Substances Included Synonyms

Therapeutic Toxic Class

A)

B)

C)

Specific Substances

1) Aluminium
2) Alumina fibre
3) Aluminum flake
4) Aluminum dehydrated
5) Aluminum, metallic, powder
6) Aluminium oxide
7) Aluminum powder
8) CAS 7429-90-5
9) NEOBEAD

1.2.1) MOLECULAR FORMULA
1) Al

Available Forms Sources

A)

1) Aluminum is the most abundant metal and the third most abundant element in the earth's crust (about 8.13 percent) surpassed only by oxygen and silicon (Bingham et al, 2001; Harbison, 1998; Lewis, 1997).
2) In moist air, aluminum forms a hard, highly impervious film of aluminum oxide (AlO3), which protects it from further corrosion (Budavari, 1996).
3) ALUMINUM SALT PERCENTAGE

ALUMINUM SALT	% ELEMENTAL ALUMINUM
Aluminum hydroxide	34.58
Aluminum oxide	52.91
Aluminum phosphate	22.12
Bismuth aluminate	20.97
Dihydroxy aluminum carbonate	18.74

4) Aluminum does not occur free in its metallic form in nature; it exists naturally combined with fluorine, silicon, oxygen and other substances in the earth's crust (Bingham et al, 2001; HSDB , 2001; Lewis, 1997). Its surface, and therefore its interface with biological media or tissue, is almost always as an oxide (Bingham et al, 2001).
5) It often occurs as an oxide and combined with silica (Budavari, 1996).
6) It is available in 65 to 70% and 99.94+% purity forms (HSDB , 2001).
7) It also is available as low-micron powder in anode grades with 99 to 99.999% purity, and in pellet form at 99.99% purity (HSDB , 2001).
8) Aluminum is available in the following forms: sheet, wire, leaf, powder, bar, plates, rods and wire foil flakes (Ashford, 1994; Lewis, 1997).

B)

1) The only method used to produce aluminum in commercial quantities is the Hall-Heroult electrolytic reduction process: Alumina is electrolytically decomposed after being dissolved in molten cryolite. (The alumina is derived from bauxite through the Bayer process.) (Ashford, 1994; Bingham et al, 2001). Two types of reduction cells exist, prebake and Soderberg (Bingham et al, 2001).
2) 'Ultra-pure' aluminum can be manufactured through the following processes: electrolytic (3-layer); zone refining; and chemical refining (HSDB , 2001).
3) Soy-based infant formulas may contain a mean aluminum content of 1,478 mcg/L and should probably not be used in infants with renal impairment or in low-birth-weight infants (Committee on Nutrition, 1986).
4) In a study from Spain, aluminum content was lowest in breast milk (23.4 +/- 9.6 mcg/L). The mean concentration in cows milk was 70 mcg/L and in reconstituted infant formulas was 226 mcg/L, with wide variation (302 to 1,149 mcg/L) in aluminum content (Fernandez-Lorenzo et al, 1999). Aluminum-free water was used for these studies, and tap water may result in still higher concentrations, depending on the source.
5) Some dialysis solutions prepared with aluminum-containing tap water have contained greater than 100 mcg/L aluminum (Lione, 1985a). The appreciation of the hazard of aluminum in dialysates led to the establishment of a maximum acceptable limit of aluminum in dialysis fluid of 10 mcg/L, and routine use of methods such as reverse osmosis to minimize dialysate aluminum concentrations. However, occasional cases of much higher dialysate aluminum concentrations still occur (Simoes et al, 1994; Burwen et al, 1995).
6) DECOMPOSITION - Alkyl aluminum compounds decompose to aluminum oxide fumes.
7) DIETARY SOURCES

a) Aluminum is present in most foods and is used in food packaging, as a food additive and in cooking utensils; intake may range from 4 to 80 mg/day (Baselt, 2000).
b) Aluminum is found in a number of commercial teas. One study found between 555 and 1,009 mcg Al per gram (dry weight) (Koch et al, 1988). However, the absorption of aluminum from tea may be very low (Powell et al, 1993).
c) The aluminum content of drinking water varies, with a mean of 0.09 and maximum of 1.3 mg/L in one survey of water utilities that use alum (Letterman & Driscoll, 1988). The contribution of aluminum in water to Alzheimer disease is controversial (Savory et al, 1996).

1) Inadvertent addition of a massive amount of aluminum sulfate to water during water treatment resulted in water aluminum concentrations of 30 to 620 mg/L (compared with the maximum admissible concentration of 0.2 mg/L) in Europe. This resulted in short-lived complaints of nausea, vomiting, diarrhea, mouth ulcers, skin ulcers, skin rashes and arthritic pain. Bone aluminum deposition was seen in two patients, indicating a short period of increased gastrointestinal aluminum absorption, perhaps from the contaminated water (Eastwood et al, 1990).

d) The main dietary source of aluminum is food additives. Approved 'generally recognized as safe' (GRAS) additives include sodium aluminum phosphates in cake mixes, frozen dough, self-rising flour and processed cheese and sodium aluminum sulfate in baking powders (Lione, 1983; Pennington & Schoen, 1995).
e) Food preparation and storage, including soft drink packaging in aluminum cans, contributes little aluminum to the diet. Preparation of acidic foods in aluminum cookware can increase their aluminum content (Muller et al, 1993).

C)

1) Aluminum's shiny silver appearance and its light weight, thermal and electric conductivity and tensile strength all contribute to its commercial value (Bingham et al, 2001).
2) The main uses of aluminum in the building industry are as construction materials, and in the highway industry, for fences, signs, lights and signal supports (Clayton & Clayton, 1994; Harbison, 1998).
3) Aluminum is commonly used for containers and packaging, especially for food, due to its light weight and ease of recycling. Aluminum cans and aluminum foil are primary products (Bingham et al, 2001; Harbison, 1998).
4) It is also used in chemical equipment that is resistant to corrosion, power transmission lines, plates for photoengraving, permanent magnets, machinery and equipment for cryogenics, rocket fuel, thermite and pyrotechnics, foamed concrete vacuum coating and metallizing, and in flake form to insulate liquid fuel (Ashford, 1994; Lewis, 1997).
5) Aluminum is used to manufacture alloys, engine and aircraft components (as an aluminum/zinc casting alloy ingredient), ship propellers, fittings, automobile engine components and plastic molding dies (as an aluminum bronze ingredient), vehicle body parts (as an aluminum wrought alloy raw material), electrical wires and cables (aluminum power cable alloy raw material), and window frames, roofs and building cladding and panels (Ashford, 1994; Baxter et al, 2000; Zenz, 1994)
6) Aluminum and aluminum compounds are also used as a blowing agent for lightweight building materials, as a lustering pigment in decorative paint, priming, industrial paints, as a pigment for heat-resistant paints and reflective bitumen paints, in pyrotechnics; in packing and insulating materials; in abrasives, as a reagent in the aluminothermic process; in sprayed metal coatings, and as a steel calorizing agent (Ashford, 1994; Zenz, 1994).
7) Aluminum and aluminum salts are commonly found in the food preparation and preservation industries as food additives, and are often used in cooking utensils (Baselt, 2000; Harbison, 1998; Zenz, 1994). Aluminum is also used to treat drinking water and sewage (Zenz, 1994).
8) MEDICATIONS -

a) Medically, aluminum compounds are used as antacids, analgesics (buffered aspirin), antiperspirants, antidiarrheals (kaolin, aluminum magnesium silicate, attapulgite) and anti-ulcer drugs (sucralfate), astringents, and as adjuvants for vaccines (Bingham et al, 2001; Harbison, 1998; Lione, 1985b).
b) Aluminum accumulation may occur in individuals with normal renal function and who receive chronic parenteral nutrition with aluminum-contaminated solutions (Klein, 1995). Dextrose, potassium chloride and sodium chloride solutions contain much less aluminum.
c) ALUMINUM CONTENT OF IV SOLUTIONS (Committee on Nutrition, 1986)

ADDITIVES & SOLUTIONS	MEAN ALUMINUM CONTENT (mcg/L)
Albumin 5%	486
Albumin 25%	1161-1647
Ca gluconate 10%	270-5056
Heparin 1000 units/Ml	684
Potassium phosphate	1890-16,598
Sodium phosphate	54-5994

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Aluminum is ubiquitous, it is the most abundant metal in the earth's crust. The majority of human exposure comes from food. It is present in some pharmaceuticals, primarily antacids, analgesics, antacids, antidiarrheals, astringents and as adjuvants for vaccines. In industry it is widely used in construction materials and packaging.
B) TOXICOLOGY: Aluminum inhibits bone remodeling, causing osteomalacia. It is believed to inhibit erythropoiesis, causing anemia.
C) EPIDEMIOLOGY: Acute toxicity is rare. Most cases of aluminum toxicity in humans are in one of two categories: patients with chronic renal failure, or people exposed to aluminum in the workplace. Soluble forms of aluminum (such as aluminum chloride (AlCl(3+)), aluminum fluoride (AlF(3)), aluminum sulfate (Al(SO4)3) and aluminum citrate (AlC(6)H(8)O(7))) have greater potential for toxicity than insoluble forms (such as aluminum hydroxide (AlOH(3))), due to their greater absorption.
D) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Acute aluminum toxicity is very unlikely to develop. Chronic aluminum hydroxide use can cause constipation.
2) SEVERE TOXICITY: Patients with renal failure are prone to aluminum toxicity, either from aluminum in the dialysate or other exogenous sources, especially aluminum-containing phosphate binders and antacids. Signs and symptoms may include dementia, memory loss, aphasia, ataxia, seizures, altered EEG, and osteomalacia.
3) PULMONARY: Chronic exposure to aluminum dust may cause dyspnea, cough, pulmonary fibrosis, pneumothorax, pneumoconiosis, encephalopathy, weakness, incoordination, and epileptiform seizures.
4) OCULAR: Aluminum particles deposited in the eye are generally innocuous. Aluminum salts may cause irritation of the eyes and mucous membranes, conjunctivitis, dermatoses, and eczema.

