Toxicity of Aluminum to Animals and Humans

The ubiquitous presence of aluminum in soil, water, food, and pharmaceuticals makes exposure to this metal unavoidable for most species. The potential toxicity to humans has been debated since at least the 1920s with the advent of commercially available aluminum-containing baking powders (330). In natural habitats, concern about toxicity increased in the 1970s with the knowledge that acidification of natural waters from acid rain, mine drainage, and deforestation increased the mobilization and bioavailability of soil aluminum (352). The growing awareness of increased exposure to aluminum and the clear demonstration of its potential toxicity to animals and humans (discussed below), combined with its possible association with Alzheimer's disease has given rise to an exponential increase in research related to the metabolism and toxicity of this metal. In the decade from 1970 to 1980, only 140 publications are listed by a bibliographic search using the keywords 'aluminum toxicity,' compared to 1035 publications in the decade from 1990 to 2000. For this reason, a detailed review of aluminum toxicity and metabolism in animals and humans is outside the scope of this section and the reader is referred to several recent reviews for this purpose (358-360). The focus of this section will be on the consequences of aluminum exposure from common sources in the food chain with reference, when possible, to potential toxic mechanisms.

Toxicity to Wildlife

Much of the concern about aluminum toxicity to wildlife stems from the fact that many lakes and streams have been acidified by natural or industrial causes resulting in increased concentrations of aluminum in their waters. Sparling and Lowe (352) presented a comprehensive review of the environmental toxicity of aluminum and discuss its toxicity in invertebrates, fish, and other wildlife.

Aquatic species, especially freshwater fish, have been studied the most, and it is clear that their survival can be reduced greatly as aluminum concentrations increase in acidic water (361). In fact, aluminum toxicity is thought to be the most common cause of fish die-offs. Levels of aluminum above 100 to 500 µg L^-1 are usually needed to cause death depending on fish species and water conditions such as the amount of dissolved organic matter and pH. Acidity is also toxic and is additive to the effects of aluminum.

The mechanisms of aluminum toxicity fall into two categories based on water pH: asphyxiation in the pH range of 6.5 to 5.5, and loss of electrolytes from the blood in the pH range of 5.5 to 4.5. At the more acidic pH range, soluble cationic species of aluminum are thought to bind to negatively charged sites on the gill surface, displacing bound calcium ions that regulate electrolyte fluxes. This displacement results in the diffusion of sodium and chloride out of the body. In the less acidic pH range of 5.5 to 6.5, the formation of uncharged Al(OH)₃ is more likely. These uncharged species form colloids and precipitates that collect on the gill surface, stimulating excess mucus formation. The excess mucus inhibits oxygen and CO₂ diffusion leading to asphyxiation (362). Aluminum appears to be relatively nontoxic to fish at basic pHs where anionic species would predominate.

Dissolved organic matter, such as humic acid, can chelate positively charged aluminum species preventing aluminum from interacting with the gill, thereby reducing aluminum stress (352). Birchall (363) has proposed that silicon can also ameliorate aluminum toxicity by forming colloidal hydroxyaluminosilicates that limit the availability of aluminum for binding to gill surfaces. Much less is known about aluminum toxicity to other aquatic species such as crustaceans, mollusks, and insect larvae. In general, these invertebrate species are more tolerant to aluminum than fish, but toxic mechanisms appear to be similar in those that have gills, i.e., related to alterations in calcium and electrolyte balance or respiration rates. In contrast to fish, however, invertebrates may accumulate large amounts of aluminum on or within their bodies reaching concentrations as high as 1000 mg kg^-1 (352,363,364).

There has been some concern about transfer of aluminum up the food chain. Nyholm (365) postulated that elevated levels of aluminum in invertebrates could affect wild birds feeding in or near aluminum-laden waters. In studies with flycatchers, it was reported that female birds had elevated bone aluminum levels and laid deformed eggs with soft shells leading to dehydration and reduced hatchability. Other concerns were with bone growth and body weight gain in growing chicks since aluminum in the diet at a level of 1000 mg kg^-1 has been shown to inhibit phosphate absorption, reduce feed intake, and accumulate in bone (366). Not all studies, however, have found significant toxic effects on wild birds (352).

Although the ecological impacts of aluminum mobilization into acidified water has been an important concern, recent studies by Palmer and Driscoll (367) indicate, at least in northern hardwood forests in the United States, that stream water aluminum concentrations are declining. They suggested that within 10 years, at the current rate of decline, aluminum toxicity would no longer pose a threat to fish. Remediation of acidic aluminum-laden water also is being accomplished by adding powered limestone (CaCO3) to increase pH and reduce levels of soluble aluminum and, in some cases, total aluminum (352).

