Environmental Research Section A 89, 101}115 (2002)
doi:10.1006/enrs.2002.4352, available online at http://www.idealibrary.com on
REVIEW
Aluminum: Impacts and Disease
Prasunpriya Nayak
Department of Physiology, Sikkim Manipal Institute of Medical Sciences, 5th Mile, Tadong, Gangtok 737102, Sikkim, India
Received January 29, 2001
Aluminum is the most widely distributed metal in
the environment and is extensively used in modern
daily life. Aluminum enters into the body from the
environment and from diet and medication. How-
ever, there is no known physiological role for
aluminum within the body and hence this metal
may produce adverse physiological effects. The
impact of aluminum on neural tissues is well re-
ported but studies on extraneural tissues are not
well summarized. In this review, the impacts of
aluminum on humans and its impact on major
physiological systems are summarized and dis-
cussed. The neuropathologies associated with high
brain aluminum levels, including structural, bio-
chemical, and neurobehavioral changes, have been
summarized. In addition, the impact of aluminum
on the musculoskeletal system, respiratory system,
cardiovascular system, hepatobiliary system,
endocrine system, urinary system, and reproduc-
tive system are discussed.  2002 Elsevier Science (USA)
Key Words: aluminum toxicity; aluminum sour-
ces; neural tissues; extraneural tissues; physiolo-
gical systems.
INTRODUCTION
Aluminum is a ubiquitous element used extensive-
ly in contemporary life. Despite its ubiquity, evolu-
tion has not conferred essentiality or utility as far as
is known in biological systems. This nonessential
metal was long considered virtually innocuous to
humans (Sorrenson et al., 1974). The impact of
aluminum on biological systems have been the
subject of much controversy in the past few decades
(Campbell and Bondy, 2000). A wealth of research
now susggests that aluminum is toxic to plants,
some aquatic animals, and humans (Ganrot, 1986;
Chadwick and Whelan, 1992; Yokel, 2000; Nayak
and Chatterjee, 2000; Pineros and Kochian, 2001).
101
SOURCES OF ALUMINUM
Environmental Exposure
Natural aluminum occurs in the soil and makes up
about 8% of the surface of the earth. Higher concen-
trations may exist in soil surrounding waste sites
associated with certain industries such as coal com-
bustion and aluminum mining and smelting (U. S.
Public Health Service, 1992, p. 67). Flux of dust from
ores and rock materials are the largest source of
particle-borne aluminum (Lee and von Lehmden,
1973; Sorrenson et al., 1974). Both natural processes
(weathering of aluminosilicate crustal material) and
human activities (mining and agriculture) contin-
ually add dust particles to the environment (Eisen-
rich, 1980; Filipek et al., 1987). In the atmosphere,
aluminum is mainly found as aluminosilicates asso-
ciated with particulate matter and the background
levels of aluminum in the atmosphere generally
range from 0.005 to 0.18 mg/m3 (Sorrenson et al.,
1974). Aluminum concentrations in natural water
normally are small but are found to be higher in the
urban areas (Constantini and Giordano, 1991). The
increasing amount of aluminum is being leached
continuously by acid rain (Harris et al., 1996) and
contributes signi7cantly to environmental inputs.
Worldwide, it has been estimated that 40% of arable
soils and perhaps as much as 70% of lands that can
be cultivated are acidic enough to have an aluminum
toxicity problem (World Food Nutrition Study,
1977). Ground-water pollution by aluminum has
been recently reported (Tsunoda and Sharma, 1999).
Dietary Exposure
Many types of foods contain aluminum because
they are grown in soil that contains aluminum.
When the soil pH is lower than 4.5}5.0, Al is
0013-9351/02 $35.00
 2002 Elsevier Science (USA)
All rights reserved.
102 PRASUNPRIYA NAYAK
solubilized in the soil water and absorbed by plant
roots (Matsumoto, 2000). Apart from this, food addi-
tives also contribute substantial amounts of alumi-
num in the diet. Aluminum is present in many
manufactured foods and is added to drinking water
for puri7cation purposes (Levesque et al., 2000).
The common foods with aluminum-containing food
additives include some processed cheese, baking
powders, cake mixes, frozen dough, pancake mixes,
etc. Another signi7cant dietary source of aluminum
is soy-based milk products, which contribute
2.1 mg/day based on the typical intake of an infant
(deVoto and Yokel, 1994; Yokel and McNamara,
2001). Leaching of aluminum from beverage cans
and cookwares can also occur (Lin et al., 1997). The
average concentration of aluminum in cola drinks
was found to be 0.1 mg/g. Dry tea leaves have
555}1009
g/g aluminum and a typical infusion has
4.5}6.0
g/ml aluminum. Infusion of coffee has an
aluminum concentration 0.04}0.30
g/ml (Koch
et al., 1988). It has been estimated that about 20%
of daily intake of aluminum comes from cooking
utensils (pans, pots, kettles, and trays) made of
aluminum (Greger et al., 1985; Regura et al., 1985;
Lin et al., 1997). Lione (1983) reported that an aver-
age human daily consumes 3}100 mg aluminum
through foods and drinks. Recently extensive
studies estimated the amount of aluminum as
3.5 mg in average daily diet in Japan (Matsuda
et al., 2001) and as 3.4 mg in that of the United
Kingdom (Ysart et al., 2000). The total diet study
showed that mean aluminum intake by an adult
male is 10 mg/day, whereas that by an adult female
is 7 mg/day (Flarend, 2001).
