminium administration in the low dose group displayed evidence of de novo bone formation, as well as an increase of bone volume (38.9% ± 1.35 vs. 25.2% ± 2.56) and trabecular number (3.56/mm ± 0.23 vs. 2.88 ± 0.11) compared to the controls. The 16 week biopsies displayed a persistence of inactive osteoid marked by a diminished mineralization front in the low dose group compared to the controls (46.0 ± 4.2% vs. 71.9 ± 2.92%). The bone biopsies obtained from the high dose aluminium group at 8 weeks displayed changes similar to those exhibited after 16 weeks of the low dose treatment. De novo bone formation was evidenced by an increase in trabecular number as compared to the controls (3.41 ± 0.18/mm vs. 2.88 ± 0.11/mm) and increased bone volume (36.5 ± 2.38% vs. 25.2 ± 2.56%). Poorly mineralized woven bone accounted for a large proportion of the newly synthesized tissue, comprising 11.5 ± 4.6% of the bone volume. High dose treatment for 16 weeks further enhanced bone volume (50.4 ± 4.61%) and trabecular number (3.90 ± 0.5/mm). The woven osteoid volume at 16 weeks decreased to 2.43 ± 0.96% of the total bone volume, indicating that heterogeneous calcification of this tissue was more complete. The observation of histological changes similar to those observed in disorders characterized by low bone turnover in the low-dose aluminium group after 8 weeks, combined with the observation of new bone formation and stimulation of cellular activity after longer treatment, suggests that aluminium may exert both inhibitory and stimulatory effects on osteoblasts.

To further examine the influence of osteoblast function on aluminium-induced of de novo bone formation, Quarles et al. () compared the effects of aluminium in TPTX beagles (n=4) with beagles which underwent thyroidectomy but had intact parathyroid glands (n=4). The animals underwent TPTX as a means to reduce osteoblast number and activity. The treatment procedure began 2 months after surgery, when sufficient time had elapsed to achieve a new steady state of bone remodelling activity. 1.25 mg AlCl3/kg was administered to both groups of animals by i.v. three times per week for 8 weeks. The TPTX animals received supplements of calcium carbonate and calcitrol in order to maintain normal plasma 1,25-dihydroxyvitamin D levels as well as normocalcemia. Both groups were administered thyroxine to sustain normal free thyroxine concentrations. Although both groups of animals received the same aluminium treatment, TPTX beagles exhibited a significantly higher (p < 0.05) serum aluminium level (.1 μg/L) as compared to the controls (.0 μg/L). Aluminium administration did not alter the plasma calcium, creatinine, or PTH from baseline levels in either group of animals. Bone biopsies taken from the control animals after 8 weeks of treatment displayed evidence of de novo bone formation as compared to baseline bone parameters. This was evidenced by an increased bone volume (47.0 ± 1.0 vs. 30.4 ± 09%) and trabucular number (4.1 ± 0.2 vs. 3.2 ± 0.2/mm). Deposition of poorly mineralized woven bone accounted for much of the enhanced bone volume (9.9 ± 2.7%). TPTX animals demonstrated significantly less evidence of bone formation. Bone volume (35.5 ± 1.7% vs. 27.7 ± 1.9% at baseline) and woven tissue volume (1.4 ± 0.8% vs. 9.85 ± 2.66%), as well trabecular number (3.3 ± 0.1/mm vs. 4.2 ± 0.2/mm) were significantly less than those of the aluminium treated non-TPTX controls. It appears that the diminished functional osteoblast pool in the TPTX beagles limited the ability of aluminium to stimulate neo-osteogenesis.

Bellows et al. () examined the effects of aluminium on osteoprogenitor proliferation and differentiation, cell survival, and bone formation in long-term rat calvaria cell cultures. The cells obtained from foetal rats were incubated in medium with or without aluminium added. The aluminium treated cells were incubated at various concentrations ranging from 1 uM to 1 mM of aluminium for up to 19 days. The numbers of mineralized and unmineralized bone or osteoid nodules in each culture dish were quantified by in situ staining. Alkaline phosphatase activity, cell viability, and cytotoxicity were also determined. Nodule formation was significantly increased (p < 0.001) by 30- μM aluminium incubation, in a dose dependent manner, at 11 days but not at 17 days. Control and aluminium-treated cultures appeared similar with respect to nodules and cell layers at day 13 of culture. However, at day 17 of culture, aluminium concentrations of 30 μM and above resulted in reduced cellularity and an increased fibrilar appearance of the matrix that had formed outside of, or adjacent to, nodules. Aluminium also increased alkaline phosphatase activity at all time points in a dose-dependent manner. Significantly fewer viable cells were present in the 300 μM aluminium-containing cultures after 13 and 17 days. The results of this experiment indicate that aluminium has a stimulatory effect upon existing osteoprogenitor cells leading to an accelerated rate of osteoblastic differentiation and nodule formation, while inhibiting nodule mineralization. The concentration of aluminium at which this effect occurred resulted in decreased cell viability and enhanced cytotoxicity.

The effect of aluminium administration on bone, in a model of osteopoenia induced by chronic acid overload in rats with normal renal function, was examined by Gomez-Alonso et al. (). Thirteen male rats with induced osteopoenia were divided into two groups. The first group (n=8) received 10 mg/kg of AlCl3 i.p. 5 times per week for 4 months, the second group (n=5) did not receive any aluminium treatment. At the end of the experiment, both tibias from each animal were extracted for the determination of aluminium content, in vitro bone densitometry, and histological analysis. Bone mineral density, measured at the proximal end of the tibia, was found to be significantly higher (<0.05) in the aluminium-treated group (0.292 ± 0.01 g/cm2) as compared to the controls (0.267 ± 0.02 g/cm2). Histomorphometric analysis showed a significant increase (p < 0.01) in bone volume (18.59 ± 5.66% vs. 7.69 ± 3.08%), cortical thickness (0.52 ± 0.06 mm vs. 0.36 ± 0.07 mm), osteoid thickness (14.05 ± 4.72 μm vs. 5.25 ± 090 μm), and osteoclast number (2.44 ± 0.52 N Oc/mm2 vs. 1.30 ± 0.01 N Oc/mm2) in the aluminium-treated group as compared to the controls. No significant differences in serum calcium, phosphorus, creatinine, hydroxyproline, or PTH were apparent between the aluminium-treated and control animals. There was no evidence of osteomalacia in the aluminium-treated rats. These findings indicate that aluminium is able to induce bone formation in rats with normal renal function even when osteopoenia is present.

