Aluminium

Note on nomenclature

Aluminium was first named (although not isolated) by Sir Humphry Davy, who originally called it alumium (1808) because it was found in alum, a name that had been extant since at least the 14th century. He later called it aluminum (1812), but others soon changed it to aluminium, in order to harmonize it with the many other elements whose names end in “ium” and because “aluminum” was thought not to have a particularly classical sound. For many years, both “aluminium” and “aluminum” were used in the USA, until the American Chemical Society adopted the form “aluminum” in 1925. However, “aluminium” is the official name recognized by the International Union of Pure and Applied Chemistry (IUPAC) and is the form that is used here.

Sources of exposure

Aluminium is widely used in medicine, pharmacy, food technology, and cosmetics. It is also a popular metal for making everyday objects, including kitchen utensils and other devices associated with food preparation. There is also some exposure, although generally limited, from the environment. Toxic effects of aluminium have been seen in patients treated with total parenteral nutrition contaminated with aluminium [ ]; high concentrations of aluminium have been detected in some intravenously administered solutions, such as human serum albumin [ ] and in artificial breast milk substitutes. Exceptionally, a metallic aluminium object can become lodged in the body and give rise to aluminium toxicity [ ]. Additive intake from multiple medical and/or non-medical sources can prove excessive, and it can be important to recognize the many circumstances in which exposure occurs. Aluminium absorbed into the system is excreted in the bile, generally without obvious consequences [ ].

Hyperaluminemia has been described in premature infants receiving prolonged intravenous alimentation, and in recipients of plasmapheresis receiving large volumes of replacement albumin solutions, which contain high concentrations of aluminium [ , ].

Many aluminium salts, including aluminium hydroxide gel, aluminium carbonate, aluminium glycinate, and aluminosilicate, are used therapeutically, and the absorption rate depends on the chemical species. Aluminium citrate is well absorbed [ ], but aluminium hydroxide gel antacid is poorly absorbed (0.003%) [ ]. Aluminium glycinate is well absorbed and excreted in the urine. Poorly absorbed aluminium-containing formulations should be preferred for those who have poor renal function particularly elderly people.

Sucralfate is a basic aluminium salt of sucrose octasulfate.

Medical uses

The external medical uses of aluminium are many; water-soluble compounds such as alum have long been used as mild external antiseptic, astringent, antihydrotic, or styptic agents, and more recently in deodorants and antiperspirants. Metallic aluminium is also used in some wound dressings.

Internal use in medicine can exploit the alkaline nature and adsorptive capacities of aluminium compounds (as in antacid mixtures, antidiarrheal drugs, and vaccines). Aluminium is found in medications for antacid therapy and phosphate depletion; alternatives have been described [ ]. Patients on dialysis take large amounts of oral aluminium hydroxide as a means of reducing serum phosphate. Sucralfate is used to treat peptic ulceration and gastritis.

Aluminium is used as a vaccine adjuvant [ ].

General adverse effects and adverse reactions

The occupational, environmental, and clinical human health risks of aluminium, aluminium oxide and aluminium hydroxide have been reviewed [ ]. Topical aluminium can occasionally cause skin irritation in sensitive individuals.

The systemic availability of aluminium is normally very low, because the gastrointestinal tract, skin, and lungs are excellent barriers to its entry; furthermore, the small amounts that pass these barriers are efficiently eliminated by the kidneys. However, problems can arise if the natural protective barriers are bypassed or if there is impaired renal function. Significant systemic effects are rare unless there is a high degree of absorption.

Aluminium is toxic in patients on chronic hemodialysis and peritoneal dialysis and in those taking oral aluminium-containing medications. Aspects of aluminium safety [ ] and metabolism [ ] have been reviewed. The association between aluminium in drinking water and Alzheimer’s disease continues to be discussed and remains controversial [ ].

Although aluminium adjuvants have proven to be safe over six decades, adverse effects, such as erythema, subcutaneous nodules, and contact hypersensitivity, sometimes occur [ ]. The aluminium body burden has been estimated in infants during the first year of life for a standard immunization schedule compared with breast milk and formula diets [ ]. The calculated body burden of aluminium from immunization exceeds that from dietary sources, but is still below the minimal risk level equivalent curve during the brief period after injection.