A small amount of aluminum is ingested by hu-
man infants through breast milk (Flarend, 2001).
It has been observed in animal experiments that
fetuses and sucklings are exposed to aluminum
through the transplacental passage and/or maternal
milk when the pregnant rats and/or lactating rats
are subcutaneously injected with 26Al (Yumoto et al.,
2001).
Iatrogenic Exposure
Introduction of aluminum directly into the blood-
stream via high-aluminum dialysate or consumption
of large oral doses of aluminum-containing phos-
phate binders or antacids is the major cause of alu-
minum overload through medication. Aluminum is
a well-known contaminant of intravenous solutions
(Wilhelm et al., 2001). Baydar et al. (1997) found
that aluminum concentration in the enteral nutri-
tion formulas and the parenteral solutions ranges
from 87.6 to 961.2 ng/ml and from 58.4 to
1232.0 ng/ml, respectively. Preterm infants on intra-
venous feed (Sedman et al., 1985; Bishop et al.,
1989), patients on total parenteral nutrition [TPN]
(Klein et al., 1982; Klein and Coburn, 1994), patients
with severe burns (Klein et al., 1994), patients re-
ceiving alum irrigation in the urinary bladder to
prevent bleeding (Kavoussi et al., 1986; Murphy
et al., 1992), and patients undergoing cranial bone
reconstruction with aluminum-containing bone ce-
ment (Hantson et al., 1994; Renand et al., 1994) are
found to be victims of aluminum exposure. These
types of acute aluminum intoxication are uncommon
in clinical practice but have been found to occur and
can be fatal (Nakamura et al., 2000). Aluminum
neurotoxicity has virtually disappeared in the dialy-
sis population; however, sporadic toxic effects
caused by contamination of water with aluminum
are still reported (Farnandez}Martin et al., 2000;
Berend et al., 2001). In addition to these, aluminum-
containing nonprescription drugs, including some
antacids, buffered aspirins, antidiarroheal products,
douches, and hemorroidal medications, are com-
monly used and may contribute to the severity of
aluminum exposure. Even a single dose of alumi-
num-containing antacid can increase the serum
aluminum and the level of increase varies with the
type of liquid taken with it (Weburg and Berstad,
1986). Griswold et al. (1983) showed that chronic
consumption of aluminum-containing antacids may
contribute to the dialysis dementia syndrome and
can produce the syndrome in people with renal im-
pairment in the absence of dialysis. Some patients
consume as much as 5 g of aluminum daily in ant-
acids and buffered aspirins (Lione, 1983). Recently
Flaten (2001) reported that regular consumers of
antacids ingest gram amounts of aluminum daily.
Aluminum-containing adjuvants are widely used
in a variety of vaccine products, such as recombinant
proteins, virus-like particles, conjugated polysac-
charides, and, recently, DNA vaccines (Zhao and
Sitrin, 2001). The commonly used vaccines, diph-
theria, tetanus, hepatitis, rabies, and anthrax, all
are based on aluminum adjuvant. In the United
States the level of aluminum in each dose of vaccine
is limited to a maximum 0.85 mg [FDA limit]
(Flarend, 2001).
Occupational Exposure
The exposure to aluminum is unavoidable due to
the increased use of aluminum in day-to-day life and
in industries. The potential of aluminum exposure is
expected to be highest among certain occupational
 ALUMINUM: IMPACTS AND DISEASE
groups, e.g., workers of aluminum re7ning and
metal industries, people employed in printing and
publishing and in automotive dealerships and ser-
vice stations, and individuals involved in fabricated
metal products (U. S. Public Health Service, 1992,
p. 82). During the past two decades a considerable
number of studies reported cognitive changes and
possible impairment and other occupational hazards
in relation to exposure to aluminum dusts and fumes
(Hosovski et al., 1990; Rifat et al., 1990; White et al.,
1992; Bast-Pattersen et al., 1994; McLachlan, 1995).
Arbour (1991) had reported an unusual case of mol-
ten aluminum inhalation. Schlesinger et al. (2000)
also recently supported the concept of gradual
accumulation and long-term retention of aluminum
within the respiratory tract of individuals repeated-
ly exposed in occupational settings. Both objective
neurophysiological and neuropsycological measures
and subjective symptomatology indicated mild
but unequivocal dose-dependent increase in
aluminum burden in the body in aluminum welders
and current mild steel welders (Riihimaki
et al., 2000).
ENTRY OF ALUMINUM INTO THE BODY
Aluminum absorption seems to be very low, but
many factors can enhance it in animals and humans
(Deng et al., 1998). One of the signi7cant routes of
aluminum absorption is through the gut (Ittel,
1993). Intestinal absorption of aluminum per se is
very poor (Flaten et al., 2001) and as low as 0.1%,
but many organic dietary components are potential
chelators of aluminum and may enhance its absorp-
tion (Deng et al., 2000; Venturini}Soriano and
Berthon, 2001). In addition, certain pathological
conditions also increase the intestinal absorption of
aluminum. Moore et al., (2000) has shown dimin-
ished ability of the gastrointestinal tract to exclude
aluminum in Alzheimer’s disease which increases
the possibility of systemic exposure. Although the
exact mechanism of absorption via the gut is not
clear (Exley et al., 1996), several suggestions have
been put forward. Feinroth et al. (1982) suggested
that aluminum is actively transported out of the
intestine. On the other hand, Cochran et al. (1993)
suggested the presence of two aluminum-speci7c
proteins, which bind aluminum with the intestinal
mucosa and thereby regulate aluminum absorption.
