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332 Bioavailable Aluminum: Its Effects on Human Health
Unexposed nickel and copper miners served as controls. describe patients on long-term TPN, from premature
Altogether, 607 miners completed three different stand- infants to adults, routinely exposed to Al3 at levels
ard cognitive tests, measuring short-term memory and sufficiently high to cause clinical signs of toxicity. Some
other properties. Of the 261 miners exposed to McIntyre have developed encephalopathy or osteomalacia despite
powder, 13% showed cognitive impairment compared to having normal kidney function before treatment with
5% of the 346 controls. Importantly, those exposed to long-term TPN.
McIntyre powder for 1020 years were 3.1 times more Parenterally fed infants have a higher risk for Al3
likely to score poorly on cognitive function tests. Those damage due to their immature bloodbrain barrier and
exposed Z20 years were 4.5 times more likely than kidneys. Diagnostic techniques used to evaluate bone
controls to show this effect. Thus, length of exposure to Al3 content in adults are inappropriate for infants.
this aluminum powder significantly correlates with cog- Therefore, these neonates may have more Al3 toxicity
nitive impairment. than currently recognized. For these reasons, the United
States Food and Drug Administration (US FDA) amen-
ded its regulations in 2004 to require labeling of Al3
Diseases Related to Medical Treatments content in TPN products.
that Involve Al3
There is no doubt that aluminum has made many posi- Al3-associated Mortality
tive contributions to health. For example, it increases Toxicity signs from very high Al3 exposure are fairly
efficacy in vaccines where it serves as an adjuvant that consistent across species. These include decreased ap-
enhances the bodys immune response to the active agent. petite, poor digestion with reduced bodyweight gain,
Aluminum antacids provide relief from indigestion, and disturbed mineral metabolism (low phosphate absorption,
most large urban water utilities use alum (aluminum hypercalcemia, and reduced bone mineralization), and
sulfate) to clarify their drinking water supplies. Alu- Al3 accumulation in body tissues.
minum is a useful component of phosphate binders, Some humans abuse aluminum antacid self-medi-
buffered aspirins, antimicrobials and antidiarrheals; irri- cation. To illustrate, a case history concerns a mother
gants for bladder hemorrhage and vaginal douches; who admitted to taking many 200 mg aluminum antacid
topical powders and creams for diaper rash, athletes foot, tablets each day throughout her pregnancy. Her daughter
and anorectal pruritis; and toothpastes, dental cements, had poor growth, anemia, impaired bone mineralization,
styptic pencils, cosmetics, deodorants and sunscreens. and abnormal bone development, all consistent with Al3
Aluminum is also used in alloy form for some prosthetic toxicity. Her mental development failed to progress
hip, shoulder, and knee replacements. However, in some after age 2 months and she died at age 9 years with a
individuals, repetitious usage of Al3-containing prod- neurodegenerative disease. Her brain showed marked
ucts has negative side-effects, with toxic reactions ran- cortical atrophy with focal astrogliosis of the hippo-
ging from irritation to organ failure. campus. Gestational Al3 neurotoxicity has been con-
firmed in fetuses and offspring of pregnant Al3-exposed
Al3 and Immune Reactions rats, mice, and rabbits.
Contact sensitivity to Al3 occasionally occurs, mostly Several reports in the literature have also described
after vaccination or hyposensitization therapies utiliz- Al3 toxicity from Al3-containing products used in
ing aluminum compounds. Injected aluminum hydroxide, medical procedures. For example, encephalopathy and
aluminum phosphate, or alum, either in conjunction with death have resulted from aluminum cement used for
antigen extracts or in an adsorbed vaccine, can cause bone reconstruction in otoneurosurgery and from alum
granulomas. Routine application of aluminum-containing irrigation of hemorrhaging bladders.