Firling et al. () examined the influence of aluminium citrate administration on tibia formation and calcification in the developing chick embryo. Tibia formation and mineralization were assessed by radiology, total bone calcium content, calcium incorporation rate, collagen synthesis rate, bone alkaline phosphatase activity, and serum levels of osteocalcin, procollagen carboxy-terminal propeptide, and PTH. The chick embryos derived from White Leghorn strain eggs were divided into three treatment groups (aluminium citrate, sodium citrate, sodium chloride), and were treated acutely or chronically. Acutely treated embryos received 100 μL of 60 mM aluminium citrate, 60 mM sodium citrate or 0.7% sodium chloride via injections into the air sac of the egg on day 8 of incubation. Chronically treated embryos received a daily 25 μL dose of the solutions beginning on day 8. The embryos were incubated for an additional 2 to 8 days following treatment. Radiographic analysis of the tibias and femurs of the embryos revealed that the mineralization of the aluminium treated animals was less dense and restricted to a shorter length of the mid-diaphysis as compared to the other two groups. The bone calcium content of embryos acutely or chronically administered aluminium and incubated for 10 to 12 days was significantly lower (p < 0.05) compared to that of the other treatment groups. The calcium content of tibias from embryos chronically treated with aluminium remained lower than the controls for 12 day and 16 day embryos while, by day 14, there were no significant differences in the total calcium content from acutely treated embryos compared to the controls. Significantly higher (p < 0.05) levels of alkaline phosphatase activity were found in the tibias collected from embryos chronically treated with aluminium incubated from 12 (2.16 units/tibia/hr vs. 1.32 units/tibia/hr) to 16 days (10.38 units/tibia/hr vs. 6.78 units/tibia/hr) as compared to the sodium chloride control group. Aluminium did not have a significant effect on the rate of tibia collagen, non-collagenous protein synthesis or serum levels of procollagen carboxy terminal propeptide, osteoclacin or PTH. The lack of change in these parameters suggests that embryonic osteoblast number and activity is not markedly diminished by aluminium exposure at these doses. The authors suggested that the observed under-mineralization of the tibias in the aluminium treated embryos may be a manifestation of the production of defective osteoid, an inhibited terminal maturation of osteoblasts, or physiochemical inhibition of mineralization nucleation sites.

Zafar et al. () investigated the effect of chronic exposure to dietary aluminium on calcium absorption and calbindin concentrations in male weanling rats fed various levels of calcium and aluminium for 3 and 6 week periods. One group of rats (n=40) was fed a calcium adequate diet, three other groups of 40 animals each were fed a calcium-deficient diet with 0, 0.05 or 0.1% aluminium, as aluminium chloride. After 3 weeks, 20 rats per group were fasted overnight and 10 rats per group were given an oral dose of 25 mg calcium labelled with 6 μCi 45Ca by gavage. The other 10 rats in each group were given 6 μCi 45Ca as an interperitoneal injection. Rats were anaesthetized the following day, blood was collected and the femurs were obtained. The remaining animals (20 per group) were switched to a calcium adequate diet containing the same level of aluminium they had been fed previously, and were maintained on these new diets for another 3 weeks. No difference in 45Ca absorption was observed among the 4 groups at either 3 or 6 weeks. Aluminium supplementation at 0.05 and 0.1% of the diet reduced calbindin concentrations (compared to the group receiving a calcium deficient diet without aluminium). Total bone calcium decreased with aluminium supplementation. The bone calcium content was significantly different (p < 0.05) in the calcium deficient-no aluminium group, and in the calcium deficient groups supplemented with 0.05 and 0.1% aluminium, as compared to the calcium adequate group at both 3 and 6 weeks of treatment. In addition, the bone calcium content was significantly lower (p < 0.05) in the calcium deficient, 0.1% aluminium group as compared to all the other groups. Aluminium treatment reduced the breaking strength parameters of the bones from rats on the calcium-deficient diets. When the animals were switched to a calcium adequate diet for 3 weeks, there were no differences in the resistance to breaking due to aluminium intake. The results of this study suggest that dietary aluminium has detrimental effects on bone quality when calcium is deficient.

Cointry et al. () analyzed the effects of aluminium accumulation on whole-bone behaviour in rats. Rats (n=14) received i.p. doses of 27mgAl/day, as aluminium hydroxide (Al(OH)3), for a period of 26 weeks. Fourteen control rats received a 20% glycerol/water solution at the same dosing schedule. At the end of the experimental period, the left tibiae was obtained from each animal for bone ash determination. Both femurs from each animal were also dissected and examined for the volumetric mineral density of the cortical bone region and for cross-sectional properties of the cortical bone region. Mechanical testing of the femurs was also conducted. The Young&#;s modulus of elasticity (a measure of stiffness) was calculated, as well as the stress of the cortical tissue at the yield point, which is an indicator of the tissue&#;s ability to support loads before any crack initiation. Aluminium concentration was significantly higher (p < 0.001) in the tibias of treated animals (103 ±18 μg/g) as compared to those of control animals (6 ±1 μg/g). The volumetric bone mineral density was significantly reduced in the treated animals with respect to the controls. Up to the yield point, the structural stiffness and strength of the bones did not differ between groups; however, an aluminium-induced impairment of the ability to resist loads beyond the yield point was observed. Treatment had a negative impact on the bending stiffness (Young&#;s elastic modulus) and the yield stress of cortical bone. These parameters were decreased by 18 and 13% respectively in treated animals as compared to those of controls (p< 0.05). The cortical second moment of inertia, which is a measure of the architectural efficiency of the cortical bone, was significantly improved in aluminium-treated rats (+10% change, p <0.01) as compared to that of the control group. This suggests that an adaptive response to aluminium treatment may have caused an improvement of the spatial distribution of the available cortical tissue resulting in an enhanced ability of the bone to resist anterior-posterior bending. The results of this study suggest that the apparent adaptive response of the bone to aluminium may have maintained normal stiffness and strength, but aluminium may have reduced the ability of the bone to resist loads beyond the yield point, or the ultimate strength of the bone.