Nowadays, it is believed that intestinal absorption of
aluminum includes (a) paracellular passage routes
along enterocytes and through tight junctions by
passive processes and (b) transcellular passage
routes through the enterocytes involving passive
103
facilitated and active transport processes (Greger,
1993; Greger and Sutherland, 1997). The 7rst route
is nonsaturable and mainly used for high aluminum
concentration, which is modi7ed by extracellular
calcium, whereas the second route is saturable
(Cunat et al., 2000). The individual contributions of
these processes to the net absorption of aluminum
through gastrointestinal tract are dependent upon
a number of factors including the chemistry of gut
lumen and health of the exposed individual.
Exposure to aluminum through dusts and aerosols
is of considerable importance in miners, smelters,
and other metal workers. It has been suggested that
the inhaled aluminum accumulates in the brain
through absorption via the olfactory system
(Roberts, 1986; Exley et al., 1996) or systemized
(a) through the lung epithelia (Gitelman et al., 1995)
and (b) via the gastrointestinal tract as particulates
are swallowed (Rollin et al., 1993). It has been esti-
mated that about 3% of aluminum is absorbed into
the blood from the lung (Jones and Benett, 1986). In
addition to olfactory nerve uptake, transsynaptic
aluminum distribution is also suggested through
animal experimentation (Divine et al., 1999). Ac-
cording to Yokel and McNamara (2001), pulmonary
aluminum absorption appears to be more ef7cient
than gastrointestinal absorption.
Dermal applications of aluminum compounds in
cosmetic, antiperspirant, and health care products
generally do not induce harmful effects on skin or
other organs (Sorrenson et al., 1974; Brusewitz,
1984). Speci7c conditions showed intradermal pen-
etration [as in elephantiasis] (Blundell et al., 1989)
and histiocytic accumulation [as in hyperhydrosis]
(Barr et al., 1993) of aluminum compounds. Under-
arm application of 26Al chlorohydrate was associated
with up to 0.012% absorption of the 26 Al through the
skin (Flarend et al., 2001). Thus the skin may be
a minor route of aluminum entry into the body.
In vivo animal studies suggest that aluminum
absorption is generally very low (1%) and the per-
centage absorbed is sensitive to amount of alumi-
num intake (Greger, 1993). To gain entry into the
body, aluminum has to cross a layer of epithelial
barrier. The interaction of gastrointestinal, olfac-
tory, pulmonary, and dermal epithelia with alumi-
num is not well understood. However, intravenous,
intramuscular, and parenteral administrations of
aluminum compounds bypass such barriers.
DISTRIBUTION OF ALUMINUM IN THE BODY
The total body burden of aluminum in healthy
human subjects is approximately 30}50 mg
104 PRASUNPRIYA NAYAK
(ATSDR, 1999; U. S. Public Health Service, 1992,
p. 26; Alfrey, 1984; Ganrot, 1986). This total body
aluminum is in a 8ux between different systemic
compartments (Exley et al., 1996). Unequal distribu-
tion of aluminum to various tissues has been re-
ported in normal, aluminum-exposed humans and in
aluminum-treated experimental animals (Yokel and
McNamara, 2001). In the general population, of the
total amount of aluminum of the body, about one-
half is in the skeleton and about one-fourth is in the
lungs (Ganrot, 1986). Whatever the route of expo-
sure, the brain is an important accumulation site of
aluminum in the body. The gray matter contains
about twice the concentration found in the white
matter (McDermott et al., 1978; Arieff et al., 1979).
Aluminum also occurs in human skin (Alfrey, 1980),
lower gastrointestinal tract (Tipton and Cook, 1963),
lymph nodes (Hamilton et al., 1973), adrenals
(Tipton and Cook, 1963), and parathyroid glands
(Cann et al., 1979).
Distribution of the metal in different target organs
varies with route, dose, and duration of exposure
(Ding and Zhu, 1997). Little is known about the
temporal pattern of pulmonary clearance of alumi-
num compounds from the lungs with repeated expo-
sure or the potential subsequent translocation to
other organs (Schlesinger et al., 2000). Lungs, hilar
lymph nodes, liver, and spleen are the main organs
of aluminum accumulation with inhalation exposure
(Teraoka, 1981). Following oral exposure retention
of aluminum is reported in brain (preferentially hip-
pocampus), bone, kidneys, muscle, and heart (Yokel
and McNamara, 1985; Anthony et al., 1986; Santos
et al., 1987; Chan et al., 1988). Studies of tissue
distribution after subcutaneous administration of
aluminum in rabbits have also shown differential
distribution of aluminum in different organs (Du Val
et al., 1986).
Highest levels of aluminum are found in bone
(Zafar et al., 1997). The brain has lower aluminum
concentrations than many other tissues (Yokel and
McNamara, 2001). Following bone, the orders of in-
creased aluminum level in different organs of the
exposed animals were kidney cortex
kidney
medulla
liver
testes
skeletal muscle
heart

brain (Du Val et al., 1986). Schetinger et al. (1999)
showed that the accumulation of aluminum was in
the order liver
kidney
brain when mice were ex-
posed to aluminum sulfate in drinking water. The
kinetics of aluminum in liver, bone, and kidney were
generally dose independent (Sutherland and Greger,
1998). The rate of aluminum eliminated from tissues
is organ dependent with estimated half-lives from 44
to over 100 days in rabbit lungs, liver, spleen, and
kidney (Yokel and McNamara, 1989b). Elimination
half-lives of liver aluminum were similar for various
aluminum treatments (Sutherland and Greger,
1998).