antiperspirants may lead to axillary eczema or rashes;
otitis externa has resulted from aluminum acetate ear- Chronic Kidney Failure
drops. Aluminum allergy is most common in pediatric
patients. In the United States, the 2005 prevalence rate for patients
with end-stage kidney failure was 514 688. Kidney failure
patients are unable to actively excrete the Al3 they
Al3 and Intravenous Feeding
absorb, and are thus prone to elevated levels of plasma
The gastrointestinal tract normally excludes much Al3 Al3, tissue Al3, and Al3-associated diseases. The latter
but it is bypassed in patients receiving long-term total include (1) dialysis encephalopathy (dialysis dementia);
parenteral nutrition (TPN). Intravenous feeding solu- (2) bone disease (mainly fractures, vitamin D-resistant
tions commonly contain Al3-contaminated ingredients, osteomalacia, and aplastic bone disease); (3) parathyroid
some at relatively high levels. Reports dating from 1982 disease; (4) microcytic anemia; (5) amyloidosis; and
Bioavailable Aluminum: Its Effects on Human Health 333
(6) kidney disease itself (as Al3 is a nephrotoxin, it can Since Alfrey et al. published their landmark paper
exacerbate kidney disease). naming Al3 as the probable cause of dialysis en-
cephalopathy, measures have been implemented to re-
Al3 and dialysis encephalopathy duce Al3 exposure in patients with chronic kidney
Kidney failure patients are unable to effectively excrete disease. These include reverse osmosis filtration to re-
phosphate. High levels of blood phosphate increase their move Al3 from dialysis fluid, avoidance of aluminum-
risk for bone disease, heart disease, and death. In the based phosphate binders, and chelation treatments. Such
1960s, aluminum hydroxide was widely prescribed as a measures have greatly reduced the occurrence of dialysis
phosphate binder to limit phosphate absorption. By the encephalopathy.
early 1970s, bone fractures and outbreaks of dialysis Deferoxamine (DFO) is a chelating agent that forms
encephalopathy (dialysis dementia) began to occur. This much stronger complexes with the trivalent metals alu-
was shown to result from high Al3 content in buffers minum (Al3) and iron (Fe3) than with calcium (Ca2)
and tap waters used for the dialysate, aluminum-based and most other metal ions. A DFO infusion test is
phosphate binders, and corrosion of aluminum com- sometimes performed in preference to routine serum
ponents in dialysis equipment. In one example of many, or plasma Al3 measurements to assess the bodys alu-
six patients undergoing hemodialysis in a Netherlands minum load. DFO therapy has been extensively used
hospital developed dialysis encephalopathy. An investi- to treat kidney patients with high Al3 burdens. Up to
gation determined the boiler used to heat their dialysis 5 mg kg1 bodyweight of parenteral DFO is sufficient to
water contained two aluminum anodes (combined weight substantially lower plasma Al3 levels, generally leading
of 32.4 kg) that completely dissolved over a 2-year period. to improvements in short-term memory and intellectual
Children dialyzed for impaired kidney function have also function.
developed encephalopathy secondary to Al3 toxicity.
In healthy adult humans, plasma Al3 levels are Al3, bone, and parathyroid diseases
usually approximately 6 mg ll and brain Al3 content The detrimental effects of aluminum in bone are com-
less than 2.0 mg g1 dry brain weight. In renal failure plex and may affect osteoblast/osteoclast coupling, dis-
patients, cognitive impairment is associated with plasma rupt the calcium/vitamin D/parathyroid hormone axis,
Al3 values greater than 60 mg ll. Dialysis encephal- and interfere with bone mineralization by inhibiting
opathy can occur with plasma Al3 levels ranging hydroxyapatite formation. Aluminum deposition in bone
between 80 and 800 mg ll. Al3 concentrations in the is associated with vitamin D-resistant osteomalacia,
cerebral cortex of dialysis encephalopathy patients are aplastic bone disease, and fractures. Patients with plasma
also high, averaging between 10 and 25 mg g1 dry brain Al3 levels greater than 30 mg l1 have increased risk for
weight. bone disease, especially osteomalacia, despite having
The clinical course for dialysis encephalopathy in- normal plasma magnesium (Mg2) and Ca2 levels.
volves: (1) a 612-month asymptomatic period; (2) loss of Even low levels of accumulated Al3 disrupt bone
short-term memory and associative learning; (3) alter- Ca metabolism. Al3 inhibits the formation of 1,25-
2
ations in muscle tone, motor control disorders resem- (OH)2-vitamin D. Precipitation of aluminum hydro-
bling motor dyspraxia; and eventually (4) myoclonic jerks xyapatite (Al(OH)2H2PO4) in bone tissue interferes
and seizures that, if left untreated, result in death. Many with the orderly, controlled deposition and dissolution
dialysis patients exhibit the early protein changes (oxi- of calcium hydroxyapatite, even at Al3 concentrations as
dation and hyperphosphorylation) that precede the for- low as 0.1 mM. Aluminum deposition in bone increases
mation of amyloid plaques and neurofibrillary tangles fragility and susceptibility to fracture. For example,
(NFTs), respectively. These are neuropathological regular usage of aluminum-based antacids increases the
hallmarks of AD. The affected brain regions in dialysis risk of a first vertebral fracture in women aged 65 or older.