Mineral Metabolism

The effects of aluminium on metabolic parameters in humans are not well understood. There have been relatively few studies of the effects of occupational exposure to aluminium on mineral metabolism. Ulfvarson & Wold () examined the levels of trace metals in the blood of welders of aluminium and stainless steel. Although the authors did not report the levels of aluminium in blood, which would have been useful in gauging exposure, other studies of aluminium welders have noted relatively high levels of exposure (Buchta et al., ). In the study by Ulfvarson & Wold (), the levels of lead, strontium, rubidium, bromine, gallium, zinc, copper, cobalt, iron, manganese, chromium, calcium, potassium, sulphur, phosphorus, silicon, and magnesium in the blood of aluminium welders were not statistically different from the levels of controls. However, significant variability in the data was noted. Little is known regarding the effects of aluminium on other metabolic parameters in humans.

Most of the data on the effects of aluminium on trace metal, and general, metabolism originates from studies on animals given aluminium by various routes. There is clear evidence that aluminium can influence iron metabolism in the context of haematopoiesis (see Effects on Laboratory Mammals and In Vitro Test Systems, Effects on Haematopoieses). However, as described below, alterations in iron levels in solid organs have also been noted, but with inconsistent outcomes. Studies of the metabolism of trace metals have yielded similarly conflicting outcomes. There have also been reports of alterations in a variety of metabolic pathways in response to aluminium exposure.

Non-haem iron and trace metals

Golub et al. () reported that mice fed diets containing as much as 1 mg Al/g for 150 days had small, but statistically significant, reductions in the levels of iron in spinal cord and liver. The calculated dose of aluminium exposure in this experiment was 200 mg/kg b.w./day, which is about 100-fold greater than dietary exposure in humans. Animals exposed to these levels of aluminium had no significant differences in body weight.

Ward et al. () injected rats (i.p.) with aluminium gluconate (2 mg/kg b.w.) 3 times a week for 8 weeks and then examined iron levels in liver, kidney, heart, spleen, and brain. Two to three-fold increases in tissue iron levels were noted in liver, spleen, and brain. Blood levels of aluminium were not reported, but the levels of aluminium in liver and spleen were recorded as 100 ng/mg protein and 150 ng/mg protein, respectively, indicating substantial exposure.

Han et al. () examined non-haem iron levels in kidney, liver, and intestine of chicks fed diets containing 0.15 and 0.3% (by weight) aluminium for 3 weeks. Chicks receiving the higher dose of aluminium were reported to have gained 28% less weight. Levels of iron in liver were reduced by 40%, with 30% reductions in iron levels in intestine.

Esparza et al. () examined the levels of manganese, iron, and copper in the brain and liver of rats given i.p. injections of aluminium lactate (5 mg/kg b.w.) 5 days per week for 8 weeks. Rats exposed to this level of aluminium showed 5-fold increases in aluminium levels in liver (8.45 μg/g compared to 48.35 μg/g) with a 2-fold increase in cerebellum (5.49 μg/g compared to 12.51 μg/g). The cortex and hippocampus of brain showed trends towards increased aluminium accumulation, but were not statistically different from those of controls. In liver, manganese levels were reduced by 40% with no alterations in iron or copper levels. In cerebellum, there were no statistically significant changes in the levels of any of these metals while, in cortex and hippocampus, the levels of copper were reduced 25 to 40%. Cortex also showed 25% reductions in manganese. Animals injected with aluminium lactate gained 25% less weight than control animals injected with vehicle.

The levels of copper, zinc, and manganese have been measured in the serum of rabbits exposed to aluminium by s.c. injection of aluminium sulphate (600 μmol aluminium/kg b.w./day) five times per week for 3 weeks (Liu et al., ). The total aluminium exposure per rabbit for the entire study was 243 mg/kg b.w. Aluminium levels in serum increased from 0.25 μg/mL to 1.3 μg/mL after 21 days of treatment before levelling to 1.2 μg/mL by day 42 of treatment. There were no statistically significant changes in the levels of zinc, copper, or manganese in serum after either 21 days or 42 days of treatment. The authors reported weight loss in the aluminium-treated group but did not specify the degree of loss.

Fattoretti et al. () examined the levels of copper, zinc, and manganese in the brains of rats exposed to aluminium through drinking water (2 g AlCl3 /L) for 6 months beginning at the age of 22 months. Serum levels of aluminium were not reported, making it difficult to assess the level of exposure. The authors sampled 3 domains of the brain; fore- and mid-brain together, pons and medulla together, and cerebellum. In cerebellum, there was no significant change in the levels of any metal. The authors reported accumulations of aluminium in fore- and mid-brain (94% increase) with increases in copper, zinc, and manganese (32, 41, and 50%, respectively). Pons and medulla showed 53% increases in aluminium accumulation with 46, 46, and 41% increases in copper, zinc, and manganese, respectively.

