C H A P T E R
26
Aluminum
BENGT SJÖGREN, ANDERS IREGREN, JOHAN MONTELIUS, AND ROBERT A. YOKEL
ABSTRACT
Aluminum is ubiquitous in the environment. Its
proportion of the Earth’s crust is about 8%. Alumi-
num can be absorbed from the gastrointestinal tract
and from the lungs. Excretion is mainly through the
kidneys, probably as aluminum citrate. Aluminum is
a well-known neurotoxicant. Significant accumulation
in the human body has been related to the presence of
aluminum in dialysis fluids and the concomitant intake
of aluminum-containing drugs by those with signifi-
cant renal impairment and to occupational exposure
in some industrial settings. Accumulation in patients
with renal impairment has resulted in dialysis enceph-
alopathy that was often fatal; this problem is now well
recognized and usually avoided. Neurotoxic effects
have been observed in welders with aluminum urine
concentrations around 100 μg/L. The upper reference
limit among nonexposed individuals is 16 μg/L urine.
There is no consensus on whether human studies pro-
vide sufficient evidence for an association between
aluminum and Alzheimer disease.
Occupational exposure to aluminum powder has
resulted in pulmonary fibrosis.
Asthma has been associated with the inhalation of
aluminum sulfate, aluminum fluoride, and potassium
aluminum tetrafluoride, and exposure to the complex
environment in potrooms during electrolytic alumi-
num production.
Cancer and ischemic heart disease have been observed
among aluminum production workers. However, it is
unlikely that aluminum is the cause of these diseases.
Reproductive and developmental toxicity are pre-
sented in Chapter 20.
Handbook on the Toxicology of Metals 4E
http://dx.doi.org/10.1016/B978-0-444-59453-2.00026-3
Recent reviews on aluminum were written by
Krewski et al. (2007), Riihimäki and Aitio (2012),
­Willhite et al. (2012), DECOS (2010), and NEG (2011).
1  PHYSICAL AND CHEMICAL PROPERTIES
Aluminum (Al): atomic weight, 26.98; atomic num-
ber, 13; density, 2.7 g/cm3; melting point, 660.4°C; boil-
ing point, about 2400°C; Chemical Abstracts Service
no., 7429-90-5.
Pure aluminum is a light ductile metal with a den-
sity approximately one-third that of iron. Aluminum is
a good conductor of heat and electricity, and it is easy
to weld. These properties make it especially suitable
for industrial purposes. When aluminum is exposed
to air or water, a thin film of oxide (about 4-nm thick)
is formed on the surface, creating a protective coating
that is resistant to corrosion. By further forced elec-
trolytic oxidation, also called anodizing, this coating
can be made thicker to increase corrosion resistance.
Aluminum is often used in alloys with copper, magne-
sium, manganese, and zinc.
Aluminum is the third most abundant element in
the Earth’s crust and constitutes about 8% by mass.
Aluminum hydroxide oxide, also known as aluminum
oxyhydroxide [AlO(OH)], is found in one of two well-
defined crystalline phases, also known as the minerals
boehmite and diaspore. These minerals are important
constituents of the aluminum ore, bauxite.
The chemical form (chemical speciation) has a great
influence on aluminum toxicokinetics and toxicody-
namics. As with most metals, soluble forms of alumi-
num are better absorbed, and consequently a larger
549 Copyright © 2015 Elsevier B.V. All rights reserved.
550 Bengt Sjögren, Anders Iregren, Johan Montelius, and Robert A. Yokel

proportion is distributed to target organs. In the absence Bauxite is the most commercially important form of
of associating ligands, aluminum, as the hydroxide, is weathered igneous minerals that contain aluminum.
least soluble at pH 6.2 (Harris et al., 1996). The rate con- It is abundant in the Earth’s crust in large areas of the
stant for water and ligand exchange with aluminum is world. The Bayer process of obtaining aluminum oxide
slower than for most metals (Burgess, 1992). (alumina) from bauxite was invented in the 1880s and
remains the most economical means of doing so. In 1886,
Héroult from France and Hall from the United States
2  METHODS AND PROBLEMS OF
simultaneously and independently invented an electro-
ANALYSIS
lytic process for aluminum production. The Hall-Héroult
process still forms the basis of aluminum production.
Because of the ubiquitous distribution of aluminum
They discovered that molten aluminum was produced
in nature, contamination may be a serious problem
when an electric current was passed through a bath of
during sampling and sample preparation. In the 1970s,
molten cryolite (Na3AlF6) containing dissolved alumina.
reported “normal” values of aluminum in serum or
The presence of cryolite in the Hall-Héroult process
plasma were around 100 μg/L, which was a reflection
enables electrolysis to proceed at a temperature < 1000°C
of contamination (Versieck and Cornelis, 1980).
(Abramson et al., 1989), which is lower than the melting
In 1994, we reported a case of aluminosis, an alu-
point of alumina (around 2000°C). A modern aluminum
minum-induced condition that was first recognized in
smelter contains a series of reduction cells or a potline.
1946. Many years after exposure, the patient developed
There are two types of pots: prebaked and Söderberg.
dementia with motor disturbances. His cerebrospi-
In prebaked pots, anodes are prepared in a carbon plant
nal fluid aluminum level was 259 μg/L (Sjögren et al.,
from calcined petroleum pitch and coal pitch. This mix-
1994). When he died in 1998, cerebrospinal fluid con-
ture is baked in solid blocks and subsequently attached
tained 7 μg Al/L, which is normal. The first reported
to conductive rods and inserted into the pots. In the
high concentration of aluminum was most probably
Söderberg process, the carbon paste is dropped into a
caused by contamination during sampling or storage
steel casing hanging above the pot and baked in situ.
(Sjögren et al., 1999). This case illustrates the impor-
Enormous quantities of energy are necessary
tance of avoiding contamination.
for the electrolytic reduction of aluminum, almost
Instrumental methods most commonly applied to
16,500 kWh/ton. Because of this fact, aluminum plants
the determination of aluminum, i.e. 27Al (the stable iso-
are usually located close to relatively cheap power
tope), include inductively coupled plasma (ICP)-atomic
sources (e.g. in the vicinity of hydroelectric power
emission spectroscopy and the more sensitive ICP-mass
plants). In the beginning, aluminum production was
spectrometry (MS) and graphite furnace atomic absorp-
very modest, but it increased rapidly in the twenti-
tion spectroscopy (WHO/IPCS, 1997). Around 1990, the
eth century, especially after World War II. The annual
application of accelerator MS as an analytical tool (devel-
aluminum production in 2012 was 48 million metric
oped in the mid-1980s) to quantify 26Al, a rare radioactive
tons (International Aluminium Institute, 2013). Recy-
aluminum isotope with a ∼730,000 year half-life, greatly
cling and remelting aluminum requires only 5% of the
improved the possibility of studying the biokinetics and
energy needed for primary electrolytic production.
bioavailability of human-relevant exposures. With this
Aluminum and its alloys are used in airplanes, trains,
technique, the detection limits were lowered and prob-
trucks, and cars, the construction industry, and food
lems with endogenous aluminum and contamination
preparation and storage. Aluminum powders are used
from the surroundings were avoided (Priest, 2004).
in paints, explosives, and fireworks.