With increasing age, the aluminum concentra-
tions of lungs, liver, kidneys, and brain were found
to be increased (U. S. Public Health Service, 1992,
p. 26). No signi7cant difference in oral aluminum
bioavailability was found between human beings
aged 36}59 and 59}76 years (Stauber et al., 1999).
However, the distribution of aluminum has been
shown to be in8uenced by parathyroid hormone and
1,25 dihydroxy vitamin D. Parathyroid hormone was
shown to increase the aluminum concentration in
liver; 1,25 dihydroxy vitamin D enhances aluminum
uptake in heart and muscles. But when applied
simultaneously, the aluminum content of bone,
liver, and brain was found to be decreased
(Hirschberg et al., 1985). Several dietary constitu-
ents signi7cantly increased the aluminum levels in
bone, whereas brain aluminum levels were raised
by the intake of lactic, gluconic, malic, citric,
and oxalic acids. Levels of aluminum in spleen
were signi7cantly increased by gluconic and
ascorbic acids, whereas gluconic and oxalic acids
also raised aluminum levels in kidneys (Domingo
et al., 1993).
CELLULAR INCORPORATION OF ALUMINUM
Like the speci7city in target organs where alumi-
num is generally being accumulated, aluminum is
not evenly distributed within the cells. Aluminum
accumulates in the lysosome (Galle, 1987), cell nu-
cleus (Kruck and McLachlan, 1988; Lukiw et al.,
1992), and chromatin (Karlik et al., 1980). An associ-
ation between intranuclear aluminum and forma-
tion of neuro7brillary tangles (an indication of
aluminum neuro toxicity) has been suggested
(Uemura, 1984). It has also been reported that alu-
minum present in the lysosome (Galle, 1987) may be
associated with dementia (van Rensberg et al.,
1997). Aluminum has been found in cytosolic,
mitochondrial, lysosomal, and nuclear components
(Exley et al., 1996; Julka et al., 1996). Speci7cities
are observed in cellular compartmentalization de-
pending upon the cell types. A nuclear accumulation
of aluminum in the neuronal cell line was observed,
whereas perinuclear and vesicular distribution of
aluminum was found in astrocytes that partially
colocalized with cathepsin D, a lysosomal marker
(Levesque et al., 2000).
 ALUMINUM: IMPACTS AND DISEASE
ALUMINUM-INDUCED PATHOPHYSIOLOGICAL
CHANGES
Aluminum toxicity is well documented but the
mechanism of action is poorly understood (Han
et al., 2000). Toxic effects of aluminum on brain,
liver, skeletal muscles, heart, and bone marrow are
well established (Galle, 1987). Similarly, there is
lack of information on its cellular sites of action
(Levesque et al., 2000). The intralysosomal ac-
cumulating mechanism of aluminum in kidney en-
ables elimination of the metal. But in other tissues it
has some speci7c toxic effects. In extrarenal tissues,
slowly accumulating aluminum can cause large de-
posits and impair proper cell functioning or even cell
survival.
Impacts of Aluminum on the Neural System
Aluminum is a neurotoxic agent; however, little
information has been obtained regarding its molecu-
lar cytotoxicity (Suwalsky et al., 1999). In contrast
to aluminum levels in other organs, brain aluminum
concentrations were found higher in young alumi-
num-exposed rats compared with old or adult alumi-
num-exposed rats (Gomez et al., 1997). Aluminum
is highly neurotoxic and at high levels inhibits
prenatal and postnatal development of the brain
in humans and experimental animals (Yumoto et al.,
2001). In young ages, the brain may be the most
susceptible target organ for aluminum.
Neuropathologies associated with aluminum
accumulation. Several neurological manifestations
have been attributed to aluminum intoxication in
humans. These includes memory loss, tremor, jerk-
ing movements, impaired coordination, sluggish
motor movement, loss of curiosity, ataxia, myoclonic
jerks, and generalized convulsions with status epi-
lepticus (Zatta et al., 1991; Crapper McLachlan and
DeBoni, 1980). The neuropathological conditions
that have been associated with elevated aluminum
in brain include Alzheimer-type senile and presenile
dementia, Down syndrome with manifested
Alzheimer’s disease, Guam and Kii peninsula, amyt-
ropic lateral sclerosis (spinal cord and brain),
Parkinsonian dementia with neuro7brillary degen-
eration, neuro7brillary degeneration adjacent to
harmatoma, dialysis encephalopathy, striatonigral
syndrome, alcohol dementia with patchy demyelina-
tion, senile plaques of Alzheimer’s disease, and
aged brain (Zatta et al., 1991; Crapper McLachlan
and DeBoni, 1980). Recent epidemiological,
neuropathological, and biochemical studies have
105
suggested a possible link between the neurotoxicity
of aluminum and the pathogenesis of Alzheimer’s
disease (Kawahara et al., 2001). However, the rela-
tionship between these pathological disorders and
aluminum is still controversial.