Sanchez et al. () described an analysis of calcium, magnesium, manganese, zinc, copper, and iron levels in rats of 3 age groups exposed to aluminium in drinking water. The doses used were 50 and 100 mg/kg b.w./day of aluminium nitrate with added citrate at 355 and 710 mg/kg/day, respectively, to increase absorption of the metal. The ages at which studies were initiated were at 21 days, 8 months, and 16 months. Studies were terminated after 6.5 months of exposure and the levels of each trace element were measured in liver, bone, testes, spleen, kidney, and brain. The authors did not report the levels of aluminium in serum or bone, so it is difficult to assess the relative exposures of the animals. The amounts of aluminium in the water were roughly 10,000 times the average exposure level of humans and the addition of citrate would likely have increased absorption. Under these conditions, for each trace element, there were statistically significant effects of aluminium for multiple tissues; however, there were not always dose-dependent responses and the response of young vs. older animals sometimes differed. Among the most striking changes were the 25 to 50% reductions in calcium levels in kidney and brain of the mid and old age groups given the highest dose of aluminium. In young animals given the highest dose, however, the levels of calcium in these organs were ~2-fold higher than in those of controls. The testes of older animals also showed 2 to 3-fold increases in calcium levels. The data on copper levels showed significant fluctuations among age and treatment groups. The most robust finding was that, in young animals exposed to both doses of aluminium, the level of copper was reduced 30 to 50% in both kidney and brain. However, in older animals there were no changes in these organs. Magnesium, manganese, iron, and zinc levels fluctuated less among age and treatment groups in the various tissues, and there was less definitive evidence that aluminium caused consistent changes the amount of these elements in the tissues examined. There was evidence of a robust and consistent effect on levels of manganese in spleen, where, in all age groups, the highest dose of aluminium correlated with the highest tissue levels of manganese. There was also evidence of an effect on iron levels in spleen of young animals given the highest dose (30% increase in iron) and in kidney of older animals (25% reduction).

The authors also examined urinary excretion of trace metals at 2 time points within the treatment (at 3 and 6.5 months). The most robust and consistent changes in excretion were noted for zinc with a 3-fold reduction in excreted zinc at both doses in middle-aged group. In all other groups and for all other elements, the changes were either far less robust or inconsistent across age and treatment groups.

Yasui & Ota () examined the levels of magnesium and calcium in serum, spinal cord, and bone in rats fed diets low in calcium (3 mg/100g diet) and high in aluminium (194 mg/100g diet) as aluminium lactate. Control diets contained mg/100g diet calcium and 10 mg/100g diet aluminium. After 60 days of exposure, the levels of aluminium in serum increased from 0.25 μg/dL to 1.25 μg/dL. Control diet low in calcium had no effect on aluminium levels and only slightly lowered serum levels of calcium. By contrast, there was a 2-fold reduction in serum calcium levels in animals exposed to both low calcium and high aluminium. None of the diets affected serum levels of magnesium. In spinal cord, the combined low calcium/high aluminium diet led to very modest reductions in the levels of magnesium (~10% reduction). However, in lumbar vertebra, magnesium levels were reduced by 25% on the combined diet. Diets low in calcium had no effect in either tissue. The authors did not comment on whether these diets affected weight gain.

In a study of much shorter duration (18 days) in which lower doses of aluminium were used (~270 μg/g of food), Greger et al. () examined the levels of phosphorus, calcium, magnesium, iron, manganese, zinc, and copper in bone, kidney, and liver of rats exposed to aluminium in diet. Two food formulations provided trace metals at levels that were at the minimum requirement and at 2-3 times the minimum requirement. The chemical form of aluminium was varied, using aluminium palmitate, aluminium lactate, aluminium phosphate, and aluminium hydroxide. No significant differences in levels of aluminium accumulation in bone were noted among the different chemical forms of exposure (control 1.9 μg/g; treated 13-15 μg/g). The authors found no significant changes in the levels of any of the studied minerals in the tissues examined in animals exposed to aluminium by any of the methods.

Boudey et al. () examined the effects of low doses of aluminium on growth rates and calcium metabolism of young weanling rats; an additional variable in the study included reductions in calcium levels. Animals were given control diets (8.4 mg Al/kg b.w. or supplemented diet (10.6 mg Al /kg b.w.), with or without altering calcium levels (7.6 g Ca /kg b.w. vs. 0.4 g Ca/kg b.w). Animals exposed to the higher dose of aluminium in calcium deficient diets weighed 40% less at the end of the 90 day study. Aluminium levels in brain, liver, and bone were approximately 3-fold higher than those of animals given diets containing normal levels of calcium and the lower dose of aluminium. The authors also noted that, in the presence of normal levels of calcium, the higher dose of aluminium caused 25 to 40% reductions in the levels of calcium in bone, liver, and brain. One conclusion of the study was that young animals may be more sensitive to the effects of aluminium if diets are deficient in calcium.

In comparison to these outcomes, Julka & Gill () reported that young (100-150 g) rats exposed to very high doses of aluminium by i.p. injection (10 mg/kg b.w. per day) for 4 weeks had elevated levels of calcium (2 to 3-fold) in cortex and hippocampus of brain. Other physiological consequences related to calcium included decreased (~40%) calcium influx in isolated synaptic preparations from the aluminium-treated animals and reduced ability of calmodulin to stimulate cAMP phosphodiesterase (~25% reduction in activity).

Mahieu & Calvo () examined renal function in rats exposed to aluminium by i.p. injection of aluminium hydroxide (80 mg/kg b.w., 3 times per week, for 6 months). After 6 months of exposure, aluminium levels in serum reached 800 μg/L as compared to controls (10 μg/L). These exposure levels are 400 to 800-fold higher than typically found in human serum (see Effects on Laboratory Mammals and In Vitro Test Systems, Neurotoxicity). Deposition of aluminium in trabecular bone was also observed, indicating significant exposure levels. Similar to results of other studies, the authors reported that treated animals showed reductions in weight (25%) and reduced efficiency of nutrient utilization. No obvious loss of renal function was noted; there were significant reductions in the excretion of phosphorus (40% less) with significant increases in calcium excretion. The suggested mechanism for the effects on renal function involved loss of PTH response, either by lower release of the hormone or reduced receptor sensitivity.