Certified reference materials for aluminum are avail-
The adjuvant effect of aluminum compounds in
able in some useful matrices but are generally lacking
vaccines was first described by Glenny and cowork-
in mammalian tissue, including brain (Yokel, 2004).
ers (1926). They investigated the immunogenicity
In vivo assessment of aluminum in human bone
of various diphtheria toxoid precipitates, including
has been performed by neutron activation analysis
those precipitated by addition of potassium alum
(Aslam et al., 2009), but this approach needs further
[KAl(SO4)2•12H2O]. Alum precipitates led to a signifi-
development.
cant increase in the toxoid-induced immune response.
Vaccines prepared by this method are referred to as
3  PRODUCTION AND USE alum-precipitated vaccines. Another such procedure is
antigen adsorption onto preformed aluminum hydrox-
In 1825, the Danish chemist Örsted produced minute ide hydrated gels. Such gels can be preformed in a
quantities of aluminum metal by reacting dilute potas- standardized way, and they adsorb protein antigens
sium amalgam with anhydrous aluminum chloride. from an aqueous solution. These vaccines are called
 26 Aluminum
aluminum-adsorbed vaccines. Aluminum hydroxide
[Al(OH)3] and aluminum phosphate (AlPO4) are now
the most commonly used adjuvants and have almost
completely replaced the alum precipitation method in
vaccine preparation (Lindblad, 2004). Their safety has
been questioned by some (Shaw et al., 2013), but alter-
natives are not likely to replace aluminum adjuvants in
the near future (Baylor et al., 2002; Mitkus et al., 2011).
Some aluminum-containing drugs, such as alumi-
num hydroxide, aluminum phosphate, and sucralfate
(a sucrose sulfate-aluminum complex), have been used
as antacids for “heartburn” and dyspepsia, and to treat
ulcers (Krewski et al., 2007; American Pharmacists
Association, 2012). Aluminum tends to cause constipa-
tion by decreasing smooth muscle tone, so is often used
with magnesium, an osmotic purgative. Aluminum
salts have been used as phosphate binders (Krewski
et al., 2007). A 1% solution of alum is used as an intra-
vesical irrigant to treat urinary bladder hemorrhage
(Phelps et al., 1999). Aluminum salts are used topi-
cally in antiperspirants; for hyperhidrosis; in products
for inflammatory conditions of the skin, such as ath-
lete’s foot (tinea pedis), as astringent and antibacterial
agents; and as a protectant against irritation of the ano-
rectal area (American Pharmacists Association, 2012).
Aluminum silicate functions as an abrasive, anticak-
ing agent, a bulking agent, and an opacifying agent in
cosmetics. Magnesium aluminum silicate is also used
as a viscosity-increasing agent in aqueous cosmetics.
According to the U.S. Food and Drug Administration
(FDA), it was used in 629 cosmetic formulations in
1998 (Elmore, 2003).
The use of aluminum-containing food additives is
approved by many governments (Yokel, 2012). Com-
mon uses include acidic sodium aluminum phosphate
(SALP) as a leavening agent in baked goods, basic SALP
as an emulsifying agent in cheese, and sodium alumi-
nosilicate as an anticaking agent in salt and powder
artificial dairy creamer. These are major contributors
to dietary aluminum intake. The Food and Agricul-
ture Organization of the United Nations and the World
Health Organization established a provisional tolerable
weekly intake of 2 mg/kg body weight that applies to
all aluminum compounds in food (FAO/WHO, 2011).
Substantial amounts of aluminum salts are commonly
used as flocculants in the treatment of drinking water.
4  DIETARY, ENVIRONMENTAL, AND
OCCUPATIONAL EXPOSURES
The usual primary source of aluminum for the
human is food. Daily median aluminum intake was 8.5,
3.6, 9.5, and 9 mg for adults in the USA and Canada,
551
Europe, China, and Japan (Yokel, 2012). The aluminum
content of food is highly variable: it is generally low in
fresh meat and fish, higher in vegetables and grains,
and high in spices (Yokel, 2013). Although the quanti-
ties of spices and herbs used in foods is generally very
small, a diet high in spicy foods may be high in alumi-
num. Baking powder containing aluminum additives is
extremely high in aluminum, providing more than 2 g
of aluminum per 100 g. The most commonly used foods
that may contain substantial amounts of aluminum-
containing food additives (other than baking powder)
are processed cheese, cake mixes, frozen dough, pan-
cake mixes, and pickled vegetables (Saiyed and Yokel,
2005). Concentrations of aluminum in tea leaves and tea
powder can be quite high, around 1 g/kg. The concen-
tration in tea was 0.7-5.9 mg/L (Fung et al., 2009). Tea
and aluminum utensils were estimated to increase alu-
minum in the diet by approximately 4 and 2 mg per day,
respectively (Jorhem and Haegglund, 1992).
Beverages from aluminum cans generally contained
higher levels of aluminum than beverages from glass
bottles. Non-cola and cola soft drinks averaged 900 and
660 μg/L from cans and 150 and 240 μg/L from glass
bottles, respectively, whereas beer in cans or bottles
averaged about 160 μg/L. However, the highest con-
centration in a non-cola soft drink packaged in a can
was reported to be 10,000 μg/L (Duggan et al., 1992).
The contribution of aluminum from drinking water
is about 100 μg/day (Yokel and McNamara, 2001).
Air aluminum concentrations vary between 20 and
500 ng/m3 in rural settings and 1000 and 6000 ng/m3 in
urban settings. Humans exposed to ambient aluminum
concentrations of 2000 ng/m3 and particle size < 5 μm
and who have a normal ventilatory volume of 20 m3/day
would inhale 40 μg aluminum/day (WHO/IPCS, 1997).
Occupational exposure to aluminum particles
reached 100 mg/m3 during the production of
stamped aluminum powder in the 1950s (Mitchell
et al., 1961). However, in the 1990s reported levels
were 5-21 mg/m3 during the production of alumi-
num powder and 1-4 mg/m3 during the production
of aluminum paste (Letzel et al., 1996). Aluminum
welding (Figure 1) produces levels of 0.2-5 mg/m3
(Sjögren et al., 1988). In summary, powder produc-
tion and aluminum welding are generally associated
with the highest occupational aluminum exposure.
5 KINETICS
5.1 Absorption
There have been several studies in animals and
humans dosed with 27Al using atomic absorption spec-
troscopic analysis, and in the last 20 years dosed with
552 Bengt Sjögren, Anders Iregren, Johan Montelius, and Robert A. Yokel

TABLE 1  High, Intermediate, and Low Aluminum

Exposures Based on Urine Levels in Different
Occupationsa
Industry Source

High aluminum exposure (urine concentrations often

above 100 μg/L)
Aluminum powder production
Welding
Cryolite production
Iregren et al., 2001; Letzel et al.,
1996 and 2000
Buchta et al., 2005; Kallio et al.,
1999; Kiesswetter et al., 2007;
Sjögren et al., 1985
Grandjean et al., 1990

Intermediate aluminum exposure (urine concentrations

FIGURE 1  Metal inert gas welding of aluminum.
26Al using accelerator mass spectrometric analysis, to
estimate the percentage of aluminum absorbed from
drinking water. The results suggest that ∼0.3% is orally
absorbed (Priest et al., 1998; Stauber et al., 1999; Yokel
et al., 2001). On the basis of daily aluminum dietary
consumption and urinary aluminum excretion, the oral
bioavailability of aluminum from the diet has been esti-
mated to be 0.1-0.3% (Ganrot, 1986; Priest, 1993; Nieboer
et al., 1995). Animal studies have investigated the bio-
availability of 26Al that was incorporated into two FDA-
approved food additives, acidic and basic SALP, which
were then incorporated into a cracker and a processed
cheese, respectively. The bioavailability was ∼0.1% from
the cracker, and ∼0.1-0.3% from the cheese (Yokel and
Florence, 2006; Yokel, et al., 2008). It was ∼0.35% from
tea (Yokel and Florence, 2008). Several studies demon-
strated increased aluminum absorption when taken
with citrate (Krewski et al., 2007). Aluminum hydrox-
ide is still used as an antacid and a phosphate binder.