0.2.20)

A) Aluminum in drinking water has been linked to central nervous system birth defects. Some aluminum compounds have proven teratogenic in laboratory animals; however, overall, aluminum is not considered teratogenic.

0.2.21)

A) Although aluminum and its compounds have shown little evidence of carcinogenicity in humans, exposure to other substances involved in the production of aluminum has been linked to carcinogenicity.

Laboratory Monitoring

A)

B)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE EXPOSURE

1) Significant toxicity is unlikely, treatment is symptomatic and supportive.

B) MANAGEMENT OF SEVERE EXPOSURE

1) Reduce exposure through decreased use of aluminum containing phosphate buffers. Dialysis patients with encephalopathy, osteomalacia or anemia should be chelated with deferoxamine.

C) DECONTAMINATION

1) Insoluble forms of aluminum are poorly absorbed from the gastrointestinal tract, decontamination is generally not necessary. Soluble forms of aluminum (eg aluminum fluoride, chloride or sulfate) may be irritating or corrosive; dilution with milk or water may be of benefit. Wash exposed skin with soap and water. Irrigate exposed eyes.

D) ENHANCED ELIMINATION

1) Hemodialysis alone will remove little aluminum because of its binding to transferrin. Deferoxamine combined with hemodialysis should be used in renal failure patients with encephalopathy, anemia or osteomalacia related to aluminum. One regimen is 5 mg/kg given 5 hours before the start of a hemodialysis session. Weeks to months of therapy is usually required.

E) PATIENT DISPOSITION

1) HOME CRITERIA: Patients with inadvertent acute ingestion can be managed at home. Patients with significant GI, pulmonary, or eye irritation should be referred to a healthcare facility.
2) OBSERVATION CRITERIA: Patients with deliberate ingestions, and those with significant GI, respiratory or eye irritation should be evaluated and observed until symptoms improve.
3) ADMISSION CRITERIA: Renal failure patients with aluminum encephalopathy should be admitted.
4) CONSULT CRITERIA: Consult a medical toxicologist or poison center for patients with significant symptoms or in whom the diagnosis is unclear. Consult a nephrologist for renal failure patients with suspected aluminum intoxication.

F) PHARMACOKINETICS

1) Insoluble aluminum salts are poorly absorbed (estimated 1% to 2%). Unabsorbed aluminum is eliminated in feces, absorbed aluminum is eliminated renally. Aluminum is widely distributed, most is bound in bone or high molecular weight complexes. About 85% to 90% of intravenously administered aluminum is eliminated within an hour, but the terminal elimination half life increases with time (up to years). In renal failure patients who stop taking aluminum containing medications, half-lives were in the range of 13 to 85 days.

G) PITFALLS

1) The biggest risk of acute exposure is overtreatment. In dialysis patients with suspected aluminum encephalopathy, careful evaluation for other potential etiologies is important.

H) DIFFERENTIAL DIAGNOSIS

1) Other causes of encephalopathy (eg infectious, metabolic, intracranial bleeding or mass).

0.4.4)

A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.

0.4.5)

A) OVERVIEW

1) Most cases of aluminum-related dermal reactions are due to chronic exposure.

Range Of Toxicity

A)

B)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

1) MILD TO MODERATE TOXICITY: Acute aluminum toxicity is very unlikely to develop. Chronic aluminum hydroxide use can cause constipation.
2) SEVERE TOXICITY: Patients with renal failure are prone to aluminum toxicity, either from aluminum in the dialysate or other exogenous sources, especially aluminum-containing phosphate binders and antacids. Signs and symptoms may include dementia, memory loss, aphasia, ataxia, seizures, altered EEG, and osteomalacia.
3) PULMONARY: Chronic exposure to aluminum dust may cause dyspnea, cough, pulmonary fibrosis, pneumothorax, pneumoconiosis, encephalopathy, weakness, incoordination, and epileptiform seizures.
4) OCULAR: Aluminum particles deposited in the eye are generally innocuous. Aluminum salts may cause irritation of the eyes and mucous membranes, conjunctivitis, dermatoses, and eczema.

Heent

3.4.3)

A) LACK OF EFFECT: Aluminum fragments, as foreign bodies, are generally non-irritating and are tolerated well, even for extended periods of time, in the posterior segment, retina, anterior chamber, iris and cornea (Grant & Schuman, 1993).
B) IRRITATION: Aluminum dust may cause eye irritation. When aluminum particles were imbedded in rabbit eyes, no serious toxic reactions occurred (Sorenson et al, 1974).

Cardiovascular

3.5.2)

A) CARDIOMEGALY

1) WITH POISONING/EXPOSURE

a) CARDIAC HYPERTROPHY: Aluminum may be partly responsible for cardiac hypertrophy in renal failure patients on chronic hemodialysis. A comparison of 36 dialysis patients with increased body burdens of aluminum, 14 dialysis patients without evidence of aluminum accumulation and 50 control subjects with normal renal function showed that patients with evidence of aluminum accumulation had increased left ventricular mass, as determined by echocardiograms (London et al, 1989).

Respiratory

3.6.2)

A) IRRITATION SYMPTOM

1) WELDING: Coughing, increased phlegm production and a sense of irritation were noted in a group of aluminum welders. These effects are believed to be related to increased ozone concentrations formed during the welding of aluminum. Pulmonary function was not affected in these workers (Sjogren & Ulfvarson, 1985).

B) FIBROSIS OF LUNG

1) Increased aluminum absorption has been linked to pulmonary fibrosis that is severe, rapidly progressive, and usually fatal, with latent periods of 1 to 5 years punctuated by periods of coughing, dyspnea and spontaneous pneumothorax (Baxter et al, 2000; Bingham et al, 2001). This is mainly of historical relevance, as it was last reported in 1962, when the use of a mineral oil-based pyropowder lubricant during the process was discontinued (Bingham et al, 2001).
2) Chronic inhalation of fine aluminum dust or fume has resulted in fibrosis of the lung (McLaughlin et al, 1962; Vallyathan et al, 1982; Gilks & Churg, 1987; Abramson et al, 1989). This has been reported in aluminum smelting (potroom) workers, in aluminum welders and polishers, and in workers involved in manufacturing alumina abrasives or explosives from stamped aluminum powders (Abramson et al, 1989; Dinman, 1987).
3) Chronic interstitial pneumonia with severe cavitations in the right upper lobe and small cavities in the rest of both lungs were reported in a man exposed to aluminum dust for 3.2 years (Stokinger, 1981).

C) PNEUMOTHORAX

1) Dyspnea, cough, pneumothorax, variable sputum production, nodular interstitial fibrosis and fatality have resulted (Stokinger, 1981).

D) ALUMINOSIS OF LUNG

1) OCCUPATIONAL EXPOSURE

a) SHAVER'S DISEASE: This illness is caused by industrial exposure to aluminum fumes or dust, which results in respiratory distress and fibrosis with large blebs. Symptoms include productive coughing and wheezing, substernal pain, weakness and fatigue; spontaneous pneumothorax is a frequent complication. Autopsy findings include emphysema and interstitial pulmonary fibrosis. Silicon is often inhaled with the aluminum, and the function of each of these elements is as yet unclear (Bingham et al, 2001; Hammond & Beliles, 1980; Harbison, 1998).
b) This is mostly of historical relevance, because the industrial process resulting in this disease was discontinued by the 1950s (Bingham et al, 2001).

E) BRONCHOSPASM

1) Workers involved in aluminum smelting have been noted to develop an asthma-like syndrome ('pot room asthma') as well as increased chronic airway disease (Baxter et al, 2000). The exact etiology is unclear, but it is probably irritant-induced, related to inhaling fumes or particulate matter released in the process of reducing alumina to metallic aluminum (Abramson et al, 1989; Baxter et al, 2000) (O'Donnell et al, 1989).

F) CHRONIC OBSTRUCTIVE LUNG DISEASE

1) Workers involved in aluminum smelting may be at increased risk of developing chronic obstructive lung disease (Abramson et al, 1989). Potroom workers experience coughing, wheezing, decreased FEV1, and asthma (Zenz, 1994).

G) GRANULOMA

1) Aluminum exposure has been linked to the development of sarcoid-like granulomatosis (Baxter et al, 2000).
2) CASE REPORT: Sarcoid-like lung granulomatosis was reported in a 32-year-old worker exposed for 8 years to a dusty atmosphere containing aluminum powders (De Vuyst et al, 1987).

