Aluminium Toxicity in Infants' Health and Disease

The following sections are included:

• Preface

• Contents

• List of Contributors

Citrate is the predominant small molecule Al³⁺ binder in the plasma, cerebrospinal fluid, milk, saliva and urine, and in all except the serum the likely main binder of Al³⁺. Citrate solubilizes Al³⁺ from both insoluble Al(OH)₃ and AlPO₄. In the serum the Fe³⁺-carrying protein serotransferrin carries about 89% of the Al³⁺ and citrate about 11%. Within a cell, Al³⁺ is not bound to the weakly basic phosphates of nucleic acid polymers but to strongly basic nucleoside di- and triphosphates, and possibly phosphorylated proteins. Administration of Al³⁺ in neutral solutions should be with excess of a complexing ligand such as citrate.

The metabolism of physiological amounts of aluminium has eluded scientists because of the lack of a suitable tracer and because of the low levels of aluminium in the body compared to the high levels in the environment. The development of accelerator mass spectrometry (AMS) has provided a practical method of detection for the only isotope of aluminium suitable as a tracer, ²⁶Al. The use of ²⁶Al as a tracer for aluminium has facilitated the study of aluminium metabolism and pharmacokinetics of aluminium-containing drugs. We present an overview of the advantages of using ²⁶Al as a tracer for aluminium and a general description of the AMS technique. To illustrate the versatility of ²⁶Al as a tracer for aluminium, ²⁶Al studies of the past several years are discussed briefly including the first study of the pharmacokinetics of an ²⁶Al-labeled drug.

There is a vast literature regarding the toxic action of aluminum [Al(III)] through biological systems. However, in spite of this abundance of data, a lot of confusion emerges from toxicological data mostly derived from ill-defined experimental protocols utilizied by various laboratories. Herein, we review how the toxicological properties of Al(III) are directly connected with the metal chemical speciation and with the biophysical properties of the metal coordination sphere that face the various biological targets.

Although aluminium is ubiquitous, exposure is limited because of the insoluble nature of aluminium compounds. Under normal conditions the major exposure to aluminium is through the oral ingestion of this element. It would appear that normal dietary intake of aluminium is less than 15 to 20 mg. A very small fraction, less than 0.1%, of the ingested aluminium is actually absorbed. Aluminium absorption occurs passively through the paracellular pathway. The major factors which modulate aluminium absorption would appear to be the integrity of the tight junction, solubility of the aluminium compound at the small intestine pH and the amount of aluminium ingested. With normal aluminium exposure the small amount of absorbed aluminium is rapidly eliminated by the kidney and the body burden of aluminium is maintained at extremely low levels throughout life. Aluminium is normally present, in small amounts, in all tissues. However, there is no evidence, at these levels, that it exerts any beneficial effect, and even though no harmful effect has either been characterized at these levels, the present increasing availability of aluminium in the environment justifies its present classification as detrimental or toxic.

Aluminium and iron are known to share some similar properties: both are carried by the same serum proteins, chelated by the same drugs and recent evidences suggest that aluminium and iron may have multiple interactions competing for important biological pathways. In iron deficiency, iron absorption is increased, but also aluminium absorption could be increased and with it the risk of aluminium tocixicity. There is also a competitive transport between alumium and iron: the iron and aluminium carried by transferrin, may along with other factors, regulate the gastrointestinal uptake of iron and aluminium. The amount of aluminium stored in the body may not only influence the incorporation of further aluminium but also the uptake of iron affecting the erythropoiesis.

The aluminium and iron interaction has also diagnostic and therapeutic implications. Patients with a similar degree of aluminium load but with significant differences in their iron stores would be difficult to compare. The iron status should always be considered when interpreting the desferrioxamine test because differences in serum aluminium increment could be a function not only of aluminium body burden but also of iron status.

In the management of renal patients, two drugs, erythropoietin and desferrioxamine are currently being used. Both drugs may affect iron and aluminium metabolism. It is important to carefully monitor serum iron, iron transferrin saturation, serum ferritin, haematocrit, and the mean corpuscular volume, together with serum aluminium levels. Iron depletion will not only diminish the hematopoietic effect of erythropoietin, but also favors conditions conductive to the development of aluminium toxicity, establishing a dangerous loop involving aluminium, iron, erythropoietin and desferrioxamine. Several groups of new chelators for iron and aluminium are undergoing preclinical and clinical evaluation to complement the use of desferrioxamine. Among them, deferiprone, one of the most used, is able to remove aluminium efficiently.