Structural changes following aluminum accumu-
lation. An autopsy study of a patient with neur-
opathy on macroscopic examinations showed
a global dilatation of ventricles with thinning of
corpus callosum and gray lesions similar to plaques
in the white matter (Lapresle et al., 1975). Varner et
al. (1998) have demonstrated that chronic adminis-
tration of aluminum to rats in drinking water can
cause distinct morphological alterations in the
brain. Their study provided evidence of reduced
neuronal density, degenerative changes such as pyk-
nosis, vacuolation, and chromatin condensation, and
other cytoskeletal and cerebrovascular abnormal-
ities (Varner et al., 1998). Microscopically, de-
myelination and the presence of aluminum and
phosphorus compounds were detected (Zatta et al.,
1991). Intracerebral administration of aluminum in-
duces formation of neuro7brillary tangles, consist-
ing of perikaryal accumulation of neuro7laments
(Savory et al., 1991). Normal-appearing neuro7la-
ments accumulated in the perikarya and dendrites
of neurons in the brainstem and spinal cord (Terry
and Pena, 1969); large spheroids containing neur-
o7laments have been noted in the neuropil (Wis-
niewski et al., 1980). Aluminum intoxication also
causes axonal swelling (Troncoso et al., 1982). Cere-
bellar atrophy along with time-related deterioration
(atrophy with eccentric and shrunken nuclei with
dark cytoplasm) of the Purkinje cells was reported in
aluminum intoxication (Ghetti et al., 1985). How-
ever, aluminum-induced alterations in the cerebel-
lar Purkinje cells are similar to those observed in
aged human brains (Yokel, 1994). Histochemical and
immunocytochemical studies of Platt et al. (2001)
suggest that the enhancement of in8ammation and
the interference with cholinergic projections may be
the modes of action through which Al may cause
learning and memory de7cits. Less morphometric
alterations were found to be associated with the
vacuolation in spinal cord in response to chronic
aluminum exposure to mice (Golub and Tarara,
1999).
Behavioral toxicity of aluminum. A decline in
visual memory was observed in hemodialysis pa-
tients who exhibited higher serum aluminum (Bolla
et al., 1992). The major reported 7ndings in adults,
on acute exposure to aluminum, include agitation,
confusion, myoclonic jerk, grand mal seizures,
106 PRASUNPRIYA NAYAK
obtundation, coma, and death (Bakir et al., 1986).
Aluminum neurotoxicity in children tends to be
manifested by regression of verbal and motor skills
(Sedman et al., 1984). Considerable importance has
also been given to aluminum as a possible causal
factor for the senile dementia, which is character-
ized by progressive cognitive decline with onset after
age 65 (Wisniewski, 1991). The dementia dialytica
(dialysis dementia) is characterized by speech abnor-
mality with subsequent memory impairment asso-
ciated with abnormal EEG spike (Wisniewski, 1991).
Thus these reports suggest that aluminum-induced
neurotoxicity is associated with cognitive impair-
ment.
In contrast, it enhanced performance during
training and performance of food-motivated operant
tasks in mice fed diets with high aluminum (Golub
and Germann, 1998).
Biochemical changes of brain in response to
aluminum. The effects of aluminum leading to
manifestation of neurodisorders may arise from its
interaction with the nervous system in various ways:
(i) by interfering with glucose metabolism leading to
reduced formation of precursors of acetylcholine and
binding with the catechol moiety of catecholamines;
(ii) by interacting with Na>}K>}ATPase and
Ca2>}Mg2>}ATPase, resulting in alteration in the
release and reuptake phenomena of excitatory
amino acids and other neurotransmitters by the
presynaptic neuronal membrane; (iii) by acting as
competitive inhibitor for calcium binding site on or
within the channel, causing modulation in the in-
tracellular calcium homeostasis; (iv) by increasing
the cAMP production; (v) by effecting changes in
cytoskeletal proteins which might result from alter-
ed phosphorylations, proteolysis, transport, and
synthesis; (vi) by interacting directly with genomic
structure; and (vii) by inducing oxidative damage
through lipid peroxidation of brain phospholipids
(Nayak and Chatterjee, 1999). The cellular nucleic
acid machinery also plays an important role in the
aluminum-induced toxicity of brain (Nayak and
Chatterjee, 1998).
In an in vitro study aluminum acetylacetonate
altered the molecular structure of the lipid bilayer,
thereby modifying the biophysical and physiological
properties of the cell membrane (Suwalsky et al.,
1999).
Formation and accumulation of  amyloid is
potentiated by aluminum. Mechanisms for this
aluminum-induced promotion of  amyloid have
been reviewed by Yokel (2000). However, aluminum
salts may also reverse the amyloid 7bril formation
(Paik et al., 1997; Chauan et al., 1997). Aluminum
also promotes the aggregation of tau protein
(Madhav et al., 1996; Scott et al., 1993) and other
neuro7brillary proteins (Shen et al., 1994; Shin
et al., 1995).
The loss of CAM1 (Ca2>}calmodulin) immunore-
activity and the occurrence of large amounts
of aluminum (anti-Al3> monoclonal antibodies
immunoreactivity) has suggested an alteration of
the active conformation of calmodulin in Alzheimer’s
disease-affected brains (Solomon et al., 2001).
Alterations in the regional distribution patterns
of aminergic neurotransmitters (Ravi et al., 2000)
and amino acid neurotransmitters (Deloncle and
Guillard, 1990; Nayak and Chatterjee, 2001) are
also signi7cant contributors to aluminum-induced
neurotoxicity.