Neurologic

3.7.2)

A) TOXIC ENCEPHALOPATHY

1) WITH POISONING/EXPOSURE

a) Dialysis encephalopathy syndrome (DES) is the most widely recognized and probably the most severe manifestation of aluminum toxicity. The relationship of this syndrome to chronic aluminum toxicity is well established (Monteagudo et al, 1989; Alfrey, 1986a; Mayor & Burnatowska-Hledin, 1986; Sprague et al, 1986; Garrett et al, 1988; Ganrot, 1986; Rovelli et al, 1988; Altmann et al, 1989).
b) DES usually requires serum aluminum levels above 100 mcg/L (Baselt, 2000).
c) DES was originally secondary to high levels of aluminum in dialysate, mainly in dialysis therapy using softened or untreated water (Harbison, 1998). Reduction in the aluminum content to 0.4 micromol/L (10 mcg/L) or less resulted in prevention (Bingham et al, 2001). Moreover, the switch to aluminum-free phosphate binders (such as calcium carbonate) to treat patients with chronic renal failure has also decreased their peroral aluminum exposure (Zenz, 1994).
d) Clinical features of 'dialysis dementia' typically include (Alfrey, 1986a; Bingham et al, 2001; Garrett et al, 1988; Lewis, 1998; Mayor & Burnatowska-Hledin, 1986; Monteagudo et al, 1989; Zenz, 1994):

1) Memory loss, include speech and language impairment (dysarthria, stuttering, stammering, anomia, hypofluency, aphasia and eventually, mutism), epileptic seizures (focal or grand mal), motor disturbance (tremors, myoclonic jerks, ataxia, convulsions, asterixis, motor apraxia, muscle fatigue), and dementia (personality changes, altered mood, depression, diminished alertness, lethargy, 'clouding of the sensorium', intellectual deterioration, obtundation, coma).
2) Visual and auditory hallucinations often leading to paranoid and suicidal ideation have also been reported. DES is usually fatal, often within 6 to 9 months after initial onset of symptoms, and recovery is rare.

e) Patients with DES have a characteristic pattern of paroxysmal EEG activity, with diffuse slowing, bursts of slow (Delta) waves, and high-voltage spike activity (Alfrey, 1986a; Mayor & Burnatowska-Hledin, 1986; Zenz, 1994).
f) In children, many clinical features of DES occur similar to those described above for adults. In addition, the following have been noted: hypotonia, mental retardation, developmental delay, regression of developmental milestones, nystagmus, athetoid movements and twitching tongue movements (Gruskin, 1988; Trompeter et al, 1986; Tsuru et al, 1987).
g) ALUMINUM-CONTAINING BONE CEMENT: A 29-year-old man and a 54-year-old woman developed fatal encephalopathy with refractory status epilepticus after vestibular neurectomies (both cases) and fistula repair (one case) in which an aluminum-containing bone cement was used (Hantson et al, 1994). Post-surgical complications included postauricular accumulation of cerebrospinal fluid in both cases and fistula with cerebrospinal fluid leakage in one case.

1) Aluminum concentrations in the cerebrospinal fluid (112 and 63 mcg/L), fistula fluid (495 and 1440 mcg/L) and in serum (4.4 and 4.3 mcg/L) were increased above normal values (normal, <1 mcg/L for serum and cerebrospinal fluid). Cerebrospinal fluid drainage, removal of the cement and administration of deferoxamine caused increased aluminum excretion but did not prevent death. Aluminum was leached from cement incubated with cerebrospinal fluid at 37 degrees C for 16 hours in an in vitro experiment.
2) Additional cases of encephalopathy after use of aluminum-containing bone cement in otoneurosurgery have been reported (Renard et al, 1994).

h) CASE REPORT: A 43-year-old man, with a history of cocaine and heroin use, presented with signs and symptoms of encephalopathy, including cognitive decline, memory loss, dysgraphia, dysarthria, ataxia, myoclonus, and tonic-clonic seizures, that occurred over the preceding 3 months. Laboratory studies indicated neutropenia and microcytic anemia and a bone marrow biopsy showed osteosclerosis and myelosclerosis. Further investigation of the patient's background revealed that he received methadone at doses of up to 170 mg daily for at least 3 to 4 years. Occasionally, he would heat the methadone solution in an aluminum-based pot, in order to reduce it to an appropriate volume, and then inject the solution intravenously. Serum aluminum level was 180 mcg/L (normal is less than 3.2 mcg/L). Treatment was initiated, consisting of supportive care, iron supplementation, and deferoxamine administration. Although, after 9 months of treatment, there appeared to be partial neurological improvement, the patient continued to show no improvement in his dysarthria. His serum aluminum level at this time was 64.5 mcg/L (Friesen et al, 2006).
i) CASE REPORT: A 42-year-old man presented with a 3-month history of seizures, ataxia, dysarthria, myoclonus, postural tremors, and short-term memory loss. For 4 years he had been intravenously injecting methadone solution that was heated in an uncoated aluminum pot to reduce the volume. His serum aluminum level, at the time of presentation, was 6650 nmol/L. Deferoxamine treatment was initiated as a continuous IV infusion at a rate of 50 mg/hour. Over the course of 7 months, the infusion rate was periodically adjusted due to renal dysfunction. After 7 months, the patient was switched to weekly intermittent IV injections for another 2 months. After 9 months of treatment, the patient showed neurological improvement and his serum aluminum level was 2390 nmol/L (a 64% reduction) (Yong et al, 2006).

B) ALZHEIMER'S DISEASE

1) Alzheimer disease is a dementing illness with deterioration of mental functions related to memory, judgment and abstract thinking, plus personality/behavior changes. The distinctive pathohistological features of this disease are neurofibrillary tangles, senile plaques and amyloid deposits. According to some sources, aluminum is linked to these senile plaques and amyloid deposits (Zenz, 1994).

a) Increased concentrations of aluminum have been found in the brain tissue of patients with Alzheimer disease. It is still unclear whether aluminum is involved etiologically in this disease or exists merely as a marker of some other pathophysiologic process (Crapper McLachlan DR, 1986b; Ganrot, 1986; Martyn et al, 1989; Monteagudo et al, 1989; Perl & Pendlebury, 1986; Yokel, 2000).
b) Rather than aluminum having an etiologic function, one theory is that some primary pathogenic event or events responsible for Alzheimer disease may affect the genetically-determined barriers to aluminum, resulting in increased amounts of aluminum being accessible to vulnerable target sites in the brain (Crapper McLachlan DR, 1986b).

2) META-ANALYSIS: Three case-control studies, involving 1056 participants, were evaluated in a meta-analysis conducted to quantify an association between occupational exposure to aluminum and the risk of developing Alzheimer's disease. Pooling the results of these studies demonstrated an odds ratio (OR) of 1 (95% CI 0.59 to 1.68) indicating that there is no association between occupational exposure to aluminum and an increased risk for Alzheimer's disease, although further investigation, including the inclusion of prospective studies, is warranted (Virk & Eslick, 2015).

C) DISTURBANCE IN THINKING

1) Decreased cognitive function and decreased psychomotor function are neurodegenerative disorders linked to aluminum exposure (Harbison, 1998). Severe brain damage is a reported effect of exposure to airborne particulates carrying aluminum (Lewis, 1998).
2) Subtle cognitive deficits have been reported in workers exposed to aluminum for years. Cognitive deficits were seen in miners exposed by inhalation to finely ground aluminum and aluminum oxide, which was used for 35 years as a prophylaxis against silicotic lung disease (Rifat et al, 1980). A few potroom workers have had cognitive deficits (White et al, 1992). Neurological syndromes, including cognitive and motor impairment, have been reported in some aluminum welders (Sjogren et al, 1990; 1997).

D) FATIGUE

1) SHAVER'S DISEASE: This industrial disease, in which aluminum is involved, is known to cause weakness, fatigue and respiratory distress (Hammond & Beliles, 1980).
2) CASE REPORT: A 43-year-old woman developed bone pain and extreme fatigue after applying 1 gram of an aluminum chlorohydrate-containing antiperspirant cream on each underarm every morning for 4 years. It was found that 1 g of the cream contained 20% aluminum chlorohydrate providing a dose of 0.108 g of aluminum(III) per day and a dose of 157.30 g over a 4-year period. Aluminum levels in plasma and urine were 3.88 mcmol/L (10.47 mcg/dL) and 1.71 mcmol/24 hours (46.1 mcg/24 hours; normal less than 1.10 mcmol/24 hours or 29.7 mcg/24 hours), respectively. Eight months after the discontinuation of the antiperspirant, she recovered completely without further sequelae (Guillard et al, 2004).

E) SEIZURE

1) CASE REPORT: A 30-year-old man sustained a tonic-clonic seizure approximately 48 hours after his work shift as a remelt furnace operator. His job involved removing slag from furnaces which melted aluminum scrap using a powdered flux of aluminum silicon fluoride. He had no family history of seizures. Physical examination was normal except for diminished sensation in a stocking-glove distribution. Generalized high-voltage sharp theta activity with photic stimulation and drowsiness without focal abnormality was noted on EEG. His plasma aluminum concentration was 22 mcg/L (normal, less than 9). He was advised to use protective equipment to reduce his exposure to aluminum and fluoride dust. Repeat plasma aluminum concentrations over the next 15 weeks were 16 and 5 mcg/L. He declined further phenytoin or other anticonvulsant therapy. At 1 year, he remained seizure free with a plasma aluminum concentration of 4 mcg/L (Freiman et al, 2005).

F) NEUROLOGICAL FINDING

1) A study was conducted to determine the relationship between the Clara cell protein (CCP), an anti-inflammatory biomarker of lung epithelium function, and aluminum neurotoxicity in smelters exposed to aluminum dust. Neurotoxicity was assessed from subjective and objective neurological surveys, EEGs, and visual evoked potential (VEP) examinations. The smelters with subjective CNS symptoms (n=24) were divided into 4 groups, according to neurophysiological examination: Group A with abnormal EEG and VEP results (n=5), Group B with abnormal EEG results (n=6), Group C with only subjective CNS symptoms (no abnormal neurophysiological exam results; n=7), and Group D with abnormal VEP results (n=6). There was an inverse relationship between serum CCP levels and serum aluminum concentrations. Groups A and C had low serum CCP levels but high serum aluminum concentrations. Conversely, Group B had the highest serum CCP level, but had the lowest serum aluminum concentration. These results suggest that subclinical neurotoxicity, particularly abnormal VEP, may be associated with internalization of aluminum ions with the lipid fractions of the lung epithelium, which may allow the aluminum ions to pass through the blood-brain barrier more readily (Halatek et al, 2005).
2) A prospective cohort study was conducted to determine the relationship between aluminum intoxication and development of a neurodegenerative disease (ND). Of 471 individuals who consecutively underwent medical examination in an outpatient clinic, 211 were selected due to evidence of aluminum burden and the subjects ability to follow protocol. The 211 subjects were divided into 3 groups: ND (n=118), healthy subjects (n=73), and patients with pathologies other than ND (not-ND; n=20). Multiple sclerosis (MS) was the most prevalent in the patients with ND (n=101; 85.6%). All of the patients underwent a chelation test with EDTA in order to determine the amount of aluminum present in urine samples collected from each patient. Analysis of the results were divided into healthy patients, MS patients, and ND patients. Following the EDTA challenge, aluminum was present in 44.8% of ND and healthy patients combined, with aluminum levels significantly higher in the urine samples of the MS and ND patients than in the healthy patients (approximately 110 mcg Al/g creatinine, 120 mcg Al/g creatinine, and 80 mcg Al/g creatinine, respectively). Patients with evidence of aluminum intoxication received 10 weeks of EDTA chelation therapy. Following therapy, aluminum concentrations were significantly reduced (Fulgenzi et al, 2014).