The recommended dose can deliver up to 1.6 g alu-
minum per day. Thus, absorption from this dose may
exceed 1 mg/day (Yokel and McNamara, 2001). The
site of aluminum absorption is the upper intestine. The
mechanisms of gastrointestinal aluminum absorption
are suggested to include passive (diffusion) and active
(carrier--mediated and vesicular) transport across
intestinal cells and paracellular diffusion between these
cells. There is evidence for an energy-dependent com-
ponent of aluminum uptake. Aluminum absorption is
enhanced by processes that mediate calcium uptake.
Citrate may enhance aluminum absorption through
the paracellular pathway by increasing permeabil-
ity between cells (Provan and Yokel, 1988; Whitehead
et al., 1997; Zhou and Yokel, 2005).
Aluminum-containing welding fume consists of par-
ticles smaller than 1 μm (Ulfvarson, 1981). Aluminum
flake powders vary from 5-200 μm in diameter and from
0.05-1 μm in thickness (Ljunggren et al., 1991). Volun-
teers previously unexposed to welding fume inhaled
sometimes above 100 μg/L)
Electrolytic production Röllin et al., 1996
Corundum production Valentin et al., 1976
Low aluminum exposure (urine concentrations seldom
above 100 μg/L)
Electrolytic production with Röllin et al., 2001
­improved technology
Aluminum sulfate production Riihimäki et al., 2008; Sjögren
et al., 1983
Grinding Elinder and Sjögren, 1990;
Harwerth et al., 1987
Melting and foundry Elinder and Sjögren, 1990;
Sinczuk-Walczak et al., 2003
Optoelectronic industry Liao et al., 2004
aAluminum levels in urine are normally below 16 μg/L.
welding fume for 1 day and excreted 0.1-0.3% of the
inhaled aluminum during the following 2 days (Sjögren
et al., 1985). Daily urinary aluminum excretion by alu-
minum welders, who may have been approaching a
steady state for their lung aluminum burden, averaged
0.1 mg. Calculated daily aluminum lung deposition
was estimated to be 4.2 mg, suggesting ∼2.4% absorp-
tion (Sjögren et al., 1997). Results from workers exposed
to ∼0.2-0.5 mg soluble Al/m3 in the air suggest ∼2%
absorption (Pierre et al., 1995). Estimated aluminum
absorption was similar in workers in another study
(Gitelman et al., 1995). In an experiment, a solution of
aluminum nitrate (containing 26Al) was dispersed to
produce an aerosol, which was dried and calcined in a
furnace. The resultant oxide particles had a mean aero-
dynamic diameter of 1.2 μm; these were inhaled by two
subjects and 26Al levels were determined in their urine.
Measurements were made at different times after inha-
lation. Aluminum excretion ceased 900 days after expo-
sure. The calculated fraction of the respiratory deposit
of aluminum that was transferred to the blood was 1.9%
(Priest, 2004). Despite this relatively low absorption,
occupational exposure to small sparsely water-soluble
aluminum-containing particles has resulted in increased
aluminum concentrations in urine (Table 1).
 26 Aluminum
Salts of aluminum such as chlorohydrate are exten-
sively used as antiperspirants. The estimated dermal
absorption of aluminum from this compound is about
0.01% (Flarend et al., 2001). Some results suggest that
aluminum might be absorbed from the nasal cavity
directly into the brain through the olfactory neurons.
The extent of absorption by this route is unknown
(Yokel, 2000).
5.2 Distribution
After absorption, aluminum is distributed by the
blood to different organs and the fetus (Yumoto et al.,
2010). Conflicting results have been presented regarding
the distribution of aluminum in blood between plasma
and erythrocytes. The percentage in erythrocytes has
varied from 10 to 90% in different studies (Riihimäki
and Aitio, 2012). In plasma, about 90% of aluminum
is bound to transferrin, while the remainder is mainly
bound to citrate (Yokel and McNamara, 2001). The total
aluminum body burden of normal human is estimated
to be 30-50 mg. The skeleton contains about 50% and the
lungs 25% of the body burden (Priest, 2004; Yokel and
McNamara, 2001). In persons occupationally subject
to long-term exposure to small sparsely water-soluble
aluminum-containing particles, e.g. aluminum-welding
fume, the content of aluminum in the lungs can be con-
siderably higher and the concentration of aluminum in
urine remains elevated many years after occupational
exposure ceases (Riihimäki et al. 2008, Riihimäki and
Aitio, 2012). Postmortem examination of two weld-
ers exposed to aluminum-containing welding fume for
more than 20 years revealed extremely high numbers of
inorganic particles in the lungs, most of them containing
aluminum (Hull and Abraham, 2002). The lung burden
was increased 158 times among rabbits inhaling alumi-
num oxide 0.56 mg/m3 for 5 months (8 h per day, 5 days
per week) (Röllin et al., 1991). On the other hand, in per-
sons exposed for many years to soluble aluminum salts,
e.g. aluminum sulfate with particle size of 1-10 μm, there
was no or only a small increase in urinary aluminum
concentration after an exposure-free period. These find-
ings indicate that this type of exposure does not result
in an increased lung burden (Riihimäki et al., 2008). The
aluminum content in bone, brain, and other organs, as
well as serum, increased with age (Zapatero et al., 1995;
Hellström et al., 2005; Markesbery et al., 1984; Roider
and Drasch, 1999). The brain has lower concentrations
than many other tissues (Priest, 2004; Krewski et al.,
2007). Increased brain aluminum is seen in patients with
dialysis encephalopathy (Alfrey and Froment, 1990).
Studies of Alzheimer disease (AD) victims inconsistently
show elevated brain aluminum levels (Krewski et al.,
2007). The primary site of aluminum entry to the brain
553
is through the blood-brain barrier. It has been suggested
that brain aluminum influx occurs through transferrin
receptor-mediated endocytosis of aluminum bound to
transferrin (Roskams and Connor, 1990) and transferrin-
independent mechanisms of aluminum citrate influx
involving cystine/glutamate transporter system Xc-
(Nagasawa et al., 2005; Yokel, 2006). There is also evi-
dence of carrier-mediated efflux of aluminum from the
brain, probably as aluminum citrate (Yokel, 2006).
5.3 Excretion
Urine accounts for more than 95% of aluminum
excretion. Reduced renal function markedly increases
the risk of aluminum accumulation. Biliary aluminum
accounts for less than 2% of the elimination. Chelators
can increase aluminum clearance, and citrate seems
to act as a chelator (Yokel, 2002). Renal clearance of
aluminum may be in the form of citrate (Yokel and
McNamara, 2001). Aluminum was also found in
human breast milk (mean, 24 μg/L; range, 7-42 μg/L)
(Fernández-Lorenzo et al., 1999).
After intravenous injection of aluminum citrate, the
half-lives for blood and trabecular and cortical bone
were about 1 h, 1.4 years, and 29 years, respectively.
Thus, a fraction of aluminum is retained in the body
for decades (Priest, 2004).
5.4  Biological Monitoring
The chemical speciation of aluminum has a great
influence on its toxicokinetics and toxicodynamics,
which consequently affects the methods used to per-
form meaningful biological monitoring.