Impacts of Aluminum on the Extraneural System
Musculoskeletal system. In more chronic alumi-
num poisoning, the skeleton is the main target (Kerr
et al., 1992). The, skeletal system has a higher level
of accumulated aluminum. Tracer studies show that
liver, kidney, muscle, and heart also accumulate
aluminum (Walker et al., 1994). Gopalan (1996) sug-
gested that aluminum may initially be deposited in
bone but, during osteoporosis of old age, the de-
mineralization of bone may transfer aluminum to
other organs, including the brain.
Aluminum is implicated in a percentage of symp-
tomatic low bone remodeling lesions in Iberoamerica
(Jorgetti et al., 2000).
Osteomalacia, bone pain, pathological fractures,
proximal myopathy, and failure to respond to vit-
amin D therapy are the common features of alumi-

num-induced musculoskeletal toxicity (Alfrey,
1991). Accumulation of aluminum in bone with
resulting osteodystrophy and fracture can precede
and accompany dialysis dementia syndrome (Ott
et al., 1982; Yokel, 1984). It has been reported that
excess bone aluminum is associated with low bone
formation rates and increased risk for fractures
(Kausz et al., 1999). Aluminum administration in
experimental animals results in osteomalacia as
characterized by osteoid accumulation and
decreased mineralization. Rodriguez et al. (1990)
showed that decreased osteoblast surface, increased
osteoid accumulation, and cessation of bone forma-
tion occurred as a result of aluminum administra-
tion. They also showed that aluminum was toxic to
osteoblast and inhibited mineralization even when
osteoblasts were not decreased. Though very low
levels of aluminum can be mitogenic in bone in
 ALUMINUM: IMPACTS AND DISEASE
experimental animals, both clinical and experi-
mental exposures of high doses of aluminum were
found to inhibit remodeling, to slow both osteoblast
and osteoclast activities and to produce osteomalacia
and adynamic bone disease (Jeffery et al., 1996). It
has been observed that the impact of aluminum on
bone is biphasic. Collagen synthesis, DNA replica-
tion, ornithine decarboxylase and alkaline
phosphatase activities of osteoblast-like cells, and
acid phosphatase (tartrate resistant) activity of os-
teoclast-like cells were found to be inhibited with
high concentrations of aluminum (
1.5;10\6 M),
while lower concentrations of aluminum were found
to stimulate these activities (Liaberherr et al., 1987).
Gomez}Alonso et al. (1999) found that in rats with
normal renal function, aluminum can induce bone
formation even when osteopenia is present.
Work with single muscle 7bers from the barnacle
Balanus nubilus has shown that the injection of
aluminum into these 7bers leads to inhibition of the
resting Na> ef8ux and that this involves both
ouabain-sensitive and ouabain-insensitive compo-
nents. The injection of aluminum into ouabain-
poisoned 7bers often leads to a rise in the remaining
Na> ef8ux. It has been shown that the stimulatory
response elicited by injection of aluminum is due to
a fall in myoplasmic pCa resulting from activation of
voltage-dependent Ca2> channels and that it in-
volves the operation of Na>}Ca2> exchanger in the
reverse mode (Bittar and Huang, 1990).
Respiratory system. Following inhalation expo-
sure, the effects of aluminum are mainly exerted on
the respiratory system. Workers in the aluminum
industry develop asthma, cough, lung 7brosis, or
decreased pulmonary function but whether these
effects are due only to aluminum are questionable
(U. S. Public Health Service, 1992). In animal stud-
ies, aluminum was reported to cause proliferation of
macrophages in broncho-alveolar lavage 8uid and
granulomatous reactions. Granulomatous reactions
were characterized by giant vacuolated macro-
phages, which were associated with pneumonia
in some cases (U. S. Public Health Service, 1992,
p. 7). Pathology of the respiratory system was not
observed from aluminum exposure by other routes.
Cardiovascular system. Accumulation of alumi-
num in the heart also occurs. It has been suggested
that the observed cardiac hypertrophy in hemodialy-
sis patients may be caused in part by aluminum
(Birchall, 1991). Myocardial cells can accumulate
aluminum in lysosomes (Galle, 1987) and an associ-
ation has been noted between aluminum accumula-
tion in myocardium and cardiomyopathy, with
107
a high prevalence of arrhythmia and sudden death
in hemodialysis patients (Birchall, 1991). Aluminum
exposures potentiates the adverse effects of diabetes
mellitus by decreasing sarcoplasmic reticulum cal-
cium uptake (Levine et al., 1990).
Hepatobiliary system. The adverse effects of alu-
minum on the liver have been well documented
(Stein et al., 1987). Intraperitoneal exposure to alu-
minum hydroxide induces development of resorption
granulomas in the liver. Aluminum was detected by
Morin 8uorescence in constituent macrophages and
giant cells. By electron probe X-ray microanalysis,
aluminum was identi7ed predominantly in lyso-
somes of macrophages and Kupffer cells (Fiejka
et al., 1996). Despite high accumulation of alumi-
num, liver function is seldom affected due to biliary
excretion. In certain cases, intracellular deposits
were present in such large quantities that hepa-
tocytes were destroyed (Galle, 1987). It is accepted
that patients receiving total parenteral nutrition
develop liver disease characterized by cholestasis,
periportal in8ammation, bile duct proliferation, and
degeneration of the hepatocytes (Klein, 1984). At
lower doses aluminum can produce hepatobiliary
dysfunction characterized by portal in8ammation
(Demircan et al., 1998).
Abnormalities in hepatic function associated with
aluminum include increased serum bile acid concen-
tration and glucuronyl transferase activity and re-
duced mixed-function oxidase level and bile 8ow. In
addition, decreased taurine conjugation with bile
acids which may be associated with cholestasis have
been reported (Klein et al., 1989).