In another study of renal function, Braunlich et al. () reported that aluminium exposure (i.p. injection of 0.5 mg/kg b.w., 5 times weekly for 12 weeks) led to increased urine output (45%) and increased sodium excretion (57%). Notably, the dose used in these studies was more in line with what would be used to achieve 10-fold increases in aluminium loads in rodents.

Mahieu et al. () examined the intestinal absorption of phosphorus and its subsequent deposition in bone in rats exposed to aluminium. Animals were injected i.p. with aluminium lactate (5.75 mg/kg b.w.) 3 times per week for 3 months. By the end of the study, serum levels of aluminium were reported to be 600 μg/dL as compared to 10 μg/dL in controls. Slight reductions in body weight (10%) at 3 weeks of treatment were noted. In serum, there were no differences in calcium or phosphorus levels between control and treated groups at any age tested. At 1, 2, and 3 months of exposure, 25 to 30% reductions in the level of phosphorus excreted in urine were noted. Small, but statistically significant, reductions in the levels of phosphorus absorbed by the intestine were also noted. Similar reductions, small but statistically significant, in calcium absorption were also reported. Slight increases in calcium urinary excretion were detected along with 10% reductions in calcium levels in bone. A significant increase in the bone accretion of phosphorous (32P deposited/32P absorbed) was also noted in treated animals as compared to controls (27% increase). Bone calcium was significantly (p < 0.03) reduced in treated rats (10% decrease). These findings indicate that phosphorous metabolism may be modified by aluminium through direct action on the intestine, kidney, and bone.

General metabolic effects

There are several reports that provide evidence that aluminium may have effects on multiple metabolic pathways. There have been two studies on the effects of aluminium on metabolic enzymes. Rats exposed to 100 μM aluminium chloride in drinking water (2.6 μg Al/mL) for 12 months showed 2-fold elevations in aluminium in brain with reductions in the activities of hexokinase and glucose-6-phosphate dehydrogenase (G6PDH) (73 and 80% of normal) (Cho & Joshi, ). Reductions in erythrocyte activities of G6PDH and glutathione reductase (82% of normal for each) were reported in rats injected i.v. with 5 mg AlCl3/kg for 3 consecutive days and then harvested at 4 weeks post treatment (Zaman et al., ).

Another study examined nutritional effects of aluminium in drinking water (administered as aluminium nitrate at doses of 360, 720, mg/kg b.w./day) for 100 days (Domingo et al., ). Young female rats exposed to the highest dose gained 50% less weight than animals on lower doses or the controls. The largest difference in weight gain occurred in the first weeks of the study. Animals on the highest dose drank less water, consumed less food, and showed less urine and faecal output. No changes in blood uric acid, cholesterol, glucose, creatine, or urea levels were detected in any treatment group.

Gonzalez et al. () reported that rats given aluminium hydroxide by i.p. injection (27 mg/kg b.w.) 3 times per week for 3 months show 25% reductions in bile flow, 39% reductions in bile salt output, 43% reductions in bile cholesterol output, and 38% reductions in total bile protein output. These effects were correlated with 40% reductions in the expression of multidrug-resistance-associated protein 2, which is the main multi-specific organic anion transporter of the bile duct. Plasma concentration of aluminium in these animals reached 750 μg /L (controls 9 μg/L), indicating very significant exposure. No change in weight was detected in the treated animals.

Effects on Haematopoiesis

One of the most common abnormalities associated with renal failure and haemodialysis is anaemia. Many patients with this disease receive high doses of hydroxyl aluminium gel over long periods to control serum phosphorus levels. As described above in Effects on Laboratory Mammals and In Vitro Test Systems, Neurotoxicity, the majority of aluminium found in serum is bound to Tf, which is responsible for the transport of iron. As described below, Tf and iron are crucial regulators of erythropoiesis; thus an immediate suggestion of a mechanism behind anaemia in patients afflicted with renal failure is evident that implicates aluminium.

However, in the majority of these patients, treatment with erythropoietin, a hormonal stimulator of haematopoiesis, is effective in restoring haematocrits (percentage of cells in whole blood that are red blood cells), at least partially (Eschbach et al., ; Sakiewicz & Paganini, ). In most patients, one physiological basis of anaemia stems from compromised production of erythropoietin by diseased kidneys, leading to chronic anaemia. The condition is often exacerbated by iron deficiency, which can arise from decreased red blood cell t½, chronic loss of blood, decreased uptake, and other nutritional deficiencies (Drüeke, ; Sakiewicz & Paganini, ; Winearls, ). In the majority of haemodialysis patients, treatments with erythropoietin and iron supplements are sufficient to raise haematocrits to levels >30% of normal, a level that alleviates most symptoms of anaemia. Although some patients are hyporesponsive to erythropoietin, the levels of iron-saturated Tf and aluminium do not provide a correlative explanation (Eschbach et al., ); unresponsive patients do not have higher serum levels of aluminium or lower levels of iron saturated Tf. Thus, in patients who are exposed to high levels of aluminium, the physiological basis for anaemia is complex and involves, at least in part, a loss of hormonal stimulation. However, as outlined below, there are both cell culture and animal model data to indicate that aluminium has the capacity of perturb haematopoiesis and thus effects on this system should be considered in assessing aluminium toxicity.

In vivo animal studies

The effects of aluminium on haematopoiesis have been investigated in various animal models. In these studies, aluminium exposure has been accomplished by both oral and injection routes. Data from selected studies involving direct injection of aluminium salts will be summarized first. As a point of reference, the average human exposure to aluminium in drinking water, is ~ 2.3 μg/kg b.w./day, with steady-state serum levels of aluminium averaging ~2 μg/L in most individuals (see Effects on Laboratory Mammals and In Vitro Test Systems, Neurotoxicity).