Clinical studies of chronic uremic patients have pro-
vided evidence for relationships between serum levels
of soluble aluminum and the occurrence of the dialysis
encephalopathy syndrome. A baseline level below 20 μg
aluminum per liter serum has been recommended for
patients (National Kidney Foundation, 2003).
Among occupationally exposed workers, inhalation
of small, sparsely water-soluble, aluminum particles
results in their retention in the lungs. Some of this alu-
minum is released into the blood and distributed to
organs, including bone and brain, and excreted in the
urine. Neurotoxicity is the critical effect of exposure to
sparsely water-soluble aluminum compounds. Effects
have been observed in welders with urine concentra-
tions of aluminum around 100 μg/L. The primary objec-
tive of aluminum biomonitoring is to prevent harmful
accumulation in the target organ. Biomonitoring can be
used in the production or use of powders and weld-
ing or plasma cutting operations (Riihimäki and Aitio,
2012). The highest aluminum exposures on the basis
554 Bengt Sjögren, Anders Iregren, Johan Montelius, and Robert A. Yokel
FIGURE 2  Concentrations of aluminum in air and urine in a welder exposed to aluminum-welding fumes for 20 years.
of urine levels have been reported among welders
and aluminum powder production workers (Table 1).
A welder exposed to aluminum for 20 years had an
average urine aluminum level of 300 μg/L (Figure 2).
Furthermore, linear relationships have been observed
between the air concentration of aluminum and the uri-
nary concentration at the end of a work shift in both
welders (Sjögren et al., 1988) and electrolytic produc-
tion workers (Pierre et al., 1995).
Soluble aluminum compounds do not accumulate
in the lungs, as indicated by the fact that urine con-
centrations decrease to low levels after exposure-free
periods (Riihimäki et al., 2008). Biological monitoring
can help to identify exposed individuals and describe
transient exposures but cannot predict health effects
because no information exists regarding cognitive dis-
turbances among workers exposed to these soluble
aluminum compounds (Riihimäki and Aitio, 2012).
Accurate measurements of aluminum in human
biological fluids such as blood and urine are difficult
because of contamination risks. Aluminum contamina-
tion can derive from airborne particles, reagents, and
labware that comes into contact with the sample. Plasma
aluminum of occupationally nonexposed humans was
most often < 5 μg/L (House, 1992; Liao et al., 2004)
and sometimes as low as 1 μg/L (Razniewska and
Trzcinka-Ochocka, 2003). In Finland, the upper refer-
ence limit among nonexposed humans was 2.7 μg/L
(0.1 μmol/L) in serum and 16 μg/L (0.6 μmol/L) in
urine (Kallio et al., 1999; Valkonen and Aitio, 1997).
A biological exposure limit has been established in
Germany (Deutsche Forschungsgemeinschaft, 2013,
heading 8 “Guidelines”).
6 EFFECTS
6.1  Gastrointestinal Symptoms
On 6 July, 1988, at the Lowermoor Water Treatment
Works near Camelford, Cornwall, England, 20 tons
 26 Aluminum
of 8% aluminum sulfate solution were inadvertently
deposited directly into the chlorine contact tank rather
than into the storage tank. The domestic water supplies
of an estimated 20,000 people in the area were affected.
The pH plunged to as low as 3 and aluminum rose to
as high as 109 mg/L at one location. Several symptoms
were reported just after the incident, including gas-
trointestinal disturbances, rashes, and mouth ulcers.
Later, continuing or new symptoms were described,
including gastrointestinal disorders, joint and muscle
pains, memory loss, and hypersensitivity. However,
the role of aluminum in producing these symptoms is
unclear. A summary of the Lowermoor Incident Health
Advisory Group reports and some dissenting opinions
have been published (Khanna, 2005).
6.2  Restrictive Pulmonary Disease
Exposure to aluminum-containing minerals such as
bauxite and corundum is often accompanied by silica.
This combined exposure may lead to the development
of fibrosis of the lung, Shaver disease (Shaver and
­Riddell, 1947).
German, Swedish, and British occupational health
studies have shown that stamped aluminum powder,
even in the absence of silica, causes lung fibrosis. Such
cases of severe lung fibrosis were reported from Ger-
many during the 1930s and 1940s (Doese, 1938; Koelsch,
1942; Meyer and Kasper, 1942), and later from Sweden
(Ahlmark et al., 1960; Swensson et al., 1962) and Eng-
land (Jordan, 1961; McLaughlin et al., 1962; Mitchell
et al., 1961). Similar cases have been reported only rarely
from North America (Gross et al., 1973). Stamped alu-
minum powder is produced by crushing and grinding
hard unmelted aluminum metal. This aluminum pow-
der is mainly used in the manufacture of pyrotechnical
products but is also used in the production of some alu-
minum dyes. Ninety-five percent of stamped aluminum
powder particles are smaller than 5 μm. Stamped alumi-
num powder has a rather large surface area because of
the flake-like form of the particles. The powder reacts
with water to form hydrogen and aluminum hydrox-
ide (Corrin, 1963). Granular aluminum particles, which
are manufactured from melted aluminum, display a
more regular particle structure and are not as reactive
as stamped aluminum powder (Corrin, 1963). Different
types of lubricating agents, generally stearin or mineral
oils, are used in the production of the powder. Cases of
lung fibrosis were first reported from industries using
mineral oil. Cases of the disease have, however, been
reported from at least one industry where only stearin
was used (McLaughlin et al., 1962).
The first signs of lung fibrosis caused by stamped alu-
minum powder exposure were respiratory problems,
555
occasionally in conjunction with coughing. X-ray of the
lungs revealed fibrosis accompanied by atrophy and
secondary emphysema (Edling, 1961). Pneumothorax
was a typical complication. The fibrosis, also known as
aluminosis, could progress rapidly and in severe cases
lead to death within a few years of onset (Ahlmark
et al., 1960; Swensson et al., 1962). No clear lowest
observed adverse effect level could be estimated.
Cases of fibrosis occurred after exposure to 4-50 mg
aluminum/m3 (Hunter et al., 1944; McLaughlin et al.,
1962; Mitchell et al., 1961; Swensson et al., 1962).
Between 1960 and 1989, only a few individuals
were compensated because of lung disease induced
by aluminum dust in Germany, and in the begin-
ning of the 1990s some further cases of fibrosis were
reported (Kraus et al., 2000). A 40-year-old worker was
employed as a stamper for 14 years in a plant produc-
ing aluminum powder. He was exposed to high levels
of aluminum and had a urine concentration of 400 μg
aluminum per liter. He also had signs of pulmonary
fibrosis on high-resolution computed tomography and
a vital capacity of 58% of expected (Kraus et al., 2000).
In 2006 a study investigated the lungs of 62 aluminum
powder-exposed workers using high-resolution com-
puted tomography. Ill-defined centrilobular nodular
opacities were found in 15 workers. These workers had
higher urine levels of aluminum compared with work-
ers without opacities. Ten of the workers with opaci-
ties had urine concentrations above 200 μg/L. Thus, it
seems that early stage aluminum-induced pneumoco-
niosis is not yet eradicated (Kraus et al., 2006). Alumi-
num powder has also been associated with a case of
sarcoid-like lung granulomatosis (De Vuyst et al., 1987).