Toxicity to Agricultural Animals

Generally, aluminum toxicity has not been a serious problem in livestock production (cattle, swine, sheep, and poultry). Levels of aluminum in most common feedstuffs, forages, pastures, and water supplies usually are not high enough to cause problems in animal performance or in the safety of food derived from animals, i.e., they result in diets that contain less than the maximum tolerable levels listed by the National Research Council: 1000 mg kg^-1 dry feed for cattle and sheep and 200mg kg^-1 for swine, poultry, horses, and rabbits (332). These values are for highly soluble forms of aluminum, and higher levels of less soluble forms may be tolerated.

Nevertheless, there has been concern about the toxic levels of intake in cattle and sheep foraging on plants that either accumulate high levels of aluminum or are contaminated with large amounts of soil, and in poultry consuming diets that contain aluminum from contaminated feed ingredients or from added zeolites. Toxicity symptoms are rather consistent across species. Symptoms include decreased feed intake, reduced efficiency in converting feed to body weight gain, disturbances in mineral metabolism including reduced phosphate absorption, hypercalcemia, reduced bone mineralization, and accumulation of aluminum in body tissues. Large intakes of soluble forms of aluminum (above 3000 to 4000 mg kg^-1 diet) can be fatal, especially in young animals, or when dietary calcium or phosphorus is low (332).

Storer and Nelson (368) were one of the first to compare the toxicity of different chemical forms of aluminum using young chickens as an animal model. They showed that compounds that were not soluble in dilute acid or water, such as aluminum oxide, did not produce symptoms of toxicity even at dietary levels up to 16,000 mg kg^-1 diet. Compounds that were soluble such as aluminum chloride, sulfate, acetate and nitrate produced severe toxicity at the 5000 mg kg^-1 level. Interestingly, aluminum phosphate, which is soluble in dilute acid but not in water, did not produce toxicity apparently due to precipitation in the alkaline environment of the small intestine and its inability to reduce the bioavailability of other forms of dietary phosphate.

Toxicity to Ruminants (Cattle and Sheep)

Aluminum toxicity to ruminants has not been reported under most livestock production systems. But, some concern has been expressed about the risks of inducing either a phosphorus deficiency or a condition known as grass tetany when ruminants consume large amounts of aluminum from soil or aluminum-rich forages. In general, soil does not appear to be toxic, but the more soluble forms of aluminum in plants may pose some risk.

Ruminants can consume large amounts of soil under some pasture conditions and, therefore, may consume large amounts of aluminum (up to 1.5% of the diet dry matter) (369). Since phosphorus is the mineral most likely to be deficient in the diet of grazing cattle, studies have looked at the effects of soil intake on phosphorus nutrition. Most have shown that soil intake has a minimal effect on phosphorus balance and animals are able to maintain normal serum phosphate levels (370,371). Apparently, the aluminum species in soil are not soluble enough in the intestinal tract of the ruminant to cause significant precipitation of available phosphate.

It is clear, however, that soluble forms of aluminum can induce toxicity. Crowe et al. (369) fed diets that contained soluble aluminum chloride hexahydrate at 2000 mg Al kg^-1 diet to Holstein dairy calves for 7 weeks. The results are typical of studies in ruminants using soluble forms of aluminum (370). Feed intake decreased by 17%, average daily weight gain decreased by 47%, and the amount of feed needed to produce a kilogram of weight gain increased by 50%. Fecal phosphorus excretion increased by 79% and plasma inorganic phosphate concentrations dropped to levels found in phosphorus-deficient animals. Aluminum accumulated in bone thereby causing demineralization, serum calcium concentrations rose, and urinary and fecal calcium excretion increased. To what extent natural aluminum species in forages can cause these symptoms is not known.

Grass tetany is a serious, often fatal metabolic disorder, characterized by low magnesium levels in the blood. Grass tetany occurs most often in female ruminants in the early stages of lactation while grazing on succulent, immature, magnesium-deficient grasses in springtime. Symptoms include poor coordination, convulsions, and death, presumably related to a metabolic deficiency of magnesium. Several outbreaks of grass tetany have been associated with pastures and forages containing high aluminum concentrations such as wheat and tall fescue containing 1000 to 2000 mg Al kg^-1 (372). Although most studies looking at soil aluminum intake have not shown significant effects on serum magnesium levels, some studies using soluble aluminum (such as aluminum citrate) have shown small decreases (370,372). It was suggested that the decrease in serum magnesium was not caused by reduced magnesium absorption. Rather, aluminum can cause hypercalcemia, which induces the loss of magnesium in urine. This loss may contribute to the appearance of grass tetany.

Toxicity to Poultry

Aluminum toxicity has not been reported as a significant problem in poultry production, but concerns have been raised due to the possible intake of soluble aluminum compounds from feed ingredients such as aluminum-flocculated algae, aluminum-contaminated mineral mixes, or the intentional use of zeolites to improve eggshell quality.

