Aluminium has been evaluated for acceptable daily intake by
the Joint FAO/WHO Expert Committee on Food Additives on numerous
Aluminium was evaluated by the 21st Committee when an ADI of
"not specified" was established (Annex 1, reference 44). Sodium
alumino-silicate and aluminium calcium silicate were evaluated by
the 13th JECFA in a toxicological monograph on silicates (Annex 1,
reference 20) when an ADI of "no limit" (except by good
manufacturing practices) was set. Aluminium potassium sulfate and
aluminium sulfate, were reviewed by the 26th Committee in 1982
(Annex 1, reference 59). The aluminium salts of fatty acids were
considered by the 29th Committee (Annex 1, reference 70). No
toxicological monograph was prepared. Sodium aluminium phosphate
(acidic and basic) was evaluated in the 21st, 26th, 29th and 30th
JECFA reports (Annex 1, references 44, 59, 70, and 73).
Toxicological monographs were not prepared at the 29th nor 30th
At the 30th meeting, the Committee reviewed the information
available on the levels of aluminium in the diet and the data on
absorption of ingested aluminium. It was noted that: a) the
accumulation of aluminium ions was increased in individuals with
chronic renal disease; b) aluminium had been implicated in the
etiology of certain neurotoxic disorders, but definitive studies
relating diet to these conditions were lacking; and c) other
dietary factors affected the absorption of aluminium. It was
pointed out that individuals with renal impairment should restrict
their intake of aluminium. Concern was expressed that there was: a)
a lack of precise information on the aluminium content in the diet,
derived from food itself and from cooking utensils; and b) a need
for additional safety data, including absorption and metabolic
studies in man, short-term feeding studies, and a multigeneration
reproduction study. The Committee considered that if data from
adequate absorption/metabolic studies and short-term feeding
studies demonstrated that there was no bioaccumulation of aluminium
in the tissues, there would be no need for a multigeneration
reproduction study. It was recommended that aluminium (in all its
forms) be reviewed in detail at a future meeting. The Committee
considered that a temporary ADI of 0-0.6 mg/kg bw aluminium should
apply to all aluminium salts added to food.
In the current evaluation of aluminium, emphasis was placed on
estimates of consumer exposure to aluminium, absorption and
distribution of dietary aluminium, and possible neurotoxicity of
aluminium, in particular the relationship of aluminium to
Alzheimer's disease. Previous monographs on aluminium and aluminium
containing compounds in which the main toxicological concern
related to the aluminium component are incorporated in the new
As the third most abundant element, constituting approximately
8% of the earth's crust, aluminium is ubiquitous in soils, water
and air. In addition to its natural occurrence, and as a result of
its inherent chemical and physical properties, aluminium finds use
in a wide variety of applications including packaging materials,
various containers and kitchen utensils, automobile bodies and
components, airplanes and building materials. Aluminium compounds
are also used in, for example, paint pigment, insulating materials,
water treatment, drugs, cosmetics as well as food additives
(Friberg, 1986; Reilly, 1980; Havas & Jaworski, 1986).
The general population is exposed to aluminium from air, water
and food. Aluminium levels in unpolluted air are generally below
100 ng/m3 and resultant intakes would be less than 2 µg/day
(0.002 mg/day). However, in industrial areas where aluminium levels as
high as 6200 ng/m3 have been reported, intakes could reach
124 µg/day (0.124 mg/day) (Ministry of Agriculture, Fisheries and Food,
1985; Havas & Jaworski, 1986; Bowen, 1979).
Aluminium concentrations in fresh (untreated) water are
generally low i.e. less than 0.001 to 1 mg/l, although values as
high as 26 mg/l have been found in certain regions. In many
instances, elevated levels have been associated with pH values less
than 5.5 or water rich in organics. Although the use of aluminium
based coagulants in processing drinking water supplies can increase
aluminium levels above natural background content, most potable
waters surveyed recently in Europe were generally below the EEC
standard of 0.2 mg/l aluminium. The intake of aluminium from
drinking 1.5 to 2.0 l water daily containing an estimated mean
level of 0.1 mg/l ranges from 0.15 to 0.20 mg/day. While such
intakes would be representative of most individuals, it is apparent
from the levels noted above, that aluminium intakes from water
could reach as high as 5 mg/day for certain persons (Ministry of
Agriculture, Fisheries and Food, 1985; Havas & Jaworski, 1986).