It has been reported that parenteral aluminum
produces a course of hepatic damage that begins
with reduced glutathione depletion and proceeds
through a sustained increase in heme oxygenase
activity, with cytochrome P450 loss being an
early event and production of hepatic malonedial-
dehyde being a late event (Fulton and Jeffery,
1994a).
It has been reported that orally administered
aluminum in rats causes increased activity of
 aminolevulinic acid [ALA] dehydratase in liver and
blood and parallel decreases in  aminolevulinic acid
in urine. Aluminum chloride also induced an in-
crease of ALA-synthetase and heme oxygenase in
the liver (Chmielnicka et al., 1994). With speci7c
aluminum salt some morphological and biochemical
changes have been observed by the second week
of treatment. The morphological changes include
midzonal coagulation necrosis. The ativities of
glutamate oxaloacetate transaminase, glutamate
108 PRASUNPRIYA NAYAK

pyruvate transaminase, lactate dehydrogenase, -
glutamoyl transferase, and alkaline phosphatase
were observed to be higher through the fourth week
of aluminum treatment (Ebina et al., 1984). On the
other hand, activities of succinate dehydrogenase
and adenosine triphosphatase showed initial elev-
ation followed by reduction, whereas late increases
in acid phosphatase were observed in male Wistar
rats treated with aluminum chloride (Nikolova et al.,
1994). It has been observed that acute administra-
tion of aluminum adversely affects hepatic drug
metabolism (Jeffery et al., 1987) and protein syn-
thesis (Cherroret et al., 1995).
Burnatowska-Hledin, 1983). Though the role of alu-
minum in the malfunctioning of parathyroid gland
is not clear, hypertropy is often associated with
aluminum poisoning (Galle, 1987). In contrast an
in vitro study showed aluminum-induced inhibition
of the parathyroid hormone release (Mayor and Bur-
natowska}Hledin, 1983) through the inhibition of
adenyl cyclase activity (Bellorin-Font et al., 1985).
Thus there may be dual impacts of aluminum on the
parathyroid gland: hyperparathyroidism at the in-
itial stage and subsequent suppression of hormone
release as tissue levels increase (Mayor and Bur-
natowska-Hledin, 1983).

Endocrine system. In dialysis-associated en-

Urinary system. Urological dysfunction can both
cephalopathy cases at autopsy, light microscopy of
cause and result from aluminum accumulation
silver-stained paraf7n sections demonstrated nu-
though impaired renal function is not a prerequisite
merous intracytoplasmic black-stained 7ne granular
for increased tissue aluminum burden (Mayor and
inclusions in endocrine tissues (Pituitary, para-
Burnatowska-Hledin, 1986) as was thought earlier
thyroid, and adrenal) suggesting accumulation of
(Mayor and Burnatowska-Hledin, 1983).
aluminum in these organs (Reusche et al., 1994).
Aluminum has been previously implicated as
Aluminum was also reported to be concentrated
a nephrotoxin (Stein et al., 1987; Yokel and
in lysosome-like structures of parathyroid gland
McNamara, 1989a). The kidney can rapidly concen-
without alteration in the cellular ultrastructure
trate aluminum but it also can get rid of this element
(Galle, 1987). High levels of parathyroid hormone
(Galle, 1987). However, signi7cant lysosomal dam-
are suggested to be associated with the preferential
age in response to aluminum has been observed in
deposition of aluminum in brain, bone, and para-
rats (Stein et al., 1987). Aluminum-induced neph-
thyroid gland (Burnatowska-Hledin et al., 1983).
rotoxicity was suggested by decreased creatinine
Parathyroid hormone levels are disrupted by alumi-
clearance during aluminum injection and found to
num in humans and animals (Jeffery et al., 1996;
be reversible after cessation of treatment by injec-
Farnandez et al., 1992). Aluminum exerts effects on
tion (Yokel and McNamara, 1989a). Somova et al.
secondary hyperparathyroidism in chronic renal
(1997) found hyperdilated proximal tubules in tubu-
failure and could in8uence the evolution of posttran-
lo-interstitial part of the kidney, in which cells were
splant parathyroid function (Garay et al., 1996).
swollen and the microvilli were largely lost after
Virgos et al. (1989) reported that aluminum can
chronic exposure to low levels of aluminum in drink-
directly inhibit parathyroid secretion. Indridason
ing water. Atrophy of some tubules, surrounded by
et al. (1998) found that aluminum is not signi7cantly
focal areas of interstitial 7brosis, was also observed
associated with changes in parathyroid hormone
by them. Some of the glomeruli were noted to under-
level in new hemodialysis patients with mild second-
go partial sclerosis and focal mesangial hypercel-
ary hyperparathyroidism. Cournot-Witmer and
lularity was reported (Samova et al., 1997). Acute
Plachot (1990) found that aluminum deposits were
proximal tubular necrosis of the kidney was also
present in parathyroid chief cell cytoplasm in lipoid
observed when aluminum nitrilotriacetate was
bodies, lipofuscin granules, and mitochondria of the
injected intraperitoneally (Ebina et al., 1984).
parathyroid glands of parathyroidectomized pa-
Exposure to aluminum sulfate in drinking water
tients on hemodialysis. They observed that the pres-
inhibited ALA}dehydratase activity in kidney
ence of aluminum deposits has not associated with
(Schetinger et al., 1999). Aluminum chloride intensi-
cellular damage or chief cell necrosis nor with
7ed acid-secreting function of kidney (Rudenko
changes in the production of parathyroid hormone
et al., 1998).