In North America, exposure to McIntyre powder,
consisting of finely ground aluminum and aluminum
oxides, was used as a prophylactic (Denny et al., 1939;
Godin, 1955) and in the treatment of silicosis (­Crombie
et al., 1944). A similar regimen was also applied to min-
ers in Australia (Peters, et al., 2013). A comprehensive
evaluation of the studies that used inhalation of alumi-
num particles in the treatment of silicosis has, however,
resulted in total rejection of this form of treatment. The
British Medical Research Council concurred with this
evaluation and recommended that aluminum powder
should not be used in the treatment or prevention of
silicosis (Kennedy, 1956). Despite this recommenda-
tion, aluminum powder was used as a prophylactic
agent until 1979 in the mines in northern Ontario, Can-
ada (Rifat et al., 1990).
Aluminum grinding and polishing have sometimes
been associated with an extremely dusty work environ-
ment. One case of pulmonary fibrosis (De Vuyst et al.,
1986) and one case of alveolar proteinosis (Miller et al.,
1984) have been reported after long-term exposure.
556 Bengt Sjögren, Anders Iregren, Johan Montelius, and Robert A. Yokel
In a factory producing aluminum oxide abrasives
employing about 1000 workers, nine had abnormal
chest X-rays. The mean exposure duration was 25 years.
In each of three lung biopsies, interstitial fibrosis with
honeycombing was found, along with an absence of
asbestos bodies and silicotic nodules. The authors con-
cluded that aluminum oxide dust was the most likely
cause, although mixed dust exposure may explain the
findings (Jederlinic et al., 1990).
Long-term exposure to aluminum-welding fume
in some case reports has been associated with chronic
interstitial pneumonia (Herbert et al., 1982), pulmonary
granulomas (Chen et al., 1978), and pulmonary fibrosis
(Hull and Abraham, 2002; Vallyathan et al., 1982).
However, in a group of 64 aluminum-exposed welders
with exposure duration between 1 and 24 years, no signs
of pulmonary fibrosis were observed (Sjögren and
Ulfvarson, 1985).
Aluminum-containing fibers have been detected in
lung parenchyma and bronchial alveolar lavage fluid
in aluminum smelter workers, despite a nonexposure
period of several years (Voisin et al., 1996). Small opaci-
ties or accentuations of the bronchopulmonary mark-
ings on chest X-ray were more common (29%) among
119 potroom workers exposed for more than 10 years
from two plants in northern Italy compared with 15%
for a similarly sized referent group of unexposed clerical
and maintenance workers from the same factories. Signs
of pneumoconiosis were more common among long-
term than short-term exposed workers (Saia et al., 1981).
In a cross-sectional study, 670 aluminum workers
from Alabama were compared with 659 pipe fitters.
Both groups were asbestos exposed. Irregular opacities
observed on X-rays were more common among alumi-
num workers (21 vs. 15%) and pleural abnormalities
less common (2 vs. 12%) than in referents. These find-
ings suggest an influence of particles or fibers other
than asbestos (Kilburn and Warshaw, 1992). Some
cases of pulmonary fibrosis have also been reported
after long-term exposure during electrolytic aluminum
production (Akira, 1995; Al-Masalkhi and Walton,
1994; Gaffuri et al., 1985; Gilks and Churg, 1987).
To conclude, exposure to high levels of small par-
ticles of aluminum powder has caused pulmonary
fibrosis, also called aluminosis. Sometimes mixed
dust exposure can explain pulmonary fibrosis among
exposed workers. It is not clear whether these workers
were very sensitive or susceptible to particle exposure
or whether they belonged to a small fraction of heavily
exposed workers. Aluminum-containing fibers have
been detected in lung parenchyma and bronchial alve-
olar lavage fluid in aluminum smelter workers; how-
ever, it is not clear whether these fibers play a causal
role in the development of pulmonary fibrosis.
6.3  Obstructive Pulmonary Disease
In 1936, asthma was described among Norwegian
workers in electrolytic aluminum production (Frostad,
1936). This is often called potroom asthma. Symptoms
of asthma, airflow limitation, and increased bronchial
responsiveness have been described in aluminum
smelters around the world. The most likely causes are
irritant airborne particulates and fumes containing
cryolite, gaseous hydrogen fluoride, and other agents
that may be adsorbed onto aluminum (WHO/IPCS,
1997). In a cross-sectional study of 1760 Norwegian
potroom workers, 11% reported work-related asth-
matic symptoms (Kongerud et al., 1990). A relationship
between the levels of fluoride exposure and work-
related asthmatic symptoms was also observed among
such workers (Kongerud and Samuelsen, 1991). In a
cross-sectional study comprising 1615 male employees
of two Australian aluminum smelters, after adjusting
for smoking and age, workers with a cumulative expo-
sure of fluoride > 0.16 mg/m3-years or inspirable dust
> 2.9 mg/m3-years were two to four times more likely
to report work-related wheezing and chest tightness
than were unexposed subjects. The effect of these two
exposure types could not be separated because there
was only one subject with work-related chest tightness
and no subjects with work-related wheezing who were
exposed to fluoride without being exposed to inspir-
able dust (Fritschi et al., 2003).
The production of aluminum fluoride and alu-
minum sulfate has been associated with reversible
bronchial obstruction or asthma (Simonsson et al.,
1985). In 1975 and 1976, six and seven cases of asthma,
respectively, occurred in a Swedish plant producing
aluminum fluoride. The number of exposed workers
was 35-40 and the mean concentration of aluminum
fluoride during this 2-year period was 3-6 mg/m3. In
1977, environmental improvements were made and
exposure was reduced to 0.4-1.0 mg/m3. During the
years 1978-1982, only two cases of asthma occurred
(­Simonsson et al., 1985).
During 1971-1980, an average of 37 workers produced
aluminum sulfate in a Swedish plant. Four workers
developed short-lasting asthma, mainly in connection
with heavy dust exposure during rinsing and repair
work. The mean aluminum sulfate concentrations var-
ied between 0.2 and 4 mg/m3 (Simonsson et al., 1985).
Potassium aluminum tetrafluoride is sometimes
used as a flux for aluminum soldering. Exposure to this
flux has been associated with asthma and bronchial
hyperreactivity (Hjortsberg et al., 1986, 1994; Larsson
et al., 2007).
One case of asthma related to aluminum welding has
been reported. Challenge exposure to aluminum welding
 26 Aluminum
with flux-coated electrodes and electrodes without flux
elicited marked asthmatic reactions. However, mild steel
welding did not cause a significant bronchial response
(Vandenplas et al., 1998). Exposure to aluminum pow-
der has been observed to cause asthma in a worker after
mixing aluminum and minimal amounts of cement
powders to make safes in a closed room. He reacted
with a decreased forced expiratory volume in 1 second
(FEV1) after inhalation of aluminum powder or alumi-
num chloride but not after inhalation of lactose powder
(Park et al., 1996). A 46-year-old smoker had a cough and
chest tightness starting 3 h after arriving at work. He had
worked as a caster of molten aluminum for 19 years. The
challenge test showed a biphasic reaction to aluminum
chloride, with a 28% immediate fall in FEV1 and a 34%
late fall in FEV1 after 7 h (Burge et al., 2000).
In a historical cohort study comprising 5627 men
who had worked in two Norwegian aluminum plants,
an increased number of deaths from chronic obstruc-
tive lung diseases (bronchitis, emphysema, and asthma)
related to fluoride exposure (Romundstad et al., 2000).
In conclusion, potroom asthma is a well-known
disease associated with complex exposure in the pot-
rooms of the aluminum electrolytic production indus-
try. Exposure to several other aluminum salts such
as aluminum fluoride, aluminum sulfate, and potas-
sium aluminum tetrafluoride has also been associated
with asthma. In some case reports, aluminum-welding
fume, foundry fume, aluminum powder, and alumi-
num chloride were also linked to asthma.