Sodium zeolite A (Na₁₂[(AlO₂)₁₂ (SiO₂)₁₂]- 27H₂O) is a synthetic aluminosilicate with cation exchange properties that has been shown to improve eggshell quality when added to the diet at 0.75 to 1.5%, as mentioned earlier under beneficial effects. When added to the diets of young chicks, however, it caused reductions in feed intake, growth, bone ash, and serum phosphate, and increased serum calcium and bone aluminum content (373–375).

The soluble forms of aluminum are relatively more toxic, but generally show the same biological effects as sodium zeolite A (340,366,376). Interestingly, however, soluble forms tend to inhibit calcium absorption from low calcium diets, whereas, zeolites seem to enhance it. No studies have been done to evaluate the effects of including natural, aluminum-loaded plant or animal products in the diet.

The fact that consuming high levels of aluminum usually decreases food intake makes it difficult to identify toxic effects of aluminum that are independent of reduced nutrient intakes. Wisser et al. (340), however, showed that adding aluminum sulfate to the diet of laying hens decreased egg production and fertility, and increased serum calcium without causing significant decreases in food intake or plasma phosphate. This implies that systemic aluminum can have direct toxic effects on metabolism.

Toxicity to Humans

There is no doubt that aluminum intake can be toxic to humans under certain conditions. Regular intake of large doses of aluminum hydroxide can cause bone disease, anemia, and neurological problems in patients with poor renal function that cannot adequately excrete aluminum from the body. Similar effects can occur in healthy individuals if aluminum intake is high enough, over a long enough period. There are questions about the relationship of aluminum to Alzheimer’s disease and the health consequences of long-term, low-level exposures that remain unanswered. The reader is referred to several recent reviews for detailed discussions of these topics (358–360).

Overview of Aluminum Metabolism

The intestine is viewed as a protective barrier against aluminum toxicity as only a small fraction (0 to 0.5%) of ingested aluminum is absorbed from any source. However, of the small amount absorbed, about half is retained in tissues and the other half is excreted, primarily in urine. Elimination from tissues is not rapid so, in the face of constant intake, tissues accumulate aluminum over time.

Drueke (377), and Yokel and McNamara (359) provide recent reviews of the absorption and metabolism of aluminum. A number of factors influence the efficiency of absorption. Most are dietary factors that affect solubility; hence, phosphate reduces absorption as does ingesting insoluble forms of aluminum such as aluminum oxide. Silicon has shown conflicting results, but does not appear to reduce absorption except when given as insoluble, oligomeric forms. The soluble aluminum salts have higher absorption efficiencies, although the hydroxide appears to be less bioavailable than more soluble forms. Citrate, as well as other organic acids including ascorbic, oxalic, lactic, and tartaric acids can greatly enhance absorption possibly by increasing solubility or charge neutralization when complexed species are formed. The mechanism, however, is not yet understood. Aluminum-accumulating plants which store aluminum bound to organic acids would be expected to contain bioavailable aluminum, but this concept has never been tested. Polyphenolic acids have recently been shown to increase tissue uptake of aluminum from food, suggesting increased absorption (378). Fluoride may also enhance absorption.

The mechanism of aluminum absorption is not well understood but appears to involve active transport through the intestinal cells as well as passive diffusion. High iron diets inhibit transport whereas low iron diets enhance it, suggesting that aluminum can follow iron transport pathways.

In the blood, about 80% of aluminum is bound to iron binding sites on transferrin, the major iron transport protein in plasma (47,48). The remainder is bound to low-molecular-weight molecules, possibly citrate. Since most tissues take up transferrin to acquire iron, this process provides a mechanism for aluminum to enter cells, including the brain. Tissue uptake from the citrate-bound form is also possible. In fact, increased dietary citrate appears to enhance tissue accumulation of aluminum as well as urinary excretion. In renal-failure patients, citrate greatly enhances risk of toxicity.

Bone is the major tissue deposition site with aluminum accumulating at areas of active mineralization, possibly as aluminum citrate. Aluminum also enters and is toxic to the bone forming cells (osteoblasts). Other tissues accumulate lesser amounts of aluminum, usually in the order: bone>liver>kidney>spleen>brain. Contrary to other tissues, the brain has not always been found to accumulate aluminum in association with increased dietary intake. Nevertheless, aluminum is routinely found in the brain in measurable amounts. Elimination of aluminum from tissues is relatively slow compared with its rapid uptake, with half-lives estimated in terms of months or years. Elimination from bone is the most rapid, and that from brain is the slowest. Body loads are typically low, 30 to 50 mg in healthy individuals on usual diets.