Gastrointestinal

3.8.2)

A) INTESTINAL OBSTRUCTION

1) Chronically administered aluminum hydroxide may cause chronic constipation, which may lead to intestinal obstruction (Salmon et al, 1978; Townsend et al, 1973; Spofforth, 1921).

B) GASTRIC ULCER

1) Sodium aluminate is considered to be corrosive (Stokinger, 1981).

Hepatic

3.9.2)

A) HEPATIC NECROSIS

1) Necrosis of the liver is a reported effect of exposure to airborne particulates carrying aluminum (Lewis, 1998).

B) CHOLESTATIC HEPATITIS

1) CASE SERIES: Abnormal liver function and cholestasis were reported in five children receiving long-term parenteral nutrition. Liver biopsy demonstrated moderate to severe histopathology in all five children (Klein et al, 1984).

C) ALUMINUM INTOXICATION

1) IMPAIRED ALUMINUM EXCRETION: Patients with liver or biliary tract disease may be at risk of aluminum toxicity. However, absorbed aluminum is mainly eliminated by renal excretion. Biliary excretion accounted for no more than 3 percent of total aluminum elimination in one human (Priest et al, 1995) and in experimental animals (Yokel, 1996). Possible enterohepatic circulation of aluminum has not been studied. Bile contained a higher concentration of aluminum than did urine in patients.
2) Two patients with chronic liver disease developed aluminum osteodystrophy despite normal renal function. The patients had been taking aluminum-containing antacids for months to years. It was suggested that the patients' lack of normal biliary excretion of aluminum led to increased aluminum levels in bone, resulting in severe osteomalacia. The authors then established that bile contained a higher concentration of aluminum than did urine in patients taking aluminum-containing antacids (Williams et al, 1986).

Genitourinary

3.10.2)

A) RENAL FAILURE SYNDROME

1) ALUMINUM SALTS: There is fairly good evidence that aluminum salts are toxic when given chronically to patients with renal failure. A dialysis encephalopathy syndrome (dysarthria, apraxia of speech, asterixis, myoclonus, dementia, focal seizures), a vitamin D-resistant osteomalacia, microcytic hypochromic anemia and increased aluminum concentrations in bone, brain and muscle have been reported in humans (Berlyne, 1980; Alfrey et al, 1976; McDermott et al, 1978; Monteagudo et al, 1989; Ganrot, 1986; Gruskin, 1988).

a) The aluminum salts may be administered orally as aluminum hydroxide in sucralfate or other forms of aluminum or may be in water used for dialysate (Davison et al, 1982; Monteagudo et al, 1989).

B) ACUTE RENAL FAILURE SYNDROME

1) Necrosis of the kidney is a reported effect of exposure to airborne particulates carrying aluminum (Lewis, 1998).

Hematologic

3.13.2)

A) MICROCYTIC ANEMIA

1) A distinctive microcytic, hypochromic anemia has been reported in patients with uremia who later developed aluminum-associated osteomalacia and encephalopathy (Short et al, 1980; McGonigle & Parsons, 1985).
2) Microcytic anemia has been associated with aluminum toxicity in chronic dialysis patients who take aluminum-containing antacids or who have been exposed to high aluminum levels in the dialysate. Discontinuing the aluminum source has led to improvement (Bingham et al, 2001; Jeffery et al, 1996). Addition of deferoxamine chelation therapy is beneficial (Gruskin, 1988; Monteagudo et al, 1989; Swartz et al, 1987; Tsuru et al, 1987).
3) Evaluation of hematologic parameters in 33 dialysis patients after unrecognized failure of a reverse osmosis system demonstrated effects even though water concentrations were only approximately 0.85 picomol/L. Over less than four months exposure patients experienced a decrease in hemoglobin, mean corpuscular volume, ferritin, and transferrin saturation. Blood aluminum levels were increased from 0.56 +/- 0.44 to 1.63 +/- 0.52 micromol/L (Gonzalez-Revalderia et al, 2000).
4) Microcytic anemia, along with chronic encephalopathy, was reported in a 43-year-old man with aluminum toxicity. The patient had been heating methadone solution in an aluminum-based pot, in order to reduce it to an appropriate volume, and then injected the solution intravenously (Friesen et al, 2006).

Dermatologic

3.14.2)

A) SKIN IRRITATION

1) Repeated contact of the skin with soluble salts of aluminum results in 'acid' irritation from hydrolysis and a congestive, anesthetic condition of the fingers (acroanesthesia). Alum (aluminum sulfate) may cause these signs and symptoms (Stokinger, 1981).

B) HYPERSENSITIVITY REACTION

1) Delayed hypersensitivity to aluminum can occur. Aluminum-adsorbed vaccines have occasionally induced delayed hypersensitivity to aluminum, although this is rare (Veien et al, 1986; Bohler-Sommerbegger & Lindemayr, 1986; Garcia-Patos et al, 1995).

C) TELANGIECTASIS

1) Hypersensitivity and telangiectases have occurred from repeated skin contact with aluminum salts. Skin telangiectasias have occurred among workers in an aluminum-producing plant and may be related to fluoride or organofluorine exposure, although the causative compound(s) has not been identified (Sjogren et al, 1997; Zenz, 1994).

D) GRANULOMA

1) Granuloma formation with persistent subcutaneous nodules has been reported rarely after accidental intradermal injection of aluminum-adsorbed vaccine material (Bohler-Sommerbegger & Lindemayr, 1986) (Vogelbruch et al, 2000).
2) Aluminum-induced delayed hypersensitivity granulomas from a tattoo have been reported (McFadden et al, 1989).
3) Aluminum chloride (in antiperspirants), aluminum acetotartrate (medical use) and aluminum adjuvants (vaccines) have all resulted, albeit rarely, in sensitization of the skin to aluminum after repeated use, producing persistent granuloma (injection site) and recurrent eczema (Zenz, 1994).

Musculoskeletal

3.15.2)

A) DISORDER OF BONE

1) ALUMINUM-RELATED BONE DISEASE (ARBD): A syndrome of aluminum-related bone disease (ARBD) has been described in renal failure patients on dialysis who receive exogenous aluminum either from excess aluminum in the dialysate (Smith et al, 1987; Kerr et al, 1986) or from chronic therapy with aluminum-containing phosphate binders (Sherrard, 1986).
2) Other terms for ARBD include aluminum-induced osteomalacia (Smith et al, 1987), aluminum-induced dialysis osteodystrophy (Kerr et al, 1986), aluminum-associated bone disease (Andress et al, 1987a), aluminum-related osteodystrophy (Andress et al, 1987b) and aluminum osteodystrophy (Williams et al, 1986).
3) Clinical features of ARBD are progressive bone pain, fractures, impaired healing, reduced bone calcification, muscle weakness and crippling deformities (Bingham et al, 2001; Sherrard, 1986; Monteagudo et al, 1989). The pain commonly is in the back of the hips, or can be generalized. Pain also can occur in weight-bearing sites, such as feet, ankles and knees, and is generally aggravated by motion (Coburn & Norris, 1986).
4) Radiological features of ARBD are osteopenia, fractures, and Looser's zones (Monteagudo et al, 1989). Subperiosteal erosions can also occur (Coburn & Norris, 1986; Sherrard, 1986).
5) Dialysis patients at particularly high risk of developing ARBD are children, long-term dialysis patients, patients who have had parathyroidectomies, a history of failed renal transplant, patients with previous bilateral nephrectomies, and patients who have had reversal of hyperparathyroidism following treatment with active vitamin D sterol (Coburn & Norris, 1986; Sherrard, 1986).
6) Severe, biopsy-proven ARBD was reported in two patients without a history of chronic renal failure. Both patients were receiving chronic therapy with aluminum-containing antacids and had chronic liver failure (Williams et al, 1986).
7) Aluminum exerts its toxic effect on bone by inhibiting osteoblast function (thereby decreasing bone formation), and by inhibiting mineralization of bone extracellularly (Monteagudo et al, 1989; Sherrard, 1986).
8) ARBD must be differentiated from the other common form of bone disease in renal failure patients: osteitis fibrosa cystica (also known as osteitis fibrosa and renal osteodystrophy). The presenting signs and symptoms may be very similar in both of these diseases although bone pain is more common in ARBD (Monteagudo et al, 1989).

a) In this 'fracturing dialysis osteodystrophy', aluminum is deposited at the junction of surface osteoid seams and mineralized bone (Zenz, 1994).
b) Osteitis fibrosa cystica is due to hyperparathyroidism. However, parathyroid hormone levels may also be increased in ARBD. Serum aluminum levels are usually increased in ARBD. A deferoxamine test may be required to document an increased body burden of aluminum (Sherrard, 1986; Norris et al, 1986; Andress et al, 1987b) (Monier-Faugere, 1994).