6.4  Central Nervous System
6.4.1  Dialysis Encephalopathy
Dialysis encephalopathy is a complication of pro-
longed hemodialysis that was first described in 1972
(Alfrey et al., 1976). The main symptoms are speech
disorder followed by the development of dementia,
myoclonus, and local seizures. The mean duration
of dialysis was 48 months; dialysis fluids were made
from untreated tap water (WHO/IPCS, 1997). Death
occurred within 12 months of symptom onset, and
recovery was unusual (Bugiani and Ghetti, 1990).
Between 1968 and 1976, 55 patients with dialysis
encephalopathy were identified from six dialysis cen-
ters in the United States. The overall attack rate of dial-
ysis encephalopathy was 4%. Encephalopathy was the
cause of death in most cases (Schreeder et al., 1983).
Dialysis encephalopathy was related to the presence
of aluminum in dialysis fluids and the concomitant
intake of aluminum-containing drugs used to decrease
serum phosphate levels. Elevated aluminum was
found in the brain, muscle, and other tissues of the
557
affected patients. Serum aluminum > 80 μg/L has been
associated with dialysis encephalopathy (Nieboer
et al., 1995). Many outbreaks of encephalopathy have
been described in association with the use of dialysis
fluids containing aluminum levels > 200 μg/L (WHO/
IPCS, 1997). Today, aluminum exposure of dialysis
patients is minimized because dialysis fluid water is
monitored at most dialysis centers and the aluminum
level is kept to < 10 μg/L. However, accidents happen,
causing occasional incidences of aluminum-associated
dialysis encephalopathy (de Wolff et al., 2002) and ele-
vated aluminum without symptoms (CDC, 2008).
6.4.2  Other Medical Aluminum Exposures
There have been several reports describing alumi-
num accumulation and toxicity in patients without
chronic renal failure. These include preterm infants
largely fed intravenously, patients on parenteral nutri-
tion, patients with severe burns, patients undergoing
cranial bone reconstruction, and patients receiving
alum irrigation of the urinary bladder.
Premature infants with gestational ages of less than
34 weeks were assigned to receive either standard or
aluminum-depleted intravenous-feeding solutions.
When tested 18 months later, those who received more
aluminum exposure had impaired neurological devel-
opment (Bishop et al., 1997).
A cement containing calcium aluminum fluorosili-
cate has been used as a bone reconstruction material in
neurosurgical operations. In five reported cases, symp-
toms and signs of encephalopathy developed, including
seizures. The concentrations of aluminum in the cere-
brospinal fluid were typically > 100 μg/L (Renard et al.,
1994). Two of the five patients died from brain failure
with persistent convulsions (Hantson et al., 1994) and
a third from septic complications (Reusche et al., 2001).
Intravesical alum instillation is a treatment for hem-
orrhagic cystitis. This treatment has resulted in acute
aluminum intoxication among patients with some
degree of renal insufficiency (Phelps et al., 1999).
6.4.3  Neurobehavioral Effects of Occupational
Aluminum Exposure
Several studies of welders have been performed
in Finland to assess the potential of occupational alu-
minum exposure to produce adverse neurobehavioral
effects. The first, comprising 17 participants, did not use
a control group but instead compared data from sub-
groups of welders with differing exposures. Dose-effect
relationships were found between aluminum levels in
serum and urine and performance on four tests of mem-
ory function (symbol learning, memory for designs, digit
558 Bengt Sjögren, Anders Iregren, Johan Montelius, and Robert A. Yokel
span, and associative learning) (­Hänninen et al., 1994).
The mean level of aluminum in urine was 75 μg/L. The
second study (Akila et al., 1999) involved 51 aluminum
welders and 28 controls, who were divided into three
groups according to the levels of aluminum in urine.
The low-exposure group had a mean concentration of
12 μg/L, the medium-exposed group had 60 μg/L, and
the high-exposure group had 269 μg/L. Dose-related
impaired performance attributed to aluminum was
found on the digit symbol, synonyms, embedded fig-
ures, memory for designs, and block design tests. A
third article from this research team reported on the
same worker groups, with the addition of further weld-
ers (Riihimäki et al., 2000). Welders were assigned to one
of three groups according to a combined measure of alu-
minum in the serum and urine to provide an indication
of aluminum body burden. The three groups contained
25, 29, and 30 workers. The median urinary aluminum
levels were 11, 49, and 192 μg/L, respectively. Significant
group differences were found with respect to symptoms
of fatigue, memory and concentration, and emotional
lability. Six out of 18 psychological tests of memory and
concentration also showed significant group differences,
with lower performance in the highly exposed groups.
Furthermore, there were electroencephalography (EEG)
differences among the exposure groups. A number of
subjects in the exposed groups exhibited mild or mod-
erate diffuse or epileptiform abnormalities. To evaluate
dose-response relationships, the prevalence of find-
ings in six critical domains (symptoms, visual accuracy,
attention, verbal, visuospatial memory, and EEG) was
examined. The proportion of deviant findings in these
domains was between 15 and 20%. A plot of the number
of deviant findings against the measure of aluminum
body burden, derived from serum and urine aluminum
concentrations, suggested a critical aluminum level of
110-160 μg/L in urine.
A Swedish study compared 38 aluminum weld-
ers with a control group of 39 steel welders (Sjögren
et al., 1996). The median employment time as alumi-
num welders was 15 years. Aluminum welders per-
formed less well than the reference group in four tests
of motor function: finger tapping, two tasks of the
Luria-Nebraska battery, and a pegboard test. For the
former three tests, this effect was dose-related and was
observed in a subgroup of 19 highly exposed weld-
ers who had a median urine concentration of 59 μg
aluminum/L. In five of the 19 welders, the urine alu-
minum exceeded 100 μg/L.
A Norwegian study compared a group of 20 alumi-
num welders with a reference group of construction
workers (Bast-Pettersen et al., 2000). The welders per-
formed better than the construction workers in sev-
eral tests. However, when performance of the welders
was analyzed separately, significant correlations were
found between increasing exposure duration in years
and poorer performance on the tremor test. There was
also a significant relation in the welders between lon-
ger reaction times and higher levels of aluminum in
the air. The median urine aluminum for this group was
41 μg/L, and the range was 19-129 μg/L.
Two German longitudinal studies of aluminum
welders were performed in the automobile industry
and in the train body and truck trailer industry. One
study involved 98 aluminum welders from the auto
industry and 50 nonexposed auto assembly workers
(Buchta et al., 2003; Kiesswetter et al., 2009). The alu-
minum welders and assembly workers were compara-
ble regarding gender (male), age, education, physical
work load, and social environment. Four years later,
92 aluminum welders and 50 controls participated.
Three repeated measurements at 2-year intervals were
performed during this 4-year period; they included
symptom questionnaires and psychometric measure-
ments. The median postshift urinary aluminum con-
centrations were 48, 40, and 16 μg/L, respectively, and
the corresponding plasma concentrations were 8, 4,
and 4 μg/L, respectively. The mean reaction time was
slower in welders compared with assembly workers.