Although new studies may shed more light on this topic, the data discussed in this chapter provide enough information to emphasize the importance of the complex iron-aluminium interaction, particularly in children due to their higher capacity to absorb metals.

Aluminium exposure in infancy is relatively high compared with adults due to the frequent use of artificial feeds and aluminium containing medications. Aluminium contamination of infant formula ranges from 3 to 60 μmol/l compared with 1.8 μmol/l in human milk. The daily aluminium intake is as high as 7000-12000 μmol if infants receive antacids. Variable amounts of aluminium are absorbed by the infant gut and then slowly excreted into the urine once exposure ceases. Infants fed parenterally receive an intravenous dose of 1.2 μmol/kg/d aluminium as parenteral nutrition is frequently contaminated. Aluminium accumulation in bones of parenterally fed infants is well documented.

Aluminium contamination of formula probably does not pose a health risk to infants with normal renal function. Antacids are a common medication used for irritable infants and the longterm effects of the significant amount of aluminium which infants absorb from antacids are unknown. However, there is increasing evidence that aluminium accumulation in bones of parenterally fed infants is a factor in osteopaenia of prematurity. Current efforts are focussed on limiting aluminium contamination of enteral and parenteral feeds used in infancy and avoiding the nonspecific use of antacids.

There is concern that infants with immature and developing tissues may be more vulnerable to the toxic effects of aluminium. However, exposure does not necessarily equate with tissue deposition and tissue deposition does not necessarily equate with symptoms as the critical tissue load that results in systemic disorder remains to be determined. Orally ingested pharmacological doses of aluminium in infants with renal failure has been clearly associated with symptomatic tissue deposition and should be avoided. Intravenous aluminium in neonates with normal renal function has been associated with deposition although whether this is symptomatic or not is more difficult to assess. The level of exposure which could be considered acceptable has yet to be determined. Oral pharmacological doses in infants with normal renal function has been associated with increased serum levels but as tissue levels have not been measured, judicious use of these agents is recommended together with careful monitoring. It is unlikely that non-pharmacological doses in infants with normal renal function are hazardous.

Aluminium-related bone disease (ARBD) is characterized by bone pain, proximal myopathy, and pathologic fractures refractory to vitamin D therapy. The most common source of aluminium loading in patients with renal failure is orally ingested aluminium-containing phosphate binding agents. Although non-invasive procedures such as plasma aluminium levels, desferoxamine test and serum iPTH levels may suggest ARBD, bone biopsy remains the gold standard for diagnosis. Withdrawal of all potential sources of aluminium loading result in significant improvement in most patients. Because of potentially fatal infections with Yersenia and Rhizopus, desferoxamine therapy should be reserved for those with severe manifestations of dialysis encephalopathy or bone disease. Preventative measures remain the cornerstone in the management of this progressively disabling disease.

Aluminium containing antacids are commonly used in infancy for symptoms of gastro-esophageal reflux. Increased gastrointestinal permeability and immature renal excretory function may increase the risk of tissue aluminium accumulation in this group of patients, with potentially adverse consequences. Although there is a paucity of available data, evidence points to the likelihood that the massive ingestion of aluminium consequent on antacid therapy is associated with significant increases in plasma aluminium concentration and urinary excretion. Given the established potential for aluminium to accumulate in tissues and cause toxicity in patients with renal impairment, the use of aluminium containing antacids in infancy should be discouraged unless more evidence of safety is forthcoming.

Although it is well established that aluminium could be a developmental toxicant following parenteral exposure, until recently there have been doubts about the embryotoxicity and fetotoxicity of oral aluminium. In recent years, it has been demonstrated that the water solubility of the specific aluminium compound plays an essential role in the developmental toxicity of this element. While no developmental effects of oral Al(OH)₃ were observed in rats and mice, the concurrent ingestion of Al(0H)₃ and citric or lactic acids, which enhance the absorption of aluminium from the gastrointestinal tract, showed some signs of maternal and developmental toxicity. On the other hand, it has been shown that during gestation and lactation an excess of dietary Al at levels which do not produce maternal toxicity, might result in persistent neurobehavioral deficits in the offspring. The maternal and embryo/fetal toxicity of aluminium, as well as the neurodevelopmental effects of this element are reviewed here. A summary of questions about the developmental toxicity of aluminium that still need to be solved are also discussed.