Chmielnicka et al. () exposed rats to high doses of aluminium chloride (4 mg/kg b.w./day) for 21 days by i.p. injection. Although the levels of aluminium in serum were not reported, this exposure level equates to 800 μg/kg b.w./day of elemental aluminium. At 3, 7, 14, and 21 days of exposure, the authors measured platelet counts, red blood cell counts, serum levels of iron, total haemoglobin levels, and haematocrits. No significant changes in platelet or red blood cell counts were noted at any age. By 21 days of exposure, small, but statistically significant, decreases in total haemoglobin and haematocrit were reported. The most robust effect identified was a 25 to 30% reduction in the level of iron in serum.

Farina et al. () exposed rats to aluminium sulphate (50 μmol/kg b.w. = 2.6 mg of aluminium/kg b.w.) through i.p. injections 5 times a week for 3 months. The levels of aluminium in serum were not reported. At the end of the exposure period, the authors reported finding several indications of toxicity to the haematopoietic system, including 32% reductions in total haemoglobin levels, 24% reductions in haematocrit, and 30% reductions in serum levels of iron. However, total iron-binding capacity of serum from exposed animals was not statistically different from controls.

I.p. injections of aluminium hydroxide (80 mg/kg b.w. &#; 3 times per week) have also been used as an experimental model of chronic exposure to aluminium. Mahieu et al. () studied animals exposed for up to 28 weeks, while Bazzoni et al. () examined animals treated for 12 weeks. Serum levels of aluminium were not reported in these studies and thus the sustained body burden is not known. The elemental aluminium content of this exposure was calculated to be ~27 mg/kg b.w. at each injection. Several haematological factors were measured in each study. Mahieu et al. () noted progressive decreases in mean corpuscular volume (microcytosis) to a maximum of 28% reductions. However, minimal reductions in red blood cell counts and haematocrit were reported. Modest reductions in total haemoglobin (20% reduction) and small increases in red blood cell fragility were reported. Bazzoni et al. () reported 20% reductions in total haemoglobin with 7% reductions in haematocrit. This latter study reported significant increases in red blood cells with deformed morphology (not quantified) with slight increases in fragility. Bazzoni et al. () also reported that red blood cells in the treated animals were 3 times more rigid and less prone to aggregate.

Farina et al. () conducted a second study of rats exposed to aluminium citrate (30 mM aluminium sulphate with 35 mM sodium citrate) in water for a total of 18 months. The daily exposure to aluminium was estimated to be 54.7 mg/kg b.w. Citrate would be expected to increase absorbance; however serum levels of aluminium were not reported. The authors reported that chronic exposure at this level led to reductions of 20% in red blood cell counts, 13% in haematocrit, 15% in total serum haemoglobin, and 40% in total levels of iron in serum. However there was no change in total iron binding capacity and no increase in red blood cell fragility. Turgut et al. () exposed mice to aluminium for 3 months through drinking water containing aluminium sulphate. The estimated dose was 877 μmol/kg b.w./day = 47 mg of aluminium/kg b.w./day. Serum levels of aluminium were not reported. Reductions in serum haemoglobin (14%) and haematocrit (13%) were described. The levels of iron in serum were elevated by 59% with a small increase in the levels of Tf.

Garbossa et al. (a) have reported evidence that aluminium exposure may have direct effects on erythroid differentiation, which may account for the reductions in red blood cell counts and haematocrit in animals exposed to aluminium. Garbossa et al. (b) conducted a study in which rats were exposed to aluminium citrate at two levels by two routes for 15 weeks; 1 μmol/g b.w./day by oral gavage 5 days/week and by drinking water containing a 100 mM solution (estimated exposure 14-17 μmol/g b.w. day). Serum levels of aluminium were measured in this study with the dose given by oral gavage leading to serum aluminium levels of 2.9 μmol/L (78 μg/L), as compared to controls with 0.8 μmol/L (21.5 μg/L). The serum levels of aluminium in animals exposed through drinking water were 3.6 μmol/L (97 μg/L). The authors reported that animals given aluminium in drinking water had reductions in haematocrit (11%), increased osmotic fragility of red blood cells (20% more fragile), and 24% reductions in red blood cell t½. At both the lower and higher dose, there were reductions in the ability of isolated bone marrow stem cells to differentiate into erythrocytes after exposure to erythropoietin (colony-forming units &#; erythroid). In a later study by the same group, Vittori et al. () exposed rats to aluminium via drinking water containing 80 mM aluminium citrate for 8 months. At the end of the study, the serum level of aluminium in the treated rats was 205 μg/L (range 120-790 μg/L) whereas the level in control animals was 15 μg/L (range 5 to 90 μg/L). These levels are between 10 (control) and 200 (treated) times the average level of aluminium in human serum (1-2 μg/L - see Effects on Laboratory Mammals and In Vitro Test Systems, Neurotoxicity). At this high exposure level, very significant reductions in erythrogenesis were found ~60% reduction in erythroid colony forming units (CFU-E) and decreased uptake of iron (~30% reduction). The authors also reported significant increases in abnormal red blood cell morphology.