Aluminium in food can derive from that which is present
naturally, that which results from aluminium-containing food
additives, and that arising from contact with Al used in food
containers, cookware, utensils and wrappings. Based on results from
more recent surveys of foods, tea, some spices and herbs (e.g.
thyme, cayenne powder), contain naturally high aluminium
concentrations. Other products, such as processed cheese, grain
products and baking powder may be high in aluminium if they contain
aluminium-based food additives. Although aluminium-containing
cookware, utensils and wrappings can increase amounts of this
substance in foods, particularly if the foods are acidic, basic or
salty, studies to date have shown that aluminium contamination from
this avenue is generally too small to be of practical importance.
Nevertheless, such studies have highlighted that adverse impact of
aluminium on the vitamin C content of foods cooked in aluminium
saucepans (Ministry of Agriculture, Fisheries and Food, 1985; Havas
& Jaworski, 1986; Sorenson et al., 1974).
Daily dietary aluminium intakes have more recently been
estimated to range from about 2 to 6 mg/day for children and from
about 6 to 14 mg/day for teenagers and adults. The major
contributors to these dietary aluminium intakes are grains and
grain products, dairy products (i.e. milk, cheese and yoghurt),
desserts and beverages. Consumption of other foods containing
elevated aluminium levels (e.g. spices and herbs, pickled
cucumbers) can also dramatically increase dietary aluminium intakes
(Ministry of Agriculture, Fisheries and Food, 1985; Havas &
Jaworski, 1986; Sorenson et al., 1974).
Finally it is important to recognize that use of certain
aluminium-containing non prescription drugs (e.g. Antacids) can
increase daily aluminium intakes by a factor of 10 to 100 (Havas &
In summary, the intake of aluminium from air, even in
industrial areas, is minor relative to that from food. Although
water does not contribute significantly to the total aluminium
intake from all sources for most individuals, elevated aluminium
levels have been found in certain areas and resultant aluminium
intakes can be as high as the dietary contribution. Aluminium
intake from foods, particularly those containing aluminium
compounds used as food additives, represents the major route of
aluminium exposure by the general public excluding persons who
regularly ingest aluminium-containing drugs.
Absorption, Distribution, Metabolism, and Excretion
Due to formation of insoluble aluminium phosphate (AlPO4) in
the gastrointestinal tract, only a minor amount of orally
administered aluminium-salts is absorbed (Jones, 1938; Kirsner,
Aluminium is primarily absorbed in the gastrointestinal tract
where it is only slightly permeable. The relationship of aluminium
dose ingested to dose absorbed has been examined in mass balance
studies. A homeostatic mechanism appears to regulate aluminium
absorption; at some point between 125 and 2000 mg aluminium/day,
this mechanism is perturbed and measurable quantities of aluminium
can cross the intestine (Skalsky & Carchman, 1983). The percentage
of net absorption of food aluminium may be on the order of 1% of
the administered dose and at very high doses the uptake mechanisms
may become saturated (Brusewitz, 1984).
Groups of 10 mice received a standard diet containing 170 ppm
or 355 ppm aluminium (as aluminium sulfate). There was no
significant difference in intake of water, but food intake was
significantly less in the group receiving the higher dose.
Aluminium balance was studied during the last six days of the test.
Intake and faecal excretion of aluminium was significantly higher
at the higher dose whereas urinary excretion and retention of
aluminium were not. In another study, aluminium balance was
measured in eight rats on diet containing 2835 ppm aluminium (as
sulfate) for a further eight days. The increased dose rate of
aluminium resulted in a reduction of food intake (20 to 15
g/rat/day) and a reduction in average body weight. Aluminium
excretion was increased significantly in the higher dose group.
About 70% of the dose was excreted in the faeces. Retention was
increased 20 times (Ondreicka et al., 1966).
Two groups of rats were maintained on diets containing 180 ppm
or 2835 ppm aluminium (as sulfate for 26 days). Analysis of tissues
for aluminium content, showed significantly increased retention in
liver, brain, testes, blood and femur of rats in the higher test
group (Ondreicka et al., 1966). In these balance studies with
mice 25-30% retention was found (Ondreicka et al., 1966) whereas
10% absorption is reported after aluminium treatment in rats
In one study in rats, doubling the aluminium content of the
diet resulted in increased fecal excretion, but there was no
increase in urinary excretion or significant retention of aluminium
in the tissues. When male Wistar rats were maintained on diets
containing 170 ppm of aluminium for 8 days, followed by 8 days on
a diet containing 2835 ppm aluminium (as the sulfate), the very
large increase in dietary aluminium resulted in an increase in
tissue deposition, primarily in bone and liver (Ondreicka et al.,
1966). In other studies with rats and mice fed or intubated with
aluminium compounds (aluminium sulfate, aluminium chloride, aluminium,
hydroxide) at dose levels equivalent to 150-200 mg aluminium/kg
bw/day, the fluoride and phosphate levels in the diet were
important factors in retention of aluminium salts (Ondreicka et
The effect of vitamin D and aluminium chelators (lactose and
tomato) on uptake of aluminium chloride from drinking water was
assessed in male Wistar rats (65-100g) over a period of 28 days.