9) Treatment of ARBD parallels that of other aluminum-related disorders in renal failure patients: limiting the amount of aluminum in the dialysate, reducing the intake of aluminum-containing phosphate binders and antacids and long-term chelation therapy with deferoxamine (Finch et al, 1986; Ott et al, 1986; Norris et al, 1986; Coburn & Norris, 1986; Smith et al, 1987; Kerr et al, 1986).
10) Decreasing the aluminum content of dialysis fluids to less than 30 mcg/L has been shown to decrease the incidence of osteomalacia induction (Bingham et al, 2001). Low deferoxamine doses (5 to 10 mg/kg) have been suggested (Barata et al, 1995).
11) CASE REPORT: A 43-year-old woman developed bone pain and extreme fatigue after applying 1 gram of an aluminum chlorohydrate-containing antiperspirant cream on each underarm every morning for 4 years. It was found that 1 g of the cream contained 20% aluminum chlorohydrate providing a dose of 0.108 g of aluminum(III) per day and a dose of 157.30 g over a 4-year period. Aluminum levels in plasma and urine were 3.88 mcmol/L (10.47 mcg/dL) and 1.71 mcmol/24 hours (46.1 mcg/24 hours; normal less than 1.10 mcmol/24 hours or 29.7 mcg/24 hours), respectively. Eight months after the discontinuation of the antiperspirant, she recovered completely without further sequelae (Guillard et al, 2004).

B) ARTHROPATHY

1) DIALYSIS-ASSOCIATED ARTHROPATHY: Aluminum accumulates in synovial tissue and fluid and articular cartilage of long-term hemodialysis patients, and may contribute to dialysis-associated arthropathy (Netter et al, 1991).

Endocrine

3.16.2)

A) HYPOPARATHYROIDISM

1) Aluminum may be directly toxic to the parathyroid gland and reduce the secretion of parathyroid hormone (Lione, 1985a).

Reproductive

3.20.1)

A) Aluminum in drinking water has been linked to central nervous system birth defects. Some aluminum compounds have proven teratogenic in laboratory animals; however, overall, aluminum is not considered teratogenic.

3.20.2)

A) HUMANS

1) CNS CONGENITAL ANOMALY

a) There was a correlation between aluminum levels in drinking water and birth defects of the central nervous system in South Wales (Morton et al, 1976). Children with birth defects had high levels of aluminum (determined by hair analysis) (Williams et al, 1986).
b) A review of the literature on neurodevelopmental effects of aluminum (Alleva et al, 1998) indicates possible effects of gestational exposure, including both neurobehavioral (altered vocalizations) and neurochemical changes (altered choline acetyltransferase activity, alterations in nerve growth factor activity). The authors suggest a need for further study.

B) ANIMAL STUDIES

1) In rats, aluminum FLUORIDE given prenatally via inhalation induced multiple anomalies. Aluminum NITRATE was also teratogenic in rats. However, aluminum CITRATE and LACTATE have been found to be negative for teratogenicity in rats. Moreover, the positive results may not have been due to the aluminum component, and reviews have indicated that the element is not considered likely to be a teratogen (Schardein, 2000).
2) Maternal and developmental toxicity occurred in rats and mice when aluminum HYDROXIDE was given concurrently with citric or lactic acid (Domingo, 1995).
3) Aluminum LACTATE given in the diet throughout pregnancy caused decreased weight gain and delayed neurobehavioral development in mice (Golub, 1987). In a follow-up study, offspring of mice fed aluminum LACTATE at a dose of 1,000 mcg Al/g of diet during pregnancy and lactation showed growth retardation, and mice exposed during gestation showed weakened forelimb grasp strength (Golub et al, 1992). Aluminum CHLORIDE also delayed neuromotor development in rats (Bernuzzi, 1986).
4) The aluminum concentrations in fetal mouse brains were higher in animals on a high-aluminum diet. The high-aluminum diet potentiated the growth retardation of a diet deficient in MANGANESE (Golub et al, 1993).
5) Reviews indicate that aluminum is a developmental toxicant when administered parenterally. They also suggest that maternal dietary exposure to aluminum in concentrations that may not be maternally toxic could cause permanent neurobehavioral deficits in weanling mice and rats (Domingo, 1995).
6) A review of the literature on neurodevelopmental effects of aluminum in mouse dams (Alleva et al, 1998) indicates possible effects of gestational exposure, including both neurobehavioral (altered vocalizations) and neurochemical changes (altered choline acetyltransferase activity, alterations in nerve growth factor activity). The authors suggest a need for further study.
7) The possible mechanisms of aluminum-induced reproductive toxicity in mice were investigated. Mice were administered aluminum chloride at zero, one eighth, and one third the LD50 intraperitoneally daily for 12 or 16 days, followed by a 2 week withdrawal period. Results showed a significant adverse effect on steriodogenesis. It also revealed the process was reversible and that subsequent increased Nox production caused by excess aluminum may inhibit testosterone levels (Guo, 2001).
8) The developmental toxicity of aluminum III in amphibians was investigated. Aluminum III was shown to be lethal at 1.5mM and seriously affected differentiation of the CNS, skeleton and eye. It also caused cephalic and trunk edemas at lower concentrations (Calevro, 1998).
9) Aluminum LACTATE given in the diet throughout pregnancy caused decreased weight gain and delayed neurobehavioral development in mice (Golub, 1987). In a follow-up study, offspring of mice fed aluminum LACTATE at a dose of 1,000 mcg Al/g of diet during pregnancy and lactation showed growth retardation, and mice exposed during gestation showed weakened forelimb grasp strength (Golub et al, 1992).
10) The aluminum concentrations in fetal mouse brains were higher in animals on a high-aluminum diet. The high-aluminum diet potentiated the growth retardation of a diet deficient in MANGANESE (Golub et al, 1993). Levels of manganese and IRON were lower in the liver and brain of mice exposed to aluminum during lactation (Golub et al, 1992).

3.20.3)

A) ANIMAL STUDIES

1) STILLBIRTH

a) In animal studies, rats on a low copper diet were susceptible to alterations of pituitary hormones by aluminum, which affected testicular function (Jiu & Stemmer, 1983). Aluminum HYDROXIDE ingestion resulted in stillborns and aborted litters in rats (Anderson, 1985). Maternal and developmental toxicity occurred in rats and mice when aluminum hydroxide was given concurrently with citric or lactic acid (Domingo, 1995).

3.20.4)

A) ANIMAL STUDIES

1) BREAST MILK

a) Injection of aluminum in rabbits increased milk aluminum concentration. Approximately 2 to 3 percent of the injected aluminum was found in the milk. Less than 1 percent of aluminum in milk was absorbed. The poor distribution of aluminum into milk and its poor oral absorption indicate that there is little risk of aluminum toxicity via milk (Yokel, 1984; Yokel & McNamara, 1985).
b) Levels of manganese and IRON were lower in the liver and brain of mice exposed to aluminum during lactation (Golub et al, 1992). Permanent neurobehavioral deficits have been induced in weanling mice and rats by dietary exposure to aluminum at levels that did not produce maternal toxicity (Domingo, 1995).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS7429-90-5 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) IARC Classification

a) Listed as: Aluminium production
b) Carcinogen Rating: 1

1) The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.

3.21.2)

A) Although aluminum and its compounds have shown little evidence of carcinogenicity in humans, exposure to other substances involved in the production of aluminum has been linked to carcinogenicity.

3.21.3)

A) CARCINOMA

1) Aluminum and aluminum compounds have generally shown no evidence of carcinogenicity (Baxter et al, 2000). However, some report that overall there is evidence of increased risk of cancer in workers involved in primary aluminum production, probably related to polyaromatic hydrocarbons rather than aluminum itself. IARC concluded some aluminum exposure is linked to lung and bladder cancer, with pitch volatives being the causative agent (Zenz, 1994).
2) A group of 4,213 male aluminum reduction plant workers showed increased incidence of bladder cancer and mortality from brain cancer; however, these workers had significant exposure to COAL TAR PITCH VOLATILES, a known human carcinogen, so the observed effects could not be attributed to aluminum itself (Spinelli et al, 1991).
3) One case of occupational lung fibrosis in an aluminum polisher was complicated by bronchial carcinoma (De Vuyst, 1986), but aluminum is not believed to cause cancer in humans.

3.21.4)

A) CARCINOMA

1) Aluminum has caused cancer in animals when injected or implanted (Ogara & Brown, 1967).

B) LEUKEMIA

1) Aluminum in the drinking water was not carcinogenic in mice but did increase leukemia and lymphoma (Schroeder & Mitchener, 1975).

Genotoxicity

A)

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) The vast majority of patients with aluminum exposure do not require any laboratory evaluation. Obtain serum aluminum concentrations in dialysis patients in whom aluminum toxicity is suspected.
B) Radiographs may help diagnose aluminum-induced bone disease. Obtain and chest radiograph and CT if aluminum-related pulmonary disease is suspected.

4.1.2)

A) Normal serum aluminum concentration is considered to be less than 10 mcg/L (Flaten et al, 1996).
B) Plasma aluminum levels have been evaluated as a predictor of bone disease development in renal disease patients. A plasma aluminum concentration of 40 mcg/L or more had a 65.2 percent sensitivity and a 76.5 percent specificity for aluminum bone disease. Overall, despite a general correlation, plasma aluminum concentration was a poor predictor of the presence or absence of aluminum bone disease (Kausz et al, 1999).

4.1.3)

A) End-of-shift urine concentrations have been set by some national authorities at 200 mcg/L (7.4 micromol/L, BAT) and 6 micromol/L (FIOH) on the basis of pulmonary fibrosis (Baxter et al, 2000). However, the relationship of these levels to disease outcome does not seem to be clearly established.

4.1.4)

A) OTHER

1) Soft tissue and bone aluminum concentrations are approximately 1 to 4 mcg/g dry weight (Alfrey et al, 1980; Hongve et al, 1996).
2) Total body burden of aluminum is approximately 25 to 60 mg in normal adults (Yokel, 1996).

Radiographic Studies

A)

1) Radiologic features of aluminum-related bone disease are osteopenia, pathologic fractures, Looser's zones and subperiosteal resorption (Monteagudo et al, 1989; Sherrard, 1986). The appearance may be similar to that of the other common bone disease in chronic renal failure, osteitis fibrosa cystica. The two conditions may be difficult to distinguish radiographically (Sherrard, 1986).
2) Based on a single case report, it seems that high-resolution chest computed tomography (CT) may be more sensitive than ordinary chest radiography for evaluation of early signs of aluminum-induced lung disease. Small, centrilobular, nodular opacities and slightly thickened interlobular septae were seen (Kraus et al, 2000).