The urine concentration of aluminum significantly
positively correlated with the reaction time (Buchta
et al., 2003). At the end of the 4-year period, no sig-
nificant differences regarding neurobehavioral perfor-
mance could be observed between the exposed and
nonexposed groups (Kiesswetter et al., 2009). A second
study compared 44 aluminum welders in the train
body and truck trailer industry with 37 nonexposed
production workers (Buchta et al., 2005; Kiesswetter
et al., 2007). The number of participants decreased to
33 welders and 26 controls after 2 years and to 20 weld-
ers and 12 controls after 4 years. The median postshift
urinary aluminum concentrations were 130, 146, and
94 μg/L, and the corresponding plasma concentrations
were 12, 14, and 13 μg/L, respectively. Welders showed
significantly poorer performance in symbol-digit sub-
stitution, block design, and, to some extent, in switch-
ing attention, but not in reaction time. The reaction
time of welders improved between the first and second
examination (Buchta et al., 2005). At the third examina-
tion, the mean exposure time for welders was 15 years.
There was no difference between welders and controls
regarding neurobehavioral performance and no rela-
tion between biomonitoring markers and performance
variables (Kiesswetter et al., 2007). The lack of observ-
able effects in these two longitudinal German stud-
ies may be explained by the short follow-up period
(4 years), a rather low exposure (Buchta et al., 2003;
Kiesswetter et al., 2009), and a substantial proportion
 26 Aluminum
of nonparticipating welders at follow-up (Buchta et al.,
2005; Kiesswetter et al., 2007).
There have been two studies of psychometric per-
formance by workers exposed to aluminum powder.
Neither study reported any differences compared
with referents. A German study was composed of 32
exposed subjects with a mean urinary aluminum of
110 μg/L (Letzel et al., 2000). A Swedish study con-
tained 16 subjects with a mean urinary aluminum of
83 μg/L (Iregren et al., 2001). In contrast, a study of
Canadian miners who had inhaled aluminum powder
as a prophylactic against silicosis reported a higher
proportion of workers with impaired cognitive func-
tions among those being treated for longer periods
(Rifat et al., 1990). However, neither blood nor urine
concentrations of aluminum was reported.
A meta-analysis included nine studies containing
449 aluminum-exposed welders, aluminum foundry
workers, or electrolytic production workers and 315
controls. The mean concentration of urinary alumi-
num among the exposed groups varied between 13
and 133  μg/L in the different investigations. Nine
overall effect sizes indicated inferior performance of
the exposed group. A significant overall effect size
was obtained for the digit symbol test, which mea-
sures speed-related components of cognitive and
motor performance. The individual results of this
test also suggested an exposure-response relationship
­(Meyer-Baron et al., 2007).
In summary, neurotoxic effects have been observed
in welders with urine concentrations of aluminum of
around 100 μg/L compared with welders with lower
levels. The consistency among these observations is
probably explained by the fact that the welders were
compared with other types of welders, i.e. they are
similar in most respects except for aluminum exposure.
It should be emphasized that it is unknown whether
these effects are reversible. Most studies of exposed
groups other than welders compare one occupational
group with another occupational group. Comparison
of workers with different training and occupations
may well bias the results, especially when psychologi-
cal outcome variables are used.
6.4.4  Alzheimer Disease
AD is a progressive deterioration of brain function,
initially characterized by cognitive deficits, with loss of
recent memory and language ability and impairment
of orientation, problem solving, and abstract thinking.
The typical neuropathological signs of the disease are
neurofibrillary tangles and senile plaques.
A large number of studies have been performed
in an attempt to replicate the first observation that
559
the concentration of aluminum is generally higher in
the brains of patients with AD than in other patients
at autopsy (Crapper et al., 1973). Some investigations
found higher levels of aluminum and some did not
(Krewski et al., 2007).
The results of several epidemiological studies sug-
gest a small increased risk of dementing illnesses,
including AD, for people living in areas of higher com-
pared to lower water aluminum concentrations. How-
ever, there are also several reports of no associations
(Krewski et al., 2007).
The inconsistent findings from autopsy and from epi-
demiological studies of water aluminum contribute to
the controversy surrounding the role of aluminum in the
etiology of AD. Even if aluminum is elevated in AD brain,
it does not prove a cause-effect relationship because AD
may produce changes in cells or cell debris that more
effectively bind aluminum. Epidemiological studies have
not observed a relationship between occupational alumi-
num exposure and AD (Santibanez et al., 2007).
In summary there is no consensus on whether, col-
lectively, the human studies provide sufficient evi-
dence of an association between aluminum and AD
(Frisardi et al., 2010; Santibanez et al., 2007; DECOS
2010; NEG 2011).
6.5 Bone
Clinical and experimental research has shown that
high doses of aluminum inhibit bone remodeling. Alu-
minum can slow osteoblast and osteoclast activities,
and produces osteomalacia and an adynamic bone dis-
ease (Jeffery et al., 1996).
A survey of 1293 patients from 18 dialysis centers in
the United Kingdom showed a correlation between dial-
ysate aluminum concentration and the incidence of frac-
turing dialysis osteodystrophy (Parkinson et al., 1979).
Serum aluminum of > 30 μg/L has been associated
with dialysis-associated bone diseases (Nieboer et al.,
1995). Bone biopsy is needed for definitive diagnosis.
Persons without renal failure who take several
grams of aluminum per day as antacids on a long-
term basis may have osteomalacia. This is attribut-
able to phosphate imbalance secondary to aluminum
intake (Insogna et al., 1980; Woodson, 1998). A marked
decrease in gastrointestinal phosphate absorption can
be observed after a rather small antacid dose (Spencer
et al., 1982). An increased risk for vertebral fractures
was observed among women over 65 years of age with
a weekly use of aluminum-containing antacids (Nevitt
et al., 2005).
Premature infants with gestational ages of less than
34 weeks were assigned to receive either standard or
aluminum-depleted intravenous-feeding solutions
560 Bengt Sjögren, Anders Iregren, Johan Montelius, and Robert A. Yokel
(Bishop et al., 1997). When studied 15 years later, the
preterm infants exposed to standard intravenous-
feeding solutions had lower hip bone mineral content
(Fewtrell et al., 2009). Some patients with severe burns
experienced reduced bone formation that was at least
partially attributed to aluminum from human serum
albumin, calcium gluconate, and other sources (Klein
et al., 1994).
Thirty-two aluminum powder-producing workers
were compared with 29 nonexposed workers from the
same factory. Lumbar spine bone density did not differ
between the groups. The median preshift urine alumi-
num of exposed workers was 110 μg/L and of referents
was 7 μg/L (Schmid et al., 1995).
6.6  Hematopoietic Tissue
Some patients receiving dialysis treatment may
develop hypochromic, microcytic anemia. This anemia
is caused by aluminum and does not respond to iron
therapy (Jeffery et al., 1996).
6.7 Skin
Applications of 2 g magnesium aluminum silicate
to human skin onto a 6-cm2 (1-square inch) area daily
for 1 week did not cause any observable effects. When
tested on rabbits, magnesium aluminum silicate was
regarded as a weak primary skin irritant (Elmore, 2003).
6.8  Allergic Effects
Allergic contact dermatitis from aluminum is rare.
Two routes of sensitization have been described: alu-
minum can be administered onto the surface of the
skin in antiperspirants, medicaments, or the aluminum
disk used in routine patch testing (Finn Chamber); or
injected in aluminum-adsorbed vaccines, hyposensiti-
zation extracts, and other forms. The risk of sensitiza-
tion is higher from the latter route (Peters et al., 1998).
Cutaneous granulomas after immunization may take
some years to heal or decrease (Kaaber et al., 1992).