Rats were allocated (n = 6 or 7) to one of the following groups:
control; subcutaneous (SC) aluminium hydroxide, 5 mg/day; oral
aluminium chloride; oral aluminium chloride with vitamin D, 50 IU;
oral aluminium chloride with 7% lactose and 5% desiccated tomato.
Due to avoidance and toxicity, aluminium, initially at 1% in the
drinking water, was reduced to 0.1% and then increased to 0.5% for
the last 18 days. Water intake was 20% lower in the aluminium
chloride groups and growth was impaired. Control groups or rats
administered aluminium hydroxide showed normal growth. Brain,
liver, heart, muscle, and bone were analyzed by atomic absorption
spectrophotometry for aluminium, calcium, and potassium. Rats fed
only aluminium chloride showed the greatest increase in aluminium
accumulation in bone (375% of control) followed by liver, heart,
and muscle (180-120% of control); brain aluminium content was not
different from control. Oral aluminium chloride increased brain
calcium content by 50% and decreased calcium and potassium content
of muscle by 40% and brain potassium levels by 50%. Rats fed
vitamin D and aluminium chloride had increased aluminium content in
heart, muscle, liver and bone. Brain aluminium content was
decreased below that of saline controls. The aluminium chelators
had variable effects on tissue aluminium content, increasing
aluminium in the heart and muscle while decreasing aluminium in
liver and bone when compared to aluminium alone. Rats administered
aluminium hydroxide SC had increased aluminium in all tissues,
excluding the brain. Calcium and potassium tissue content were
variably effected by the presence of aluminium, vitamin D, or
chelators (Anthony et al., 1986).
Young adult male Sprague-Dawley (SD) rats were dosed daily by
gastric intubation with 100 mg aluminium/kg as either aluminium
hydroxide (9 wk) or aluminium citrate (4 wk) with citric acid
(4 wk) or with tap water (control, 9 wk). At the end of the test
period several regions of the brain (cerebral cortex, hippocampus,
cerebellum) and samples of bone from each rat were analyzed for
aluminium. No significant increase in aluminium concentration was
observed in the tissues of the rats receiving aluminium hydroxide.
Rats treated with aluminium citrate showed a significant increase
in aluminium levels in all regions of the brain studied, as well as
in the bone (Slanina et al., 1984).
Absorption of aluminium along pathways for essential metals
was tested in rat small intestine perfused in situ with 0, 10,
15, 20, and 25 mM aluminium chloride and 5 mM Fe(II) or Fe(III)
chloride (pH 3) alone or in combination. Intestinal absorption and
luminal disappearance of aluminium was measured by sampling
perfusate and systemic and portal blood. Atomic absorption
spectrophotometry was used to detect aluminium and iron. There were
no morphological differences in the intestinal walls of test rats
or saline perfused or non perfused control rats. Fe(II) chloride
enhanced the luminal disappearance, the effect being greatest at
45 min and with lower aluminium concentrations. The appearance of
aluminium into systemic and portal blood was immediate and most
pronounced at higher aluminium concentrations. Fe(III) chloride had
no effect on luminal disappearance or absorption of aluminium. The
authors previous conclusions that intestinal absorption of
aluminium was biphasic and increased with concentration and low pH
were confirmed (Van Der Voet & DeWolff, 1987).
The effect of vitamin D on aluminium absorption and tissue
retention was evaluated in SD weanling rats (sex not given). Four
groups of 4 rats were administered vitamin D (16 ng/kg/day),
vitamin D plus aluminium hydroxide (160 mg aluminium), vitamin D
plus aluminium citrate or water by gavage for 10 days. Blood
cerebral cortex, hippocampus, cerebellum, and left femur were
sampled for aluminium determination by atomic absorption
spectrophotometry. The aluminium content of the hippocampus from
rats receiving vitamin D plus aluminium hydroxide (162 +/- 150 µg)
or vitamin D plus aluminium citrate (136 +/- 70 µg) was greater
than rats receiving only vitamin D or water (2.7 g): hippocampal
aluminium was not determined in rats receiving aluminium alone.
Aluminium content of other tissues was not different among groups
(Santos et al., 1987).