Methods

A)

1) Many methods exist for analyzing aluminum. The method most commonly used for serum, water, dialysate and acid-digested tissues is graphite furnace atomic absorption (Baselt, 2000) Berlin, 1982-1983; (Monteagudo et al, 1989).
2) For analyzing aluminum in plasma and urine by atomic absorption spectroscopy, a transversely heated graphite atomizer with a transverse Zeeman background-correction system reduced analysis time by one-third (Bradley & Leung, 1994).

B)

1) Methods to determine subcellular aluminum concentrations use microprobe techniques such as laser microprobe mass spectrometry, energy-dispersive x-ray microanalysis and secondary ion mass spectrometry (Lovell et al, 1996). Diagnosis of ARBD from bone biopsy includes bone histology and determination of aluminum deposition at the bone-osteoid interface and within bony trabecules (Malluche & Monier-Faugere, 1994).

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Renal failure patients with aluminum encephalopathy should be admitted.

6.3.1.2) HOME CRITERIA/ORAL

A) Patients with inadvertent acute ingestion can be managed at home. Patients with significant GI, pulmonary, or eye irritation should be referred to a healthcare facility.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a medical toxicologist or poison center for patients with significant symptoms or in whom the diagnosis is unclear. Consult a nephrologist for renal failure patients with suspected aluminum intoxication.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with deliberate ingestions, and those with significant GI, respiratory or eye irritation should be evaluated and observed until symptoms improve.

Monitoring

A)

B)

Oral Exposure

6.5.1)

A) SUMMARY

1) Insoluble forms of aluminum are poorly absorbed from the gastrointestinal tract, GI decontamination is generally unnecessary.
2) Ingestions of large amounts of soluble forms of aluminum such as aluminum chloride, aluminum fluoride, or aluminum sulfate may cause GI irritation; sodium aluminate is considered a corrosive. Dilution with small volumes of water or milk may be beneficial.

6.5.2)

A) SUMMARY

1) Insoluble forms of aluminum are poorly absorbed from the gastrointestinal tract; GI decontamination is not necessary.
2) Ingestion of large amounts of soluble forms of aluminum such as aluminum chloride, aluminum fluoride or aluminum sulfate may cause GI irritation; sodium aluminate is considered a corrosive. Dilution with small amounts of water or milk may be beneficial.

6.5.3)

A) GENERAL TREATMENT

1) The probability of aluminum poisoning in patients with chronic renal failure treated by long-term hemodialysis may be reduced by moderating the use of aluminum containing oral phosphate binders and reducing the amount of aluminum in the dialysate (Wills & Savory, 1983). Oral calcium carbonate is often substituted for aluminum-containing phosphate binders to prevent or treat aluminum toxicity in renal failure patients (Salusky et al, 1986; Monteagudo et al, 1989).

B) MONITORING OF PATIENT

1) The vast majority of patients with aluminum exposure do not require any laboratory evaluation. Obtain serum aluminum concentrations in dialysis patients in whom aluminum toxicity is suspected.
2) Radiographs may help diagnose aluminum-induced bone disease. Obtain and chest radiograph and CT if aluminum-related pulmonary disease is suspected.

C) DEFEROXAMINE

1) EFFICACY

a) SUMMARY: Aluminum intoxication may be treated with the chelating agent deferoxamine, with symptomatic relief of dialysis encephalopathy and osteomalacia (Wills & Savory, 1983).
b) TISSUE MOBILIZATION: Deferoxamine can mobilize aluminum from tissue deposits and increase serum aluminum concentration. Once in the serum, this deferoxamine-chelated aluminum can be cleared by hemodialysis, hemofiltration or peritoneal dialysis (Chang & Barre, 1983) (Simon et al, 1983b).
c) OSTEOMALACIA: Deferoxamine has been used successfully in the treatment of aluminum-related bone disease (Ott et al, 1986; Coburn & Norris, 1986; Norris et al, 1986; Felsenfeld et al, 1989).
d) ENCEPHALOPATHY: Deferoxamine therapy has been effective in reversing aluminum-induced encephalopathy in patients with chronic renal failure (Sprague et al, 1986; Monteagudo et al, 1989; Ackrill et al, 1986).
e) CASE REPORT: Deferoxamine intramuscularly (1 gram over 14 days) was used successfully in a patient with chronic renal failure and osteomalacia to reduce aluminum and aid bone healing (Kingswood et al, 1983).
f) CASE REPORT: A 31-month-old boy with renal insufficiency was treated for aluminum intoxication with deferoxamine given by the intraperitoneal route and was reported to be clinically improved after 6 months of chelation therapy (Warady et al, 1986).
g) CASE SERIES: Eight chronic dialysis patients with microcytic anemia, presumed secondary to aluminum toxicity due to aluminum-containing phosphate binder therapy were treated with deferoxamine. The mean hematocrit value improved from 24 volume percent (pretreatment) to a maximum value of 36 volume percent (2 to 6 months after starting deferoxamine therapy). The MCV increased from 68 cubic microns to 88 cubic microns. Bone pain, presumed to be secondary to aluminum-induced osteodystrophy, also improved in six of eight patients (Swartz et al, 1987).
h) CASE REPORT: Deferoxamine was given to a 43-year-old man, who developed encephalopathy (cognitive decline, memory loss, dysgraphia, dysarthria, ataxia, and myoclonus) following aluminum toxicity. The patient had been heating methadone solution in an aluminum-based pot, in order to reduce it to an appropriate volume, and then injected the solution intravenously. Over the course of 7 months, deferoxamine was administered as a continuous IV infusion at doses ranging from 12.5 mg/hr to 125 mg/hr (average 69 mg/hr). After hospital discharge, the patient continued to receive deferoxamine, 5 mg/kg/day 5 times per week for 2 months. After 9 months of treatment, the patient continued to show no improvement in his dysarthria. His initial serum aluminum level was 180 mcg/L (normal is less than 3.2 mcg/L); after 9 months of deferoxamine treatment, his serum aluminum level was 64.5 mcg/L (Friesen et al, 2006).
i) CASE REPORT: A 42-year-old man presented with a 3-month history of seizures, ataxia, dysarthria, myoclonus, postural tremors, and short-term memory loss, after intravenously injecting methadone solution, that was heated in an uncoated aluminum pot, over the course of 4 years. His serum aluminum level, at the time of presentation, was 6650 nmol/L. Deferoxamine treatment was initiated as a continuous IV infusion at a rate of 50 mg/hr. Over the course of 7 months, the infusion rate was periodically adjusted due to renal dysfunction. After 7 months, the patient was switched to weekly intermittent IV injections for another 2 months. After 9 months of treatment, the patient showed neurological improvement and his serum aluminum level was 2390 nmol/L (a 64% reduction) (Yong et al, 2006).

2) DOSE

a) The Consensus Conference on Diagnosis and Treatment of Aluminum Overload in End-Stage Renal Failure Patients held in Paris, 1992, recommended low-dose deferoxamine: 5 mg/kg. When 5 mg/kg was given 5 hours before the start of a hemodialysis session, deferoxamine-related neurological side effects were fewer than when the drug was given at the conventional time, during the last hour of a dialysis session. The 5-mg/kg deferoxamine treatment was safe and effective for aluminum overload (Barata et al, 1996).
b) INTRAMUSCULAR

1) All patients not in shock: 1 gram initially then 0.5 gram every 4 hours for two doses. Subsequent dose of 0.5 gram every 4 to 12 hours.

c) INTRAVENOUS

1) Intravenous deferoxamine was given to chronic hemodialysis patients with aluminum toxicity during the last 2 hours of each thrice-weekly dialysis treatment at a dose of 500 to 1,500 milligrams, depending on side effects, for several months (Swartz et al, 1987).

d) INTRAPERITONEAL

1) Intraperitoneal deferoxamine was given to chronic peritoneal dialysis patients with aluminum toxicity at a dose of 1,500 milligrams overnight three times per week (Swartz et al, 1987).

e) DURATION OF THERAPY

1) Usually weeks to months of chelation therapy with deferoxamine are necessary before improvement in aluminum toxicity is noted (Gruskin, 1988; Norris et al, 1986; Coburn & Norris, 1986; Sprague et al, 1986; Swartz et al, 1987).

3) ADVERSE EFFECTS

a) THROMBOCYTOPENIA

1) CASE REPORT: Thrombocytopenia developed after 5 doses of deferoxamine in a 63-year-old chronic hemodialysis patient with osteomalacia attributed to aluminum toxicity. Platelet counts were normal when deferoxamine was withheld and decreased upon rechallenge (Walker, 1985).

b) ENCEPHALOPATHY

1) Deferoxamine mobilizes aluminum from tissues and may precipitate encephalopathy (Yokel, 1994). Therefore, serum aluminum levels should be monitored and the dose of deferoxamine decreased if symptoms worsen or if serum levels approach 1,000 mcg/L (Norris et al, 1986; Gruskin, 1988).

c) HYPOTENSION

1) HYPOTENSION occurred in some patients with aluminum toxicity receiving chelation therapy. This effect was minimized by either decreasing the dose or decreasing the rate of infusion (Norris et al, 1986).
2) PULMONARY TOXICITY

a) Adult respiratory distress syndrome has been reported in patients receiving prolonged high dose infusions (15 milligrams/kilogram/hour for 45 to 98 hours) for acute iron poisoning (Tenenbein et al, 1992). Severe or fatal pulmonary toxicity developed in 8 of 14 patients who received infusions of longer than 24 hours. Pulmonary toxicity did not develop in 29 patients treated for less than 24 hours (Tenenbein et al, 1992).
b) A "pulmonary syndrome" has been associated with high dose intravenous (10 to 25 milligrams/kilogram/hour) deferoxamine therapy for several days for acute and chronic iron overload patients; features can include tachypnea, dyspnea, hypoxemia, cyanosis, fever, eosinophilia, preceding urticaria, and/or interstitial infiltrates (Ioannides & Panisello, 2000; Freedman et al, 1990; Scanderbeg et al, 1990; Benson & Cheney, 1992; Prod Info deferoxamine mesylate subcutaneous injection, intramuscular injection, intravenous injection, 2012).