In vitro studies

Studies of the effects of aluminium on erythroid cell differentiation have suggested potential mechanisms by which aluminium could impact haematopoiesis. In a study by Vittori et al. (), direct evidence that aluminium inhibits erythroid differentiation was reported. Erythroid progenitor cells were concentrated from human blood and exposed to 100 μmol aluminium citrate (8 mg/L elemental aluminium) for 10 days and induced to differentiate with erythropoietin. The authors reported 30% reductions in CFU-E activity. However, in a similar study, Mladenovic () reported that aluminium at levels of 1,035 ng/mL (1.035 mg/L) in medium did not significantly diminish CFU-E. However, if Tf was added to the medium along with aluminium, then CFU-E was diminished by 90%. If Tf was first saturated with iron, aluminium had no effect. The negative effects of Tf-aluminium were not overcome by adding excess levels of erythropoietin. One conclusion that could be drawn from this study was that a primary effect of aluminium on erythroid differentiation was mediated by competition for the Tf receptor. If excess Tf saturated with aluminium is present, then erythroid differentiation is inhibited by the binding of aluminium-metallated-Tf (aluminoxamine) to its receptor. However, the affinity of Tf for iron is 5 orders of magnitude greater than its affinity for aluminium. Hence excess aluminium alone cannot displace the iron from Tf-iron complexes that pre-exist in culture medium. Adding demetallated Tf to the medium allows aluminium to bind and thus creates the opportunity for Tf-aluminium-complexes to compete for binding to the Tf receptor. The extent to which a similar scenario may occur in vivo depends upon the levels of free Tf in serum at the time of aluminium exposure and on the level of iron in the serum. If sufficient iron is present, then aluminium binding to Tf would be less favoured. Individuals with iron deficiency could therefore be at greater risk for developing haematopoietic abnormalities upon exposure to aluminium.

Direct effects of aluminium salts on the morphology of red blood cells have been reported (Suwalsky et al., ; Vittori et al., ; Zatta et al., ). However, as outlined above in Effects on Laboratory Mammals and In Vitro Test Systems, Neurotoxicity, most studies of aluminium metabolism indicate that most of the aluminium, absorbed from drinking water or food, present in plasma would be bound to Tf. Thus, the amount of soluble aluminium salts that red blood cells would be exposed to is limited. However, Tf-mediated delivery of aluminium to erythroid progenitors does provide a means to expose these cells directly to the metal. Vittori et al. () noted that red blood cells exposed to aluminium citrate in vitro acquired abnormal morphology and showed increased degradation of a protein involved in maintenance of cell shape (band 3 protein). Suwalsky et al. () similarly reported that red blood cells exposed to aluminium fluoride in vitro developed abnormal morphology.

Dermal application

Aluminium was applied in 0.5 mL solution as 2.5, 5, 10 and 25% aluminium chloride, or 10 or 25% aluminium chlorhydrate to 2 cm2 of shaved skin on the back of TF1 strain mice for 5 consecutive days. Aluminium was similarly applied for 5 days to mice, New Zealand rabbits and white strain pigs (1 mL of solution to 4 cm2) as 10% aluminium chloride, nitrate, chlorhydrate, sulphate, hydroxide (in suspension) and basic acetate (in suspension), and as 25% aluminium chlorhydrate. The 10% solutions of aluminium chloride and nitrate produced epidermal changes that included slight to severe hyperplasia with focal ulceration, epidermal damage, dermal inflammatory cell infiltration, hyperkeratosis, acanthosis, microabscesses, aluminium deposition and abnormal keratin (Lansdown, ). The other 4 aluminium forms did not produce these changes. The author suggested that the aluminium ion interacted with keratin to denature it, making the stratum corneum more permeable, thereby allowing aluminium penetration through the stratum corneum to cause toxicity to the epidermal cells. Magnesium aluminium silicate was a weak primary skin irritant in rabbits (CFTA, ). Therefore, aluminium can produce dermal irritation that is aluminium species-dependent.

In vitro test systems

Many reports are cited in Effects on Laboratory Mammals and In Vitro Test Systems, Irritation, Inhalation Exposure / Intratrachael Exposure, and Effects on Humans, Effects from Occupational Exposure, Irritation, Inhalation Exposure of the ability of aluminium to cause pneumoconiosis, an inflammation of the lung that can progress to fibrosis, which is typically caused by inhalation of dust. There are also many reports of negative findings. The discrepancy may be due to the chemical form (species) of the inhaled aluminium, granular vs. flake-like particles. In this section, studies addressing the mechanism(s) of action of these irritant effects are discussed.

Corrin (a;b) noted that aluminium reacts with water but is not able to do so when coated with inert aluminium oxide. Granular aluminium coated with aluminium oxide is produced without use of lubricating agents, such as spindle oil and stearine. The author attributed many of the reports of negative effects to exposure to aluminium oxide or aluminium oxide-coated aluminium. The author also found that spindle oil- or stearine-coated aluminium powder reacted with water, presumably forming reactive aluminium hydroxide, whereas stearine-coated aluminium powder did not, and noted that the substitution of mineral product for stearine coincided with the onset of aluminium-induced pneumoconiosis. The explanation offered was that respirable aluminium particles that can react with water in the lung can be toxic.

Aluminium oxide was shown to release histamine from rat peritoneal mast cells (Casarett et al., ). The greatest effect, seen with 4.4 μm maximal median diameter particles at pH 6.8, was comparable to that see with iron oxide but less than seen with chromium oxide. This may contribute to bronchoconstriction caused by inhaled aluminium particles. Four clays containing aluminium silicate (montmorillonite, bentonite, kaolinite and erionite), caused lysis of human umbilical vein endothelia, N1E-115 neuroblastoma and ROC-1 oligodendroglial cells (Murphy et al., ). The authors suggested these clays might disrupt the BBB, allowing their entry into the brain. Exposure of mouse peritoneal macrophages, human type II alveolar tumour (A549) cells and Chinese hamster V79-4 lung cells to 11 minerals, including short and long fibres of attapulgite (a hydrated magnesium aluminium silicate) revealed some dusts that were non-toxic to all three cell types, some that were toxic toward mouse peritoneal macrophages, as shown by LDH release, and some that were toxic to all 3 cell types, additionally causing increased diameter of the A549 cells and reduced survival of 79-4 cells (Chamberlain et al., ). The results suggest differential sensitivity of cells to toxicity produced by these dusts and that long-fibred dusts are more toxic than short-fibred dusts. Exposure of rabbit AM to hydrated aluminium silicate resulted in toxicity, as evidenced by reduced viability and ATP (Hatch et al., ). Hydrated aluminium silicate caused concentration-dependent haemolysis of erythrocytes (Woodworth et al., ). Murine neuroblastoma cells exposed to hydrated aluminium silicate showed an increase in membrane electrical conductance and loss of excitable activity, as evidence of toxicity (Banin & Meiri, ).