The effects of aluminium cookware and the form of aluminium on
aluminium absorption and tissue retention was assessed in 13-week
old male SD rats. Rats (number not given) were intubated 3 times a
week for 10 weeks with either aluminium hydroxide (100 mg
aluminium/kg bw) with or without citric acid, aluminium citrate
(100 mg aluminium/kg bw), citric acid, or tap water. Aluminium
concentration of cortex, femur and blood were determined by atomic
absorption spectrophotometry. Aluminium concentration of bone,
blood or brain from rats fed aluminium citrate or aluminium
hydroxide with citric acid was increased above water or citric acid
controls (blood aluminium values for citric acid fed rats were not
given). A sub-group of older rats were gavaged 3 times/week for 11
weeks with 0.8 ml of black currant soup/kg bw from aluminium (17 mg
aluminium/L) or stainless sauce pans (0.4 mg aluminium/L). There
was no difference in aluminium accumulation in brain or bone in
either group (Slanina et al., 1985).
Increased concentrations were found in liver, brain, testes,
femur, and blood (Ondreicka et al., 1966), while also increased
bone concentration was observed in uremic rats (Thurston et al.,
Ingested aluminium is mainly excreted in faeces, but the
urinary aluminium concentration is also increased after aluminium
treatment (Ondreicka et al., 1966). Although 75-90% of an oral
dose of aluminium was reported to be excreted in the faeces,
however, urinary excretion is the major excretory route once
aluminium enters the blood stream (Skalsky & Carchman, 1983).
Studies in man
Men were fed biscuits containing alum phosphate baking powder
(ca 8%) in addition to normal dietary items, and blood and urine
samples collected two, four, six and eight hours after the meal.
Aluminium was frequently found in blood of control men (trace -
0.1 mg/100 ml), and ingestion of the aluminium rich diet caused
occasional slight increase of levels of aluminium in the blood.
Urine of man before and after ingestion of the aluminium rich diets
only contain small amounts of aluminium (less than 0.5 mg excreted
in 26 hours) (Underhill et al., 1929). Elevated serum aluminium
levels was reported in 2 out of 6 patients (with chronic renal
failure) ingesting 3-6 g aluminium hydroxide a day (Berlyne et
Aluminium antacids may cause inhibition of intestinal
absorption of phosphorous and this may be followed by an increase
in calcium loss. The effect is probably due to the binding of
dietary phosphorous in the intestine by the aluminium. This effect
was not observed when phosphorous-containing aluminium salts were
used (Spencer & Lender, 1979).
A 40 day balance study was carried out with 8 adult males. Two
levels of aluminium were fed, 5 mg/day for 20 days (control) and
125 mg/day for 20 days (test diet). The subjects excreted 74% and
more than 90% of the aluminium intake in feces, when fed the test
and control diets. Aluminium excretion in urine increased two to
five fold in individuals fed test diets. Significantly higher
levels of aluminium were also observed in sera of these
individuals. The combined fecal and urinary excretion of aluminium
accounted for all the ingested aluminium (Greger & Baier, 1983).
Normal subjects were administered aluminium hydroxyde gel for
28 days (total dose/day = 2.5 g aluminium), Analyses of feces and
urine showed almost complete recovery of aluminium in the feces.
There was no detectable aluminium in urine, in the period prior to
dosing, and urinary excretion was either undetectable, or detected
to a maximum value of about 2 mg/day. It appeared that there was no
significant absorption of aluminium. There was no change in calcium
balance. Phosphorous balance changed in a positive direction during
the test period (Camn et al., 1976). in contrast, in a study in
which patients with chronic renal disease were given a daily dose of
aluminium hydroxide (equivalent to 1.5 - 3.4 g aluminium) for 20-32
days, 100-568 mg of aluminium was absorbed daily, based on fecal
excretion of aluminium. No aluminium was detected in the urine at
quantities greater than 1 mg/day. Plasma aluminium was only
slightly increased during the test period. There was no significant
change in calcium balance, and phosphorous balance became more
negative. Some of the absorbed aluminium was deposited in bone
(Clarkson et al., 1972).
The metabolic balance of aluminium was studied in individuals
on controlled diets (about 5 mg aluminium/day) either unaltered or
supplemented with aluminium hydroxide (equivalent to 2.5 g
aluminium/day). Most of the ingested aluminium was excreted in the
faces. However, an increase in urinary excretion of aluminium
(approximately 3x) occurred during the period of aluminium
supplementation. However the total amount excreted by this route
did not contribute significantly to the total excretion. There was
some retention of aluminium during the test period (Gorsky et
The role of biliary excretion was examined in 6 patients with
T-tube drainage of the common bile duct following biliary surgery.