(Cournot-Witmer and Plachot, 1990).
It has been speculated that aluminum-induced
neurological disorders, bone disease, and anemia Blood and hemopoietic system. Microcytic, hypo-
may indirectly cause in many dialysis patients, chromic anemia or decreased numbers of red blood
parathyroid hormone toxicity, which may arise by cells (RBC) are indicators of the toxicity of alumi-
in8uencing the metabolism of aluminum (Mayor and num to the hemopoietic system (O’Hare and
 ALUMINUM: IMPACTS AND DISEASE
Murnaghan, 1982). Decreased hemoglobin, hema-
tocrit, mean corpuscular hemoglobin mass, and
mean corpuscular hemoglobin concentration were
noted after 3 weeks of aluminum chloride exposure
to rats (Chmielnicka et al., 1996). Decreased iron
concentration in erythrocytes, blood, and spleen was
also noted. Increased erythrocyte protoporphyrins in
blood is reported to be the most sensitive indicator of
exposure (Nasiadek and Chmielnicka, 2000). The
study of Verma et al. (1999) highlights the high
prevalence of hypochromic anemia in patients with
adequate dietary intake and aluminum overload in
chronic renal failure. Even in the absence of signs
of anemia, ingested aluminum may depress hema-
topoiesis by affecting RBC production and cell
destruction (Garbossa et al., 1996). The exact mecha-
nism of aluminum-induced anemia is still debatable.
Flora et al. (1991) had demonstrated that aluminum
elevated the activity of blood  aminolevulic acid
dehydratase (ALA-D: an heme-synthesizing en-
zyme). However, no changes of ALA-D acitivity in
the liver, the kidney, and the blood were observed by
Chmielnicka et al. (1996). In vitro studies with ALA-
D showed that it is activated at relatively low con-
centrations of aluminum (Schroeder and Caspers,
1996) and inhibited at high concentrations (Pimen-
tal Vieira et al., 2000). Aluminum may also interfere
with iron incorporation (Kaiser and Schwartz, 1985).
This type of anemia usually occurs in the context of
other aluminum toxicity, such as bone disease or
encephalopathy. However, inhibition of hemoglobin
synthesis was shown in hemodialysis patients with
no aluminum toxicity symptoms (Tielemans et al.,
1985). It has been reported that aluminum may
cause resistance to erythropoietin (Rosenlof et al.,
1990). In accordance with this, in vitro studies with
Friend leukemia cells demonstrated excess iron ac-
cumulation when treated with aluminum, without
incorporation into ferritin or heme (Jeffery et al.,
1996). This aluminum-induced anemia is resistant
to erythropoietin therapy, but both anemia and res-
istance to erythropoietin can be reversed by chela-
tion of aluminum with deferoxamine (Casati et al.,
1990), which is not reversible by iron (Jeffery et al.,
1996). Aluminum has also been shown to cause
anemia in rats and rabbits (Alfrey, 1994). Zaman
et al. (1990b) showed aluminum-induced increase
followed by decreases in enzymes in bone marrow
(Zaman et al., 1990a). The increased heme oxygen-
ase activity, with subsequent increased destruction
of heme and/or heme proteins, is discussed as a
possible mechanism for the microcytic, hypochromic
anemia associated with aluminum overload (Fulton
and Jeffery, 1994a).
109
Reproductive system. Testes accumulate high
aluminum over age in rats (Gomez et al., 1997).
Light microscopy of silver-stained paraf7n sections
of testes demonstrated numerous intracytoplasmic
black-stained 7ne granular inclusions in Leydig cells
(Reusche et al., 1994). Sexual behavior of male rats
was suppressed after ingestion of aluminum chloride
(Betaineh et al., 1998). Focal necrosis within 2 days
and destruction of all spermatozoa within 7 days was
observed after intratesticular injection of aluminum
sulfate (Kamboj and Kar, 1964). Decreased absolute
and relative testes weights and seminal vesicles
weights were found after aluminum chloride inges-
tion (Betaineh et al., 1998). Chronic subcutaneous
administration of aluminum sulfate to mice causes
reduced testicular weight, shrinkage of tubules, and
spermatogenic arrest (Kamboj and Kar, 1964).
Gonadotoxic effects in male rats (Krasovskii et al.,
1979) and maternal death associated with fetal
death in pregnant rats (Benett et al., 1975) was
reported with aluminum chloride exposure. More
recently it has been reported that oral aluminum
exposure increases the incidence of foetal abnormal-
ities in rats and mice (Belles et al., 1999).
CONCLUSION
Multiple manifestations of clinical, pathophysio-
logical, and neurobehavioral toxicity are associated
with aluminum exposures. In addition, several path-
ological conditions are factors for the accumulation
of aluminum in speci7c target organs.
Despite this research in the 7eld of aluminum
toxicity, some points still remain unresolved. These
include (a) what are the organ-speci7c variations in
aluminum toxicity, (b) what is the role of differential
aluminum kinetics in different organs; (c) how does
aluminum enter the body by different routes, and
(d) what are the molecular mechanism(s) of alumi-
num toxicity that may characterize features of alu-
minum toxicity common to all target organs?
To prevent aluminum accumulation, reduced use
of aluminum is of crucial importance. Awareness of
aluminum is the primary factor in preventing alumi-
num-induced toxicity.
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