Immunotoxicity/Immunosuppression

The immune system and its reactions involve interactions between various cell types and soluble mediators. These responses can be clustered into innate (natural and non-specific) and acquired (adaptive) responses for which the reaction is directed to an antigenic determinant or epitope. Non-specific responses involve effector cells such as macrophages, natural killer cells, granulocytes, and mediator systems such as the complement system. Biologically, components of the immune system are present throughout the body and interactions between the immune system and other organ systems are a normal component of immunoregulation. While a number of metals have been demonstrated to have immunotoxic properties, little has been reported for aluminium (IPCS/WHO, ). In addition, aluminium hydroxide has been used as an adjuvant in many human vaccines (Roit et al., ) (see Table 7). Vaccine efficiency is enhanced by aluminium&#;s capacity to absorb antigen particles forming granulomas in the point of injection. Early studies suggested altered immune responses following excess aluminium exposure. Pregnant Swiss-Webster mice exposed to aluminium (500 or 1,000 μg Al/g diet; as aluminium lactate) showed a lower resistance to bacterial Listeria monocytogene infection while non-pregnant mice showed the reverse (Yoshida et al., ). Acute injection of aluminium (1-10 mg/kg body weight to non-pregnant mice) resulted in a lower mortality rate to L. monocytogenes as compared to controls (Yoshida et al., ). In these studies, the offspring showed no differences in mortality rates. However, Golub et al. () suggested that excess aluminium exposure ( μg Al/g diet; as aluminium lactate) in Swiss Webster mice from conception to 6 months of age resulted in alterations in immune effector cell function. Splenic lymphocytes showed a depressed response to concanavalin A. When the spleen weight was measured in mice fed ppm in the food from weaning to adulthood (4 week and 8 week exposures) no changes were detected relative to controls (Golub & Keen, ). Based upon these studies, Tsunoda & Sharma () examined pro-inflammatory cytokine mRNA levels in the brain and immune organs of mice following a 1-month exposure to 125 ppm aluminium ammonium sulphate in the drinking water. Isolated splenic macrophages and lymphocytes showed no aluminium-related changes in the basal mRNA levels of TNFα, IL-1β, or IFNγ. However, the authors suggested that, while low and somewhat variable, basal mRNA levels for TNFα were increased in the brain of aluminium exposed mice (Tsunoda & Sharma, ).

Effects on the Endocrine System

With the exception of experimental studies in which the effect of aluminium exposure on the reproductive system has been examined (Effects on Laboratory Mammals and In Vitro Test Systems, Reproductive and Developmental Toxicity, Reproductive Toxicity), those designed to examine adverse effects on the endocrine system have been limited to the parathyroid response given that aluminium overload leads to PTH suppression.

Many of the PTH receptors of interest for aluminium toxicity are present in both the bone and kidney; thus, much of the data with regard to the effect of aluminium exposure on the bone discussed in Effects on Laboratory Mammals and In Vitro Test Systems, Effects On Bone is related to the alterations in serum PTH levels and calcium homeostasis. For example, Pun et al. () demonstrated that lower concentrations of aluminium (4μm and 40 μM) inhibited the cyclic AMP response to PTH challenge via a decrease in PTH receptor binding in both clonal osteoblastic UMR-106 cells and in dog renal cortical membrane. Bourdeau et al. () examined the endocrine response of porcine parathyroid gland tissue slices to aluminium at concentrations of 20 to 500 ng/mL. High concentrations of aluminium inhibited induced PTH release in a calcium-dependent manner. Gonzalez-Suarez et al. () reported that 8 weeks of exposure to aluminium chloride (AlCl3) (i.p. daily) reduced serum PTH levels and cell proliferation in the parathyroid glands, yet did not alter serum phosphorus levels, cell apoptosis or the calcium sensing receptor expression in young adult male Wistar rats surgically nephrectomized (7/8th tissue excised). In a similar study, Diaz-Corte et al. (), surgically nephrectomized adult male Wistar rats maintained on a high dietary phosphorus intake received 2 daily ip. injections of AlCl3 five weeks after surgery and examined 2 weeks post-injection. While significant decreases in serum PTH levels and mRNA levels for PTH in the parathyroid gland were seen in the aluminium-injected group, no differences were seen in serum calcium and phosphorus levels, renal function or body weight. Similar decreases in plasma PTH concentrations have been reported in cats with stable chronic renal failure when maintained on a diet restricted in phosphorus and protein with aluminium hydroxide included as an intestinal phosphate binding agent (Barber et al., ).

Interactions Between Aluminium and Other Agents

With additional investigation, the roles of social, environmental, and biological factors as either modifiers of potential risk or susceptibility factors for adverse effects from chemical exposure are becoming more evident. With regards to genetic factors, Fosmire et al. () examined the level of aluminium in the brains of 5 strains of inbred mice following dietary exposure to 260 mg Al/kg b.w. for 28 days. While no difference could be detected between the A/J, BALB/c, and C57BL/6 strains, higher levels of aluminium were seen in the brains of DBA/2 and C3H/2 strains. Interestingly, the C3H/HeJ and the C57BL/6 strain differ in bone density (Beamer et al., ) and calcium metabolism which is thought to occur partially via the vitamin D and PTH endocrine systems&#; regulatory influence on extracellular calcium (Chen & Kalu, ), both of which can be influenced by aluminium. Tf plays a significant role in the biological availability of aluminium to organ systems. The ability to saturate Tf with iron was reported to be approximately 10 times greater in C57BL/6 and BALB/c mice than in DBA/2 and AKR mice; however, serum Tf levels were equivalent across these strains (Leboeuf et al., ). For a discussion of other potentially modifying factors such as age, and interactions with other chemical species, see Toxicokinetics.

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