encephalopathy and its animal models are basically A rat model for human osteomalacia and parathyroid
the same that are affected in AD. Some dialysis patients suppression involves kidney surgery and repeated intra-
are reported to exhibit fully formed plaques and tangles peritoneal Al3 injections (9.25 mg over 33 days). This
but these features do not consistently occur in this results in profound osteomalacia similar to the human
patient population that is generally younger than the condition characterized by unmineralized osteoid, de-
Alzheimer population and has different Al3 exposure creased bone formation, lower bone resorption, and de-
characteristics and comorbidities. To simulate Al3 levels pressed parathyroid activity.
that occur in dialysis encephalopathy, cat and rabbit Several reports describe transient stimulation by Al3
brains have been injected with Al3 into the lateral on bone growth while others show Al3 inhibits bone
ventricles. These animals exhibit a similar clinical pro- growth. These apparently contradictory observations are
gression to dialysis encephalopathy, ending in convul- reconciled by the finding that osteoblast response to Al3
sions and death. is biphasic. Cultured osteoblasts initially undergo cell
334 Bioavailable Aluminum: Its Effects on Human Health
division in response to Al3 in their growth medium. studies and histological staining for Al3 show that it is
After accumulating Al3, osteoblasts develop metabolic reabsorbed in droplet form in the proximal convoluted
abnormalities and exhibit growth inhibition. A similar tubules (Figure 1(a)). In aged kidney tissue of Al3-ex-
response occurs at the molecular level where Al3 ini- posed rats, the proximal tubule cells eventually show
tially stimulates mRNA synthesis and then inhibits it. nuclear and cytoplasmic Al3 staining in nondroplet
Likewise, in human kidney disease and its animal models, form (Figure 1(b)).
high plasma Al3 levels initially stimulate parathyroid Stained for Al3, kidney tissue from a stillborn human
activity, resulting in hyperparathyroidism. As Al3 fetus is Al3-negative (Figure 2(a) and 2(b)). In contrast,
accumulates in parathyroid cells, hypoparathyroidism a strong Al3 staining response occurs throughout the
eventually develops. Recognition of this biphasic nature deteriorated kidney tissue of an adult human who died
is important to understanding Al3 toxicity. with chronic kidney failure (Figure 2(c) and 2(d)).
Figure 1 Adult rat kidney processed with the modified Walton stain for Al3. (a) Proximal convoluted tubules show magenta droplets
indicative of filterable Al3 (arrowhead). (b) Renal cells of proximal convoluted tubules in aged rat kidney have pale pink cytoplasm
(arrowhead), indicating dispersed Al3. Some exhibit nuclei that stain pink-magenta for Al3. Scale 10 mm.
Bioavailable Aluminum: Its Effects on Human Health
Figure 2 Human kidney tissue processed with the modified Walton stain for Al3. (a) This kidney tissue, obtained from a stillborn human fetus, shows a glomerulus and surrounding tubules
that are completely Al3-negative. Blood cells in the glomerulus are aluminum-negative, staining bright turquoise (e.g., arrow). (b) Kidney tubules (arrowhead) from this fetus are also Al3-
negative. (c) Kidney tissue from an adult human who died with end-stage kidney failure. Blood cells in the glomerulus (e.g., arrow) stain bright magenta for Al3. The nuclei of glomerular cells
stain for Al3, whereas their cytoplasms are Al3-negative. (d) Kidney tubules (arrowhead) from the same patient are comprised of deteriorated cells that are entirely Al3-stained.
Scale 10 mm.