1) ONSET: usually 3 to 9 days after initiating deferoxamine therapy (Anderson & Rivers, 1992).

c) Pulmonary toxicity may be related to the duration of infusion and high daily doses (Macarol & Yawalkar, 1992).

3) SEPSIS

a) The use of deferoxamine in patients with acute iron overdose or chronic iron overload has been associated with Yersinia enterocolitica septicemia, and with mucormycosis in chronic iron overloaded patients (Boelaert et al, 1993; Melby et al, 1982).
b) Deferoxamine may have provided the iron siderophore growth factor required by the bacteria Yersinia and the fungus Rhizopus (Boelaert et al, 1993).

4) VISUAL AND AUDITORY TOXICITY

a) Impaired color vision, bilateral scotomas, night blindness, decreased visual acuity and retinal pigmentation have been reported in patients receiving chronic deferoxamine treatment (Bene et al, 1989; Pengloan et al, 1987; Olivieri et al, 1986; Blake et al, 1985; Davies et al, 1983). Cataracts, retinal abnormalities and night blindness have been reported (Prod Info deferoxamine mesylate subcutaneous injection, intramuscular injection, intravenous injection, 2012; Yokel, 1994).
b) Hearing disturbances have been reported, including tinnitus and hearing loss (Prod Info deferoxamine mesylate subcutaneous injection, intramuscular injection, intravenous injection, 2012).

4) DEFEROXAMINE INFUSION TEST

a) A deferoxamine test combined with serum immunoreactive parathyroid hormone (iPTH) determination can contribute to the differential diagnosis of aluminum-related bone disease, increased risk of aluminum toxicity and aluminum overload. These three conditions were defined by bone aluminum content, bone surface aluminum (aluminon staining) and bone formation rate.
b) For the deferoxamine test, a single deferoxamine dose is given and the increase in serum aluminum is determined. The low-dose (5 or 10 mg/kg) deferoxamine test and serum iPTH were able to diagnose these conditions with sensitivities and specificities >84% (D'Haese et al, 1995).
c) The criteria for aluminum-related bone disease were a post-deferoxamine serum aluminum increment of 50 and 70 mcg/L with 5 and 10 mg/kg deferoxamine, respectively, and a serum iPTH <150 ng/L. The criteria for increased risk of aluminum toxicity were a post-deferoxamine serum aluminum increment of 50 and 70 mcg/L with 5 and 10 mg/kg deferoxamine, respectively, and a serum iPTH <650 ng/L.
d) The criteria for aluminum overload were post-deferoxamine serum aluminum increases of 50 and 70 mcg/L with 5 and 10 mg/kg deferoxamine, respectively.

D) EXPERIMENTAL THERAPY

1) Animal studies have indicated that other chelators may be effective for aluminum accumulation and toxicity (Yokel, 1994). Further studies are necessary before any recommendations can be made regarding use of these agents in humans.
2) EDTA CHELATION THERAPY: A prospective cohort study was conducted to determine the relationship between aluminum intoxication and development of a neurodegenerative disease (ND). Of 471 individuals who consecutively underwent medical examination in an outpatient clinic, 211 were selected due to evidence of aluminum burden and the subjects ability to follow protocol. The 211 subjects were divided into 3 groups: ND (n=118), healthy subjects (n=73), and patients with pathologies other than ND (not-ND; n=20). Multiple sclerosis (MS) was the most prevalent in the patients with ND (n=101; 85.6%). All of the patients underwent a chelation test with EDTA (calcium sodium edetate, 2 g/10 mL in 500 mL saline infused intravenously over 2 hours) in order to determine the amount of aluminum present in urine samples collected from each patient. Analysis of the results were divided into healthy patients, MS patients, and ND patients. Following the EDTA challenge, aluminum was present in 44.8% of ND and healthy patients combined, with aluminum levels significantly higher in the urine samples of the MS and ND patients than in the healthy patients (approximately 110 mcg Al/g creatinine, 120 mcg Al/g creatinine, and 80 mcg Al/g creatinine, respectively). Patients with evidence of aluminum intoxication received EDTA chelation therapy (2 g in 500 mL saline infused intravenously over 2 hours, administered once weekly for 10 weeks). Following therapy, aluminum concentrations were significantly reduced (Fulgenzi et al, 2014).

Inhalation Exposure

6.7.1)

A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

6.8.1)

A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

6.9.1)

A) DERMAL DECONTAMINATION

1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

6.9.2)

A) CHRONIC POISONING

1) Most cases of aluminum related dermal reactions are due to chronic exposure.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

A)

1) Hemodialysis, hemofiltration and peritoneal dialysis remove little serum aluminum in the absence of deferoxamine, due to the extensive binding of aluminum to transferrin (Wills & Savory, 1983).
2) Although hemodialysis can remove small amounts of aluminum, intravenous chelation with deferoxamine in conjunction with hemodialysis significantly increases the removal of aluminum from the body (Canteros et al, 1998) (Milliner et al, 1986; Nakamura et al, 2000).

B)

1) Chronic ambulatory peritoneal dialysis eliminated 41.1 +/- 8.7 micrograms of aluminum per 24 hours (1.2% of ingested dose) following a bolus ingestion of 1,800 milligrams of aluminum-chloride-hydroxide-complex (Passlick et al, 1989).
2) CONCLUSION: Chronic ambulatory peritoneal dialysis does not remove significant amounts of aluminum.

C)

1) Decrease of aluminum levels was greater after 4 hours of dialysis with carbon cartridges than with dialysis alone. The minimum net aluminum removal was from 1,862 +/- 174 to 3,007 +/- 43 micrograms/treatment (Delmez et al, 1989). This is an increase of approximately 1-milligram in aluminum removal, which may be clinically insignificant if the body burden is in gram amounts.
2) Hemodialysis patients with aluminum toxicity who were being chelated with deferoxamine were treated with coated charcoal hemoperfusion. Total removal of aluminum was better with hemodialysis plus hemoperfusion than with hemodialysis alone (McCarthy et al, 1988).

Abstracts

Case Reports

A)

1) OTHER

a) A 62-year-old woman with end stage renal failure received 22 units (8800 mL) of 4.5% human albumin solution during hemodialysis over a 39 day period. Serum aluminum increased dramatically to 294 micrograms/L during this time period and decreased when the treatment was stopped (Maher et al, 1986).
b) A 13-year-old girl with end-stage renal disease developed increasing plasma aluminum levels, despite weekly therapy with deferoxamine, while receiving sucralfate 1 gram three times daily for gastritis. Other sources of aluminum were considered including contaminated dialysate. When sucralfate therapy was withdrawn, plasma aluminum concentrations decreased substantially (Robertson et al, 1989).
c) ALUMINUM-CONTAINING ANTACIDS are generally considered not to cause aluminum bone disease in individuals with normal renal function. However, a single case with documented phosphate depletion and severe aluminum deposition on bone has been reported in a 39-year-old woman who had used very large amounts of antacid. Total elemental aluminum consumption over the 8-year period of use is estimated at 18 kg. Treatment with phosphate supplementation and withdrawal of antacids was successful (Woodson, 1998).

Range Of Toxicity

Summary

A)

B)

Therapeutic Dose

7.2.1)

A) GENERAL

1) Average daily aluminum consumption in the United States is 2 to 25 mg from food and beverages, of which 1% or less is absorbed (Greger, 1993).
2) SUCRALFATE - 1 gram orally four times daily one hour before meals and at bedtime (Prod Info Carafate(R), sucralfate, 2000).

Minimum Lethal Exposure

A)

1) A 22-year-old British worker experienced a rare fatal case of pulmonary fibrosis from inhalation of a heavy concentration of fine aluminum dust. The worker had been exposed to varying concentrations of many particle sizes; in the air, the concentration of dust below a size of 5 microns was on the order of 19 mg/m(3) (Hathaway et al, 1996).
2) A 49-year-old British workman who had worked for more than 13 years in the ball-mill room of an aluminum powder factory died of rapidly progressive encephalopathy. No other cases of encephalopathy with increased levels of aluminum in the brain of aluminum workers have been reported over the past 80 years (McLaughlin et al, 1962).

B)

1) An 11-month-old girl died of progressive encephalopathy after receiving phosphate binders containing aluminum. Higher-than-normal aluminum levels were found in the serum and cerebrospinal fluid (Harbison, 1998).
2) The industrial process used to manufacture aluminum was classified by IARC as a Group I carcinogen (sufficient evidence of carcinogenicity in humans) (IARC , 1998).

Maximum Tolerated Exposure

A)

B)

1) A 1989 report suggests a possible correlation between concentrations of aluminum in public water supplies and the occurrence of Alzheimer disease in 88 county districts of England and Wales. In districts where the mean aluminum concentration in water exceeded 0.11 mg/L, rates were 1.5 times higher than in districts where the mean levels were less than 0.01 mg/L.

a) The results of this study have been challenged on the basis of study design and data interpretation; however, subtle cognitive deficits have been reported (Hathaway et al, 1991; (Rifat et al, 1990).

2) There have been several similar studies, some suggesting a link between aluminum in drinking water and Alzheimer disease. Other studies do not suggest such a link (McLachlan, 1995; Savory et al, 1996).
3) In 19 patients undergoing dialysis with softened or untreated water, 7 experienced encephalopathy associated with the dialysis procedure and high aluminum concentration in the brain (Harbison, 1998).