Itching nodules were found in 645 children out of
76,000 vaccinees (0.8%) after subcutaneous and intra-
muscular injections. A majority of the affected chil-
dren (75%) had symptoms after a median duration of
4 years, and 77% of the children with nodules showed
contact hypersensitivity to aluminum (Bergfors et al.,
2003). Sensitization has also occurred after aluminum
particles were accidentally impelled into the skin from
a compressed air pistol (Peters et al., 1998). Tattooing
with aluminum silicate to create blepharopigmenta-
tion has resulted in a delayed hypersensitivity granu-
lomatous reaction (Schwarze et al., 2000).
6.9  Ischemic Heart Disease
Australian gold miners who inhaled aluminum
powder in order to prevent silicosis had a slightly
increased cardiovascular mortality compared to other
gold miners (hazard ratio, 1.02 per year of exposure;
95% confidence interval, 1.00-1.04) (Peters et al., 2013).
Some studies of aluminum production workers
have reported an increased risk of ischemic heart
disease (Rønneberg, 1995; Thériault et al., 1988).
This effect might be explained by possible asso-
ciation between exposure to air pollutants and the
occurrence of ischemic heart disease mediated by an
inflammatory response that increases blood coagula-
tion (Sjögren, 2004). It is unlikely that aluminum per
se is responsible for this effect, but is more likely that
it is due to air pollutants in general. Slightly higher
levels of fibrinogen were observed among aluminum
smelter workers at Söderberg pots exposed to high
levels of air pollutants compared with those work-
ing with prebaked electrodes and exposed to lower
levels of air pollutants (Sjögren et al., 2002). A high
plasma fibrinogen level is an established risk factor
for coronary heart disease (Danesh et al., 1998). Fur-
thermore, cumulative benzo(a)pyrene exposure was
associated with ischemic heart disease mortality in
the highest exposure category among Canadian alu-
minum production workers using Söderberg pots
(Friesen et al., 2010).
6.10  Carcinogenic Effects
Most animal studies have failed to demonstrate carci-
nogenicity attributable to aluminum powder or to sev-
eral aluminum compounds (Léonard and Gerber, 1988).
The German Commission for the Investigation of
Health Hazards of Chemical Compounds in the Work
Area classifies aluminum oxide (fibrous dust) as a
category 2 carcinogen because of the unequivocally
positive results of intrapleural injections in animals
(Deutsche Forschungsgemeinschaft, 2013).
In 1987, the International Agency for Research on
Cancer (IARC) concluded that there is sufficient evi-
dence that certain exposures occurring during alumi-
num production cause cancer of the lung and bladder
(Group 1, occupational exposures during aluminum
production are carcinogenic to humans). Pitch volatiles
have fairly consistently been suggested in epidemiolog-
ical studies as possible causative agents (IARC, 1987).
Synthetic abrasive materials containing aluminum
oxide, silicon carbide, and different additives have
been used for more than 70 years (Wegman and Eisen,
1981). Exposure to these compounds occurs during
production and when they are used for metal grinding
 26 Aluminum 561

and polishing. An increased risk of stomach cancer TABLE 2  Occupational Exposure Limits for Aluminum
has been observed in two studies (Järvholm et al., in Some Countries Expressed as Time-Weighted Averages
1982; Wegman and Eisen, 1981), and an increased risk Form of Country or TWA
of lung cancer has been observed in one (Siemiatycki aluminum organization (mg/m3) Source
et al., 1989). It is difficult to assess the impact of alu-
minum oxide as a cause of cancer during occupational Metal dust NIOSH 10 NIOSH, 2012
Sweden 5 Swedish Work
exposure to synthetic abrasives. Thus, further studies
Environment
are needed to explore whether components in syn- Authority, 2011
thetic abrasive materials are carcinogenic. Respirable metal ACGIH 1 ACGIH, 2013
dust Germany 1.5 Deutsche Forsc-
hungsgemein-
schaft, 2013
7  OTHER ALUMINUM COMPOUNDS NIOSH 5 NIOSH, 2012
Sweden 2 Swedish Work
Aluminum phosphide is used as a fumigant to Environment
protect stored grain from insects and rodents. In the Authority, 2011
presence of moisture, aluminum phosphide releases Pyro powder NIOSH 5 NIOSH, 2012
(as Al)
phosphine, which is highly toxic. Since being first
Welding fume NIOSH 5 NIOSH, 2012
reported in India, aluminum phosphide poisoning is (as Al)
now recognized as one of the most common causes of Soluble salts NIOSH 2 NIOSH, 2012
poisoning among agricultural pesticides. Survival is (as Al) Sweden 1 Swedish Work
unlikely if more than 1.5 g is ingested. However, the Environment
Authority, 2011
case fatality ratio has declined since the early 2000s
Potassium alumi- Sweden 0.4 Swedish Work
due to improved intensive care (Gurjar et al., 2011). num tetrafluo- Environment
ride (inhalable) Authority, 2011

8 GUIDELINES ACGIH, American Conference of Governmental Industrial Hygien-

Aluminum is used as a coagulant in water treat-
ment. According to the World Health Organization,
a health-based guideline value cannot be derived.
However, practical levels based on optimization of
the coagulation process in drinking-water plants
using aluminum-based coagulants have been derived:
0.1 mg/L or less in large water treatment facilities, and
0.2 mg/L or less in small facilities (WHO, 2004). Simi-
larly, Health ­Canada (2012) established an operational
guidance value of < 0.1 mg/L for drinking water from
treatment plants using aluminum-based coagulants
and < 0.2 mg/L for other types of treatment systems.
The occupational exposure limits for airborne alumi-
num have been lowered since 2000 in many countries
and current values are presented in Table 2. Occupa-
tional biological exposure limits are established in some
countries. Germany has a urinary biological tolerance
value for occupational exposure of 60 μg aluminum per
g creatinine (Deutsche Forschungsgemeinschaft, 2013).
This concentration corresponds to approximately
80 μg/L, according to the equation given by Riihimäki
and Aitio (2012). As a rough approximation an alu-
minum urinary concentration of A μg/L corresponds
to 1.3 × B μg/g creatinine, at the urine relative density
of 1.021. Riihimäki and Aitio (2012) also proposed an
action limit value of 80 μg/L in a sample collected pre-
shift after 2 days without occupational exposure.
ists; NIOSH, National Institute for Occupational Safety and Health
(USA); TWA, time-weighted average.
It has been recommended in the Association for the
Advancement of Medical Instrumentation standards
that aluminum in dialysis water should be < 10 μg/L
(Vlchek et al. 1991; Willhite et al., 2012), but lower
concentration limits (< 5 and < 2 μg/L) have been sug-
gested (Rob et al., 2001).
Aluminum compounds are the only adjuvants used
in the manufacture of currently licensed vaccines
in the United States. Chapter 21 of the U.S. Code of
­Federal Regulations governs the amount of aluminum
permitted in the recommended single human dose
of a ­product. The amount of aluminum is limited to
0.85 mg/dose if the level is assayed or 1.14 mg if deter-
mined by calculation on the basis of the amount of alu-
minum compound added (Baylor et al., 2002).
The daily intravenous intake of more than 4-5 μg
aluminum/kg body weight from total parenteral
nutrition solutions can produce aluminum accumula-
tion and central nervous system and bone toxicity. To
address this problem, the FDA established a labeling
requirement that the aluminum content of large vol-
ume parenteral drug products used in total parenteral
nutrition therapy must not exceed 25 μg/L and the
maximum level of aluminum present at expiry must
be stated on the label of all small volume parenteral
562 Bengt Sjögren, Anders Iregren, Johan Montelius, and Robert A. Yokel
drug products and pharmacy bulk packages used in
the preparation of parenteral nutrition solutions (FDA,
2013; Bohrer et al., 2010; Wier and Kuhn, 2012).
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