335
336 Bioavailable Aluminum: Its Effects on Human Health
Aluminum lake dyes Coloring agent for nonliquid products Cereals, snack foods, jams, margarine,
maraschino cherries, artificially colored
oranges, cake mixes, ice cream,
candies, fruit yoghurts, margarine,
vitamin pills, medicinal capsules
Aluminum maltolate Flavor enhancer Blueberry muffins
Aluminum silicates Anticaking agent Table salt, nondairy creamer, pancake
mix, cocoa mix, corn chips
Aluminum sulfate (alum), aluminum Coagulant, acidifying agent, firming agent Drinking water treatment; food dyes;
ammonium sulfate, potassium adjuvant in vaccines; baking powder
aluminum sulfate, sodium aluminum (e.g., 70 mg Al3 per teaspoon),
sulfate chocolate cake (e.g., 515 mg Al3 per
slice); free-rising flour, pickles, frozen
strawberries, candied fruits
Polyaluminum chloride Coagulant Drinking water treatment
Sodium aluminum phosphate, basic Emulsifier, easy melting, meat-binding Blue cheese, gongonzola, provolone,
agent Swiss processed American cheese
(e.g., 14 mg Al3 per 20 g slice),
luncheon meats
Sodium aluminum phosphate, acidic Leavening agent Self-rising flour; biscuit, pancake, cake,
muffin, and doughnut mixes; yeast
doughs
Aluminum hydroxide (contaminant) Infant soymilk formulas (e.g., 460
930 mg l1)
Aluminosilicate (natural contaminant) Calcium supplements from crushed
oyster shells (e.g., 12 mg Al3 per day)
Miscellaneous uses of aluminum compounds are as follows: to strengthen dough, swell pastas, bleach flour and cheeses, ingredient in reconstituted
vegetable protein, stabilizers, thickeners, texturizers, and buffers.
amounts contributed by aluminum additives. Also, car- water analysis involving water from three treatment
bonated drinks and beer are subject to Al3 contamin- plants showed inorganic monomeric Al3 accounted
ation, if stored for more than a few months in aluminum for 449% of the total dissolved Al3 in pretreatment
cans, from corrosion of the inner protective lining. For water. After polyaluminum chloride treatment, this
example, soft drink Al3 rose from 0.16 to 250 mg l1 fraction increased to 4188% of the total dissolved Al3.
when cans were stored for up to 173 days; Al3 in beer A survey of 186 water supplies showed alum-treated
increased from 50 to 547 mg l1 when cans were stored at water had a median Al3 concentration of 112 mg l1
room temperature for 5 months. compared to 43 mg l1 in drinking water without coagu-
Most large cities use rapid water filtration to clarify lant treatment. Some brands of bottled water also have a
their drinking water supply. This process requires add- high aluminum content, suggesting clarification with
ition of a coagulant. Alum and polyaluminum chloride alum treatment.
are widely used for this purpose although iron salts are Since most humans living in modern urban society
also used effectively. Coagulants clarify water by binding routinely ingest dietary Al3, and many drink alum-
to organic matter and aggregating suspended particles treated water, their tissues gradually accumulate Al3
that can harbor bacteria. This causes the particles to over time. The total body Al3 content for humans has
settle, facilitating their removal by filtration. Metal-based been estimated at 300 mg. Tissues of elderly individuals
coagulants are able to clarify (without disinfecting) the contain more Al3, presumably because of their longer
brackish drinking water available in some developing Al3 exposure. When stained for Al3, aged human
countries. hippocampal pyramidal neurons show Al3 accumulation
Before treatment, total Al3 concentrations in water either in their nucleolus, throughout their nucleus,
sources range from undetectable to more than 1 mg l1. throughout their entirety or, where present, in NFTs.
Addition of aluminum-based coagulants reduces the
total Al3 concentration while significantly increasing the
level of monomeric inorganic Al3 in drinking water, Alzheimer Disease
a form significantly more bioavailable than the poorly
absorbable aluminosilicate clay particulates and colloids AD is a condition that makes its sufferers mentally
that they effectively remove. For example, a drinking incompetent as they progressively lose self-help skills.
Bioavailable Aluminum: Its Effects on Human Health 337
were reported to have improved short-term memory with the extent of neuropathological change that
and intellectual functioning. Oral placebo and untreated occurs in these regions. At Al3 concentrations found in
controls declined twice as rapidly as the DFO-injected AD-affected brain, Al3 binds to heterochromatin of
group in performance tests of daily living skills (docu- cultured human neural cells and represses gene activity.
mented on video tape) and in the progression of their Neurons in AD-affected regions characteristically exhibit
motor dyspraxia (where one knows what one wants to do chromatin condensation and repressed or aberrant gene
but cannot control ones body to achieve it). After 5 years, activity. AD brain samples contain approximately 17
there were nine deaths in the control (non-treated) group times more aluminum per gram DNA in highly con-
and one in the DFO-treatment group. Despite these densed heterochromatin than in other cell fractions and
promising results, confirmatory trials have not been almost twice as much aluminum per gram DNA than
performed, largely due to the labor-intensive protocol. controls.