C)

1) Inhalation of aluminum powder with a particle size of 1.2 microns (96 percent), given over 10- or 20-minute periods several times weekly, resulted in no adverse health effects among thousands of workers over several years (Martyn et al, 1989).
2) In the same work environment, 6 of 27 workmen who were heavily exposed to aluminum powder showed symptoms of pulmonary fibrosis. The finer the aluminum dust, the more dangerous it was found to be. Two of the twelve men exposed to fine aluminum powder died and two were affected. Two the 15 who worked only with the coarse powder had radiologic changes but no symptoms (Hathaway et al, 1996).
3) Studies done in the 1930s and 1940s in Germany, Great Britain and Sweden produced the following results: When humans were exposed to 0.1 to 2.7 mg/m(3) or 0.2 to 45 mg/m(3) of abrasive respirable aluminum dust, no cases of fibrosis of the lung (of 92) and 9 cases (of 1000) were reported, respectively (Zenz, 1994).

a) When humans were exposed to stamped aluminum powder at a level of 0.2 to 10 mg/m(3), 4 to 50 mg/m(3) or 50 to 100 mg/m(3), fibrosis of the lung occurred in 1 to 3 (of 53), 5 to 8 (of 35) and 6 (of 27) cases, respectively (Zenz, 1994).
b) Cases of fibrosis of the lung are reported very infrequently in North America (Zenz, 1994).

D)

1) CASE REPORT - A 43-year-old woman developed bone pain and extreme fatigue after applying 1 gram of an aluminum chlorohydrate-containing antiperspirant cream on each underarm every morning for 4 years. It was found that 1 g of the cream contained 20% aluminum chlorohydrate providing a dose of 0.108 g of aluminum(III) per day and a dose of 157.30 g over a 4-year period. Aluminum levels in plasma and urine were 3.88 mcmol/L (10.47 mcg/dL) and 1.71 mcmol/24 hours (46.1 mcg/24 hours; normal less than 1.10 mcmol/24 hours or 29.7 mcg/24 hours), respectively. Eight months after the discontinuation of the antiperspirant, she recovered completely without further sequelae (Guillard et al, 2004).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) SUMMARY

a) Serum aluminum is not very indicative of aluminum body burden (Monteagudo et al, 1989; Gruskin, 1988). A deferoxamine infusion test is more predicative.
b) TOXIC ALUMINUM SERUM LEVELS

1) Normal levels are thought to be 1 to 4 mcg/L, or less than 10 mcg/L (Baselt, 2000; Zenz, 1994).
2) Levels greater than 60 mcg/L are indicative of excessive aluminum absorption.
3) Levels greater than 100 mcg/L indicate a potential for clinical concern, and have been associated with signs of toxicity (Gruskin, 1988; McCarthy et al, 1986; Winney et al, 1986).
4) Levels greater than 200 mcg/L generally are associated with symptoms (Berlin, 1982-1983). A baseline level of 200 mcg/L was associated with aluminum-related bone disease (specificity, 93%); however, lower values did not preclude the diagnosis (sensitivity, 43%) (Milliner et al, 1984).
5) There is a statistically significant increase in mortality with increased serum aluminum levels greater than 40 mcg/L.
6) Levels greater than 200 mcg/L were associated with increased morbidity and mortality in patients treated chronically with dialysis (Chazan et al, 1988).
7) Serum aluminum levels of 114 to 633 mcg/L were associated with microcytic anemia and bone pain in chronic dialysis patients (Swartz et al, 1987).
8) An increase in serum aluminum of 50 or 70 mcg/L after a low-dose (5 or 10 mg/kg) deferoxamine test is indicative of aluminum overload and probably warrants further treatment.

2) CASE REPORTS

a) ANTACID: A 50-year-old woman with chronic renal failure, serum creatinine 454 micromol/L (normal, 50 to 110 micromol/L), had an estimated daily intake of 5 g aluminum in the form of aluminum hydroxide gel during the course of hospitalization. After 13 days of antacid therapy, Shohl's solution (mixture of citric acid and sodium citrate), 90 mL per day was begun for treatment of metabolic acidosis. Five days later, the serum aluminum was 3,124 mcg/L. Sodium bicarbonate was substituted for Shohl's solution beginning 3 days after the aluminum level was obtained. Nine days later, the serum aluminum was 479 mcg/L. The patient had no history of aluminum-containing antacid therapy before hospitalization (Kirschbaum & Schoolwerth, 1989).
b) SUCRALFATE: A 13-year-old girl with end-stage renal disease developed increasing plasma aluminum levels, despite weekly therapy with deferoxamine, while receiving sucralfate 1 gram three times daily for gastritis. Other sources of aluminum were considered, including contaminated peritoneal dialysate. When sucralfate was withdrawn, plasma aluminum concentrations decreased substantially (Robertson et al, 1989).
c) BOILED METHADONE: The serum aluminum levels in two encephalopathic patients (a 43-year-old man and a 42-year-old man) who, over the course of several months to years, boiled methadone in aluminum pots and intravenously injected the solution, were 180 mcg/L (6.65 mcmol/L) and 6650 nmol/L, respectively (Friesen et al, 2006; Yong et al, 2006).

Workplace Standards

A)

1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.

a) Adopted Value

1) Aluminum metal

a) TLV:

1) TLV-TWA: 1 mg/m(3)
2) TLV-STEL:
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: A4
2) Codes: R
3) Definitions:

a) A4: Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.
b) R: Respirable fraction; see Appendix C, paragraph C (of TLV booklet).

c) TLV Basis - Critical Effect(s): Pneumoconiosis; LRT irr; neurotoxicity
d) Molecular Weight: 26.98

1) For gases and vapors, to convert the TLV from ppm to mg/m(3):

a) [(TLV in ppm)(gram molecular weight of substance)]/24.45

2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:

a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance

e) Additional information:

b) Adopted Value

1) Aluminum metal and insoluble compounds

a) TLV:

1) TLV-TWA: 1 mg/m(3)
2) TLV-STEL:
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: A4
2) Codes: R
3) Definitions:

a) A4: Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.
b) R: Respirable fraction; see Appendix C, paragraph C (of TLV booklet).

c) TLV Basis - Critical Effect(s): Pneumoconiosis; LRT irr; neurotoxicity
d) Molecular Weight: Varies

1) For gases and vapors, to convert the TLV from ppm to mg/m(3):

a) [(TLV in ppm)(gram molecular weight of substance)]/24.45

2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:

a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance

e) Additional information:

B) NIOSH REL and IDLH Values for CAS7429-90-5 (National Institute for Occupational Safety and Health, 2007):

1) Listed as: Aluminum
2) REL:

a) TWA: 10 mg/m(3) (total) 5 mg/m(3) (resp)
b) STEL:
c) Ceiling:
d) Carcinogen Listing: (Not Listed) Not Listed
e) Skin Designation: Not Listed
f) Note(s): ,

3) Listed as: Aluminum (pyro powders and welding fumes, as Al)
4) REL:

a) TWA: 5 mg/m(3)
b) STEL:
c) Ceiling:
d) Carcinogen Listing: (Not Listed) Not Listed
e) Skin Designation: Not Listed
f) Note(s): ,

5) Listed as: Aluminum (soluble salts and alkyls, as Al)
6) REL:

a) TWA: 2 mg/m(3)
b) STEL:
c) Ceiling:
d) Carcinogen Listing: (Not Listed) Not Listed
e) Skin Designation: Not Listed
f) Note(s):

7) IDLH: Not Listed

C) Carcinogenicity Ratings for CAS7429-90-5 :

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A4 ; Listed as: Aluminum metal

a) A4 :Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.

2) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A4 ; Listed as: Aluminum metal and insoluble compounds

a) A4 :Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.

3) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
4) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 1 ; Listed as: Aluminium production

a) 1 : The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.

5) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: Aluminum
6) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: Aluminum (pyro powders and welding fumes, as Al)
7) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: Aluminum (soluble salts and alkyls, as Al)
8) MAK (DFG, 2002): Not Listed
9) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

D) OSHA PEL Values for CAS7429-90-5 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Listed as: Aluminum, metal (as Al) (Total dust)
2) Table Z-1 for Aluminum, metal (as Al) (Total dust):

a) 8-hour TWA:

1) ppm:

a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.

2) mg/m3: 15

a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.

3) Ceiling Value:
4) Skin Designation: No
5) Notation(s): Not Listed

3) Listed as: Aluminum, metal (as Al) (Respirable fraction)
4) Table Z-1 for Aluminum, metal (as Al) (Respirable fraction):

a) 8-hour TWA:

1) ppm:

a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.

2) mg/m3: 5

a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.

3) Ceiling Value:
4) Skin Designation: No
5) Notation(s): Not Listed

Pharmacology Toxicology

Toxicologic Mechanism

A)

B)

C)

D)

1) Aluminum metal particulates generated in grinding were mostly non-respirable; that is, greater than 7 microns in size. No disease was seen in workers exposed to these particles (Dinman, 1987).
2) Aluminum metal powder (granular particulates less than 5 microns) inhaled for an estimated lung dose of 1.6 g did not appear to produce pulmonary disease (Crombie et al, 1944; Gent et al, 1980).
3) Mineral oil-lubricated aluminum flake was demonstrated in vitro to alter protein structure, whereas stearin-coated aluminum flake did not (Jager & Jager, 1941). Pulmonary pathology has been associated with mineral oil-lubricated fine aluminum pyropowder (Dinman, 1987).

E)

Physicochemical

Physical Characteristics

A)

1) Aluminum is also described as a crystalline solid (Lewis, 1997).

B)

Molecular Weight

A)

Other

A)

1) Odorless (Harbison, 1998) NIOSH, 2001)

Animal Toxicology

References

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ALUMINUM

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Hematologic

Dermatologic

Musculoskeletal

Endocrine

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Radiographic Studies

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Inhalation Exposure

Eye Exposure

Dermal Exposure

Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Toxicologic Mechanism

Physical Characteristics

Molecular Weight

Other

General Bibliography