Observational studies

During trials in Gothenburg, Sweden, of aluminium-adsorbed diphtheria–tetanus/acellular pertussis vaccines from a single producer, persistent itching nodules at the immunization site were observed in an unexpectedly high frequency: in 645 children out of about 76 000 immunized (0.8%) after both subcutaneous and intramuscular injection. The itching was intense and long-lasting. After a median of 4 years 75% still had symptoms. There was contact hypersensitivity to aluminium in 77% of the children with itching nodules and in 8% of their symptomless siblings who had received the same vaccines [ ]. The authors suspected that the high incidence of itching nodules was related to the injection technique used. Post-marketing surveillance data from other regions in Sweden, Denmark, and Norway have suggested that the incidence of itching nodules is low after correct intramuscular administration of aluminium-adsorbed vaccines manufactured by Statens Seruminstitut in Copenhagen, Denmark [ ].

The effect of reducing the aluminium content of a combined reduced-antigen-content Tdap vaccine on immunogenicity and safety has been evaluated in 647 healthy adolescents aged 10–18 years [ ]. Of those enrolled, 224 (35%) received a Tdap formulation with aluminium 0.5 mg, 209 (32%) a formulation with aluminium 0.3 mg, and 214 (33%) a formulation with aluminium 0.133 mg. One month after administration of the booster dose, all the subjects were seroprotected against diphtheria and tetanus toxoids. All were seropositive for anti-filamentous hemagglutinin and anti-pertactin antibodies, but 4% of those who were initially seronegative in both reduced aluminium groups did not seroconvert for anti-pertussis toxin. Booster responses did not differ significantly between the groups for any antibody, but geometric mean concentrations of anti-pertussis toxin after booster immunization differed significantly between groups and fell when vaccine aluminium content was reduced. There were no clear differences between the study groups in local or general adverse effects. The most frequently reported symptoms after immunization were injection site pain (90–91%), fatigue (42–47%) and headache (41–45%). This study showed that the aluminium content has a specific influence on the immunogenicity of this Tdap vaccine.

Respiratory

Specific chemical exposures and exposure assessment methods relating to studies in the alumina and primary aluminium industry have been reviewed [ ]. In aluminium smelting, exposure to fluorides, coal tar pitch volatiles, and sulfur dioxide has tended to abate in recent years, but there is insufficient information about other exposures. Published epidemiological studies and quantitative exposure data for bauxite mining and alumina refining are virtually non-existent. Determination of possible exposure–response relations for this part of the industry through improved exposure assessment methods should be the focus of future studies.

Dental technicians are potentially exposed to various occupational dusts and chemicals and pulmonary granulomatosis has been reported [ ].

• A dental laboratory technician developed progressive exertional dyspnea and cough associated with pulmonary granulomatosis. Lung function studies showed a restrictive pattern with a low diffusion capacity. A high-resolution CT scan showed micronodules in both lungs, corresponding to non-caseating foreign body granulomas at histological examination. Mineralogical studies showed the presence of silica, silicates, and aluminium. The lymphocytic transformation test was positive for beryllium with the bronchoalveolar lavage.

Combined histological, mineralogical, and immunological studies led to a diagnosis of pneumoconiosis, most likely related to occupational exposure to beryllium and aluminium.

The role of aluminium in the development of occupational asthma has never been convincingly substantiated. Occupational asthma has been attributed to aluminium welding [ ].

• A 32-year-old man working in a leather plant performed electric arc welding on mild steel, using manual metal arc and inert gas metal arc techniques. About once a month he welded aluminium pieces using a manual arc process with a flux-coated electrode. After 4 years of intermittent exposure to these various welding processes, he developed chest tightness and wheezing that occurred specifically on days when he was welding aluminium. His asthmatic symptoms started 1–4 hours after the end of exposure to aluminium and persisted for several hours. He never had myalgia, chills, or fever. He was treated with inhaled budesonide (400 micrograms/day) and salbutamol when necessary. Inhalation challenges combined with exposure assessment provided evidence that aluminium can cause asthmatic reactions.