Intramuscular DFO injection of rabbits, with NFTs in- A few studies have been unable to show quantitative
duced in their brains by intraventricular Al3 injection, difference in brain Al3 content between aged humans
significantly mitigated their neuropathology compared with AD and aged nondemented controls. It has been
to controls. This experiment suggested a confirmatory suggested that this may result from technical difficulties
human trial could succeed with fewer DFO injections. involved in detecting low levels of nonuniformly dis-
tributed Al3 in a biological matrix or dissecting out
small samples that include pyramidal neurons with
Tissue Al3 Levels and AD
minimal extracellular matrix.
Plasma 26Al measurements taken after consuming a
standardized 26Al dose at either dietary or pharma-
ceutical levels have shown subjects who develop AD
Al3 Disregulation of Iron Metabolism
absorb significantly more 26Al than age-matched non-
demented controls. Consistent with these findings, six Free Al3 and free iron are both toxic to neurons.
out of seven studies in peer-reviewed journals reported Intracellular Al3 is free to participate in, and interfere
AD patients have significantly higher basal plasma or with, cellular reactions. In contrast, iron levels in neurons
serum Al3 levels than nondemented controls. The are normally controlled by iron regulatory proteins
single negative study is statistically underpowered. Thus, (IRPs) that sense the free iron concentration in cells. If
plasma or serum Al3 measurements made under con- too high, IRP-1 up-regulates the synthesis of ferritin, a
trolled conditions may be useful for predicting indi- protein that binds excess iron and allows only a small
viduals at higher risk for AD. transit pool of unbound iron to be freely available for
As the human brain ages, Al3 preferentially accu- cytoplasmic reactions. If low, IRP-2 responds by up-
mulates in large pyramidal neurons to a much greater regulating the synthesis of transferrin receptors to in-
extent than in surrounding neuropil. More than 12 crease iron uptake.
laboratories in seven countries, employing a variety of Experiments with Al3-loaded rats and Al3-loaded
analytical techniques, have reported in peer-reviewed cell cultures have shown Al3 accumulation in neurons
journals that certain brain regions of AD patients have dramatically interferes with their iron metabolism. Al3
higher Al3 concentrations than those of age-matched stabilizes IRP-2, preventing its breakdown. This pro-
controls. In AD-affected brain regions, controls typically motes the synthesis of transferrin receptors and blocks
contain 12 mg Al3 g1 dry brain weight, whereas AD the synthesis of ferritin. Such interference makes
patients have 35 mg Al3 g1 dry brain weight, and more free iron available in neurons where Al3 has
patients dying with dialysis encephalopathy have Z10 mg accumulated, thus increasing their risk for oxidative
Al3 g1 dry brain. Thus, between each of these damage. Al3 amplifies iron-initiated lipid peroxidation
categories, there is a two- to threefold difference. Al3 several-fold.
concentrations that occur in AD cortical tissue are Human brains affected by AD have disregulated
neurotoxic for laboratory cats and rabbits. Recordings iron metabolism. IRP-2 fails to degrade in neurons,
from single neurons in cat visual cortex containing 4.7 mg showing striking increase. Consequently, free iron attains
Al3 g1 dry brain weight show altered electrical spike toxic levels, causing oxidative damage via the Fenton
activity. Al3 toxicity and LD50 (lethal dose in 50% of reaction. This has been described as one of the
rabbits given an intracerebral Al3 injection), occurs earliest features of AD. 4-Hydroxynonenal and the iso-
at a brain aluminum concentration of 5.5 mg Al3 g1 prostane 8,12-iso-iPF2a-VI markers of oxidative dam-
(dry weight). In vitro, media containing between 1 and age are present at significantly higher levels in AD
50 mM Al3 are toxic to primary neural cells. brain than in control brains. Both markers have also
Al3 content is significantly higher in the temporal been identified in rodent brains after long-term low-dose
cortex than in the frontal cortex of AD brain, consistent Al3 exposure.