The intracellular metabolism of aluminum is poorly understood. Presumably, it initially follows the pathways of iron metabolism being incorporated with transferrin-bound iron into endosomes. Its subsequent fate, or the fate of citrate bound aluminum are unknown.

Overview of the Biochemical Mechanisms of Aluminum Toxicity

The biochemical mechanisms of aluminum toxicity leading to neurodegeneration, bone loss, and anemia are not understood and an explanation for these symptoms cannot be made at this time. At its most fundamental level, the systemic toxicity of aluminum is probably related to its strong binding affinity for three-oxygen-donor ligands, especially negatively charged oxygen donors found in organic phosphates and proteins with carboxylic acid or phosphorylated residues (379). This strong binding can displace magnesium ions, alter the structure and function of substrates, enzymes, regulatory and structural proteins, and in poorly understood ways interfere with iron metabolism. The biochemical aspects of aluminum toxicity in animals and man have recently been reviewed (360). It is likely that the basic biochemical effects of aluminum are similar in plant and animal cells.

Before systemic toxicity is discussed, it should be remembered that dietary aluminum toxicity often induces a phosphate deficiency. Appetite and growth are depressed. Bone mineral is dissolved in an attempt to raise serum phosphate levels and hypercalcemia may result. Skeletal muscle may also lose intracellular phosphorus and magnesium to the blood, resulting in lowered ATP synthesis and a general lack of phosphate for metabolic use within the muscle. Intracellular calcium levels become elevated. Bone pain, muscle weakness, and neurological symptoms including confusion, seizures, and coma can occur (380).

Once aluminum gains entry into the body and enters cells, it is thought to bind to phosphate ligands, particularly ATP. It also binds to proteins. Bound aluminum may alter enzyme activity by displacing cofactors such as Mg⁺, by affecting the binding of substrates such as ATP, or by inducing conformational changes. For example, aluminum has been shown to inhibit ATP dependent enzymes such as hexokinase. The mechanism is thought to involve formation of Al-ATP that is much more stable and binds much tighter to proteins than Mg-ATP, inhibiting enzyme action. More than 20 other enzymes are reportedly inhibited or stimulated by aluminum (379).

Aluminum may also influence protein–protein interactions (381). For example, aluminum may bind to calmodulin, a calcium-activated regulatory protein that controls the activity of more than 40 different enzymes by binding to them via hydrophobic interactions resulting in the induction or inhibition of activity. Aluminum binding does not affect calcium binding to calmodulin; rather, aluminum induces conformational changes that inhibit the ability of calmodulin to bind target proteins.

Aluminum also can cross-link proteins by forming intermolecular bridges between binding sites on amino acid side chains. The binding of aluminum to proteins may also affect their turnover, either stabilizing them, such as in insoluble aggregates, or enhancing degradation via conformational changes.

Since many signal transduction processes involve phosphate group transfers, this is another likely site for aluminum toxicity (382). The phosphatidylinositol 4,5-bisphosphate (PIP2) signaling pathway has been inhibited by aluminum. Aluminum apparently binds to phosphate groups of PIP2 in membrane phospholipids inhibiting PIP2 hydrolysis by phospholipase C. An alteration in signal transduction pathways may help explain the altered pattern of gene expression seen in tissues exposed to aluminum (383). G-proteins and protein kinases are also reportedly affected by aluminum (383).

Aluminum has been shown to interfere with iron metabolism. It blocks the incorporation of iron into heme resulting in poor hemoglobin production and anemia (384). Aluminum also appears to disrupt the mechanisms that control intracellular iron homeostasis. The result may be altered iron distribution in the cell leading to increased levels of reactive or “free” iron and iron-induced oxidative stress (384–386). Normally, increasing intracellular “free” iron concentrations coordinately stimulate the synthesis of the iron storage protein ferritin, and inhibit the synthesis of transferrin receptors that control iron uptake. Studies suggest that aluminum antagonizes the ability of intracellular iron to regulate the translation of mRNAs for both ferritin and the transferrin receptor. Under these conditions, the amount of “free” iron in the cell becomes elevated relative to the amount of its storage and detoxification by ferritin, thus increasing the risk for iron-induced oxidative stress. Aluminium has also been shown to inhibit the ATP-dependent proton pump on endosomes, resulting in the trapping of transferrin-bound iron inside these vesicles. The trapping of iron would limit its ability to stimulate ferritin synthesis. Aluminium may also inhibit the incorporation of iron into ferritin, further increasing the levels of reactive “free” iron in the cell.

Recent studies have shown that aluminum can induce oxidative stress even though it is not a redox metal, and that antioxidants can attenuate this effect supporting the concept that aluminum toxicity involves oxidative damage (387,388). Oxidative stress could result from altered membrane structure, a reduction in antioxidant defense systems, or the induction of free radical generating systems such as increased levels of reactive “free” iron.