A syndrome known as “pot-room asthma” occurs in around 2% of new aluminium smelters each year, with a wide range of incidences around the world [ ].

• In 1529 men in two smelting factories, work-related respiratory symptoms were reported significantly more often among the ingot mill, anode, and pot-room groups in factory A after adjusting for age and smoking, while in factory B, ingot employees were more likely to report work-related wheeze and pot-room employees were more likely to report work-related rhinitis [ ]. Symptoms tended to increase with increasing time in the pot-rooms, but were more likely to occur in new employees in the ingot mill and anode process groups.

Nervous system

The toxicology of aluminium in the brain has been reviewed [ , ].

Since 1976, aluminium has been known to be a cause of encephalopathy, a potentially fatal condition occurring primarily in patients on chronic dialysis [ ]. Difficulties in speech, disturbances of consciousness, and ataxia can be followed by psychotic episodes, personality changes, myoclonic jerks, electroencephalographic abnormalities, convulsions, and dementia. Accumulation of aluminium can be demonstrated in the gray matter of the brain and in other tissues. If not too advanced, the condition can recede after reduction of aluminium intake and use of deferoxamine.

• Intravesical irrigation with 1% alum for hemorrhagic cystitis resulted in sufficient absorption to produce encephalopathic symptoms in a teenage girl [ ].

An identical condition can occur in aluminium plant workers and miners, and can be reproduced in animal experiments. However, some clinically similar encephalopathies do occur spontaneously (or possibly as a result of uremia) in children where no link with aluminium exposure can be found.

There have been reports that the use of surgical aluminium-containing bone cement can cause epileptic seizures as well as encephalopathy, at least when the cement is in direct contact with the cerebrospinal fluid, as can happen in neurosurgery [ ]. In this connection it should be noted that such bone cements can produce high circulating concentrations of aluminium. One French study in six patients [ ] noted mean plasma aluminium concentrations of up to 9.2 ng/ml, while up to 176 ng/ml was present in the postauricular cerebrospinal fluid. This aspect of aluminium cement merits further study.

Aluminium-containing antacids have been suggested to be the cause of idiopathic Parkinson’s disease in a study of 200 patients and 200 age- and sex-matched controls. There was a significantly higher incidence of ulcers (diagnosed by X-ray or surgery) in the patients with Parkinson’s disease compared with controls (14% versus 4%) [ , ]. The ulcers typically preceded the diagnosis of Parkinson’s disease by 10–20 years. Parkinson’s disease occurs worldwide, suggesting perhaps that some ubiquitous toxin plays a role in its pathogenesis. Aluminium absorption resulting in raised blood concentrations has been detected in babies given “Infant Gaviscon” (which is based on aluminium alginate and is not in fact recommended by the manufacturers in the very young) and in adults given aluminium sucrose sulfate, though without apparent ill-effect.

Acute neurotoxic adverse effects of aluminium have been attributed to aluminium-containing surgical cement.

• A 52-year-old woman had a resection of an acoustic neuroma [ ]. Bone reconstruction was performed with an aluminium-containing cement and 6 weeks later she had loss of consciousness, myoclonic jerks, and persistent tonic–clonic seizures, effects resembling those of dialysis encephalopathy. She died 6 months later with septic complications. Light microscopy and electron microscopy of the brain showed pathognomonic aluminium-containing intracytoplasmic argyrophilic inclusions in the choroid plexus epithelia, neurons, and cortical glia. These changes are characteristic of dialysis-associated encephalopathy. Atomic absorption spectrometry showed an increase in the mean aluminium concentration in the cortex and subcortex, up to 9.3 μg/g (reference range under 2 μg/g); a laser microprobe showed increased aluminium in subcellular structures.

This case shows again the extraordinary neurotoxic potency of aluminium, which was initiated by about 30 mg and apparently caused by direct access of aluminium to the brain parenchyma via cerebrospinal fluid leakage.