Bioavailable Aluminum: Its Effects on Human Health 339
Al3 Involvement in Amyloid Plaque Formation amyloid plaques in their brains after consuming a diet
supplemented by Al3 for 1 year than their transgenic
Ample published data describe Al3 involvement in
counterparts that ingest the diet without added Al3.
amyloid plaque formation:
This change is countered by vitamin E, indicating
1. Gene microarrays show Al3 up-regulates expression Al3 stimulates amyloidogenesis via a mechanism
of the gene for amyloid precursor protein (APP) in involving free radical production and oxidative stress.
primary cultures of human neural cells.
2. Nanomolar amounts of Al3 inhibit the activation of
Al3 Involvement in Neurofibrillary Tangle
protein kinase C (PKC) by 90%. This enzyme allows
Formation
APP cleavage via its nonamyloidogenic a-secretase
pathway as opposed to its b-amyloidogenic pathway. Human NFTs develop within aluminum-rich cyto-
Al3 inhibition of PKC activity can reasonably explain plasmic areas of pyramidal neurons (Figure 3(a) and
why Al3 increases b-amyloidogenesis in cultured 3(b)) located in specific brain regions including: the
neuroblastoma cells. neocortex (particularly layers II and V), hippocampal
3. Al3 accelerates the in vitro formation of an aberrant formation, entorhinal cortex, amygdala, olfactory bulb,
splicing isoform of presenilin-2 that also occurs in AD substantia nigra, basal nucleus of Meynert, dorsal raphe
neural tissue. nucleus, and locus coeruleus. These cells all have high
4. In vitro studies with circular dichroic spectroscopy densities of transferrin receptors. The same regions ac-
have shown human b-amyloid exposed to Al3 at cumulate Al3 in dialysis encephalopathy and in Al3-
brain-relevant levels becomes altered from a soluble injected rabbit brains where NFTs form.
form with random structure to a fibrillar precipitate Evidence from in vivo and in vitro studies has shown
with b-pleated structure. Al3 inhibits the activity of protein phosphatase 2A
5. Amyloid142 oligomers are stabilized by, and increase (PP2A). Inhibition of PP2A activity is an early feature of
in, the presence of aluminum. These are regarded by NFT formation in AD. Kinases add phosphates to protein
some as the most toxic form of amyloid. and PP2A is the main phosphatase in neurons that
6. Al3 induces b-amyloid fibrils to aggregate as in AD removes phosphates. Inhibited PP2A activity results
plaque formation. in hyperphosphorylation of cellular proteins (mainly
7. b-Amyloid aggregates induced by Al3 exposure stain neurofilament and microtubule-associated proteins such
with both Congo red and thioflavin S as in AD as tau). As hyperphosphorylated tau proteins accumulate,
plaques. they aggregate and polymerize to form the so-called
8. Plaque formation is species-specific but mice, trans- paired helical filaments of NFTs, which are actually
genic for human APP, develop more and larger single filaments with a twisted ribbon structure.
Figure 3 AD hippocampal neurons stained for Al3 with the modified Walton stain. (a) This pretangle neuron has a deep purple
(Al3-rich) region in its cytoplasm (arrow). Reproduced from Walton JR (2010) Evidence for participation of aluminum in neurofibrillary
tangle formation and growth in Alzheimers disease. Journal of Alzheimers Disease 22: 6572, with permission from IOS Press.
(b) Another neuron has an NFT (arrow) within Al3-rich cytoplasm. Scale 5 mm.
340 Bioavailable Aluminum: Its Effects on Human Health
E
1
A
C
B
D
E
0
0 1 2 3 4 5 6
Time after drink (hrs)
nigra and globus pallidus that normally synthesize Alzheimer A (1907) Ueber eine eigenartige Erkrankung der Hirnrinde.
and secrete epinephrine and, in particular, dopamine. Zentralblatt fur Nervenheilkunde und Psychiatrie 30: 177--179;
Allgemeine Zeitschrift fur Psychologie 64: 146147.
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ses, including head injury, encephalitic virus, exposure to Alters. Zeitschrift fur die gesamte Neurologie und Psychiatrie 4:
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, a 356--385.