Aluminium has been documented to contaminate parenteral nutrition solutions in the US and Europe. The small-volume parenterals are more significantly contaminated than the large-volume parenterals, with calcium gluconate and phosphate salts being almost universally contaminated, followed by albumin, heparin, trace element and multivitamin solutions. Aluminium contamination results primarily from either failure of sufficient purification or contamination during industrial processing. Infusion of aluminium-contaminated products leads to accumulation in bone with subsequent manifestations of metabolic bone disease. Little has been done to-date to regulate the aluminium contamination of parenteral nutrition solutions.

Aluminium contamination of intravenous solutions (parenteral nutrition solutions, albumin, drugs) has been suggested as a possible causal factor of some cases of osteopenia, unexplained encephalopathy and cholestasis in newborns. Parenteral nutrition solutions may suppose an aluminium load of of 15-30 μg/kg/day to neonates, with calcium salts representing between 81 and 89% of this intake. This load have been shown to lead to tissue aluminium accumulation. The use of intravenous drugs does not appear to suppose an aluminium load capable per se (<3 μg/kg/day) of producing aluminium tissue accumulation, although these drugs may constitute a considerable source when their aluminium content is added to that of other sources. Although it may not be easy to totally avoid product contamination, it would be most important to limit the aluminium content of large-volume parenteral drug products to less than 25 μg/L and also to reduce contamination of calcium salts.

The status of aluminium contamination of human serum albumin solutions is reviewed. Aluminium is loaded in patients during the therapeutic use of aluminium contaminated albumin solutions. This is a special problem for patients with impaired renal function as the amount of aluminium retained is dependent on the renal function of the patients.

The main sources of contamination during the manufacturing process have been identified as contact with diatomaceous earth used during processing as well as leaching of aluminium from the glass storage containers used for the final product. However, even though it is possible to manufacture human albumin solutions with very low aluminium contents, new investigations still report cases of high aluminium concentrations in albumin solutions. The contamination problem can therefore not be considered to be generally solved.

Commercial albumin products have been shown to contain 200-1000 ppb of aluminium. We have confirmed that the major sources of this aluminium are filter aids and filter pads used during the production processes, and the glass bottles used as containers for these products. In this chapter we also show that trace amounts of transferrin in the albumin products accelerates leaching of aluminium from glass final containers. We report that the aluminium content of albumin can be reduced by modification of the production process to include an ion exchange column or an ultrafiltration step. We also report that leaching of aluminium from the glass container can be suppressed by using soft glass (Type II USP) final containers.

Aluminium compounds have been most widely used for many years as a vaccine adjuvant for human and veterinary use.

A vaccine adjuvant is an agent that increases specific immune responses to an antigen. Aluminium-adsorbed vaccines produced a high incidence of local side reactions as compared with plain vaccines. Particularly, they have been injected into children and infants. The toxic effects of aluminium compound as a vaccine adjuvant are discussed.

Concerns about aluminium (Al) in the food supply have been raised in reports of encephalopathy in renal patients due to aluminium-contaminated dialysis water or aluminium-containing antacids; reports of high levels of Al in the brains of Alzheimer's patients; and epidemiological studies purporting to show that minute differences in the Al content of drinking water could increase the incidence of Alzheimer's disease. Of the three causes of concern, only the toxicity of Al to renal patients is established. More precise analytical methodology, which minimizes contamination of specimens by extraneous Al, no longer finds elevated Al levels in the brains of Alzheimer's patients or even elevated Al levels in the plaques and tangles characteristic of brains of Alzheimer's patients. More rigorous epidemiology does not support a connection between the concentration of Al in drinking water and the incidence of Alzheimer's disease. Genetic and other risk factors are being established for Alzheimer's disease, but no convincing linkage to Al has been made. No clinical syndrome has ever been noted for the very low intake of dietary Al. The oral intake of medically-administered Al with adverse effects and of Al in the diet differ by orders of magnitude. This difference is so great that no public health threat due to Al in the food supply can be detected.

The following sections are included:

• Index