Baker MN (1981) The Quest for Pure Water: The History of Water
heroin-like opiate contaminant), and certain pesticides. Purification from the Earliest Records to the Twentieth Century, 2nd
Al3 toxicity may be involved in Parkinson disease edn., vol. 1. Denver: American Water Works Association.
because some Parkinson patients develop AD-type de- Exley C, Price NC, Kelly SM, and Birchall JD (1993) An interaction
of beta-amyloid with aluminium in vitro. FEBS Letters 324:
mentia. Also, the catechol moiety of the catecholamine 293--295.
neurotransmitters epinephrine and dopamine is a po- Flaten TP (2001) Aluminium as a risk factor in Alzheimers disease,
tentially important Al3-binding site. Although epi- with emphasis on drinking water. Brain Research Bulletin 55:
187--196.
nephrine and dopamine are poor Mg2 binders at Greger JL (1993) Aluminum metabolism. Annual Review of Nutrition 13:
millimolar levels, they bind Al3 at nanomolar levels. In 42--63.
Parkinson brains, the substantia nigra and locus ceruleus Humphrey GM (1889) Old Age: The Results of Information received
Respecting Nearly Nine Hundred Persons who had Attained the Age
exhibit high Al3 and Fe3 concentrations in neurome- of Eighty Years, including Seventy-Four Centenarians. Cambridge:
lanin granules and in Lewy bodies, abnormal hallmarks Macmillan and Bowes.
of dead and dying neurons. Evidence for Al3-dis- McLachlan DRC (1995) Aluminium and the risk for Alzheimers disease.
Environmetrics 6: 233--275.
regulated iron metabolism is that neurons in relevant Miu AC and Benga O (2006) Aluminum and Alzheimers disease: A new
regions of Parkinson brains have excessively high iron look. Journal of Alzheimers Disease 10: 179201.
levels, yet fail to increase their ferritin levels. The re- Rifat SL, Eastwood MR, McLachlan DR, and Corey PN (1990) Effect
of exposure of miners to aluminium powder. Lancet 336:
sulting oxidative damage could contribute to neuronal 1162--1165.
death in the substantia nigra and other brain regions Savory J, Exley C, Forbes WF, et al. (1996) Can the controversy of the
affected in Parkinson disease. role of aluminum in Alzheimers disease be resolved? What are the
suggested approaches to this controversy and methodological
issues to be considered? Journal of Toxicology and Environmental
Health 48: 615--635.
Conclusions Walton JR (2007) An aluminum-based rat model for Alzheimers
disease exhibits oxidative damage, inhibition of PP2A activity,
In its metallic form, aluminum has conferred many hyperphosphorylated tau, and granulovacuolar degeneration.
Journal of Inorganic Biochemistry 101: 1275--1284.
benefits to modern society, even making mass air travel Walton JR (2009) Brain lesions comprised of aluminum-rich cells that
possible. However, bioavailable Al3 in the body is re- lack microtubules may be associated with the cognitive deflicit of
active, toxic, and causal to, or at least involved in, a Alzhemer disease. Neurotoxicology, doi: 10.1016/j.neuro.
2009.06.010.
number of disease conditions. Health problems associated Walton JR (2009) Functional impairment in aged rats chronically
with occupational Al3 exposure and medical treatments exposed to human range dietary aluminium equivalents.
containing Al3 products are well documented. There Neurotoxicology 30: 182--193.
are suitable non-Al3 alternatives for many of these
products. Current research indicates chronic Al3 ex-
posure, primarily from aluminum additives in the diet,
water, and other ingested or injected products, adds to the Relevant Websites
bodys Al3 burden, and contributes over time to neuro- http://books.google.com/books?id iNzG8PoyW4AC&pg RA1-
degenerative conditions. PA113&lpg RA1-PA113&dq %22tea leaves%22 and
aluminum or aluminium&source web&ots 7WxXttkJh0&sig-
C4kQk8P685KwbuBxHLmkUlwF1ns#PRA1-PA113,M1
See also: Bioavailable Aluminum: Its Metabolism and Encyclopedia of Food and Color Additives, George A. Burdock.
Effects on the Environment. http://www.usrds.org
United States Renal Data System.
Further Reading
Alfrey AC, LeGendre GR, and Kaehny WD (1976) The dialysis
encephalopathy syndrome; possible aluminum intoxication. The
New England Journal of Medicine 294: 184--188.