All patients had normal hepatic and renal function. Patients were
given 30 ml of an aluminium hydroxide antacid (7.2 g aluminium
every 4 hours). Urine and bile samples were taken at 24 and 48
hours. All samples were elevated by 5 fold following aluminium
ingestion (Nutrition Reviews, 1987).
Plasma and urinary aluminium were measured by flameless atomic
absorption spectrophotometry in 13 healthy adults before and
following ingestion of 2.2 g of aluminium, administered as
aluminium hydroxide, aluminium carbonate, aluminium phosphate or
dihydroxyaluminium aminoacetate, between meals. Three days after
aluminium ingestion plasma levels were increased by 3-11 µg
aluminium/L. The cumulative increase in urinary aluminium excretion
over 3 days was 123-1,430 µg. Of the aluminium compounds tested,
aluminium phosphate was minimally absorbed followed by aluminium
carbonate, aluminium hydroxide and dihydroxyaluminium aminoacetate
(Kaehney et al., 1977).
Influence of aluminium on metabolism of phosphorous
Groups each of 10 mice were maintained on a diet containing
160 ppm or 355 ppm aluminium (as the chloride) for a period of 40
days, and the phosphorous balance studied during the last six days.
At the high dose level, phosphorous retention was significantly
lowered, and on some days was negative. The concentration of
phosphorous in the liver and femur, was not significantly affected.
In another study eight rats were maintained for eight days on a
standard diet, and then another eight days on the diet plus
2665 ppm aluminium as the sulfate.
Addition of aluminium to the diets resulted in decreased food
intake, and a reduced excretion of phosphorous in the urine.
However, the excretion of phosphorous in the feces was increased
(Ondreicka et al., 1966).
Rats were dosed with n single oral dose of aluminium chloride
(188.2 mg/kg bw), and then with 32p labelled Na2H32PO4. The
distribution of radioactivity was measured in test and control
animals. There was significant decrease in incorporation of 32p
into blood and all tissues examined. Further studies in which rats
were administered aluminium chloride daily (36.5 mg/day) for a
period of 52 days, or by a single intragastric dose, each treatment
being followed by the i.p. injection of 32p labelled sodium
phosphate showed that where as the specific activity of the soluble
phosphorous fractions isolated from kidney, spleen and liver was
not affected by either chronic or acute intoxication, the
incorporation of 32p into phospholipids, RNA and DNA fractions was
significantly decreased. In another study the influence of
chronically administered aluminium chloride (55 days at 36.5 mg of
223 mg aluminium/kg as the chloride on day 56 of the study), on the
blood serum level of AMP, ADP and ATP of rat, showed that aluminium
chloride caused an increase of AMP, ADP and a decrease of ATP
(Ondreicka et al., 1966).
Effects on enzymes and other biochemical parameters
Liver homogenates prepared from the livers of rats fed 150 to
300 mg/kg/day bw of aluminium sulfates or hydroxide, showed a
marked decrease in oxygen consumption when compared to liver
preparations from control animals (Berlyne et al., 1972).
Rats treated with aluminium chloride (AlCl3) (200 mg
aluminium/kg bw incorporated in the diet) showed a decrease in
glycogen content of liver and muscle after 18 days exposure. Lactic
acid was simultaneously increased in these organs, like pyruvic
acid in the liver and blood. The co-enzyme A content of the liver
was lowered (Kortus, 1967).
Aluminium salts are reported to interfere with the absorption
of glucose from the GI-tract (Gisselbrecht et al., 1957).
In vitro studies showed a dose-related inhibition of the
conversion of citric acid to alpha-ketoglutarate (Kratchovil et
al., 1967), while the decarboxylation of pyruvic acid was
increased by aluminium (Langenbeck & Schellenberger, 1957),
Aluminium-nitrate did not decrease adenylcyclase and
phosphodiesterase activities in rat cerebellum homogenates
(Nathanson & Bloom, 1976).
In another study on the effect of aluminium hydroxide on the
mineral metabolism of rats, weanling male SD rats fed semi-
synthetic diets containing 0, 257 or 1075 µ8 aluminium/g diet had
no effect on growth and feed efficiency of the test animal. However,
animals in the high dose group had significantly lower body weights
than controls. Animals fed test diets accumulated significantly more
aluminium in tibias, kidneys and liver than controls, but there was
no significant difference between the levels of aluminium in these
tissues in animals fed diet containing either 257 or 1075 µg
aluminium/diet. The reported levels of aluminium in the tibias were
11.3, 10.40 for the 257, 1075 µg/g aluminium diet groups and 4.04
and 3.13 µg aluminium/g for the two control groups. The breaking
strength of bones from animals fed the 1075 µg aluminium/g diet was
less than that of animals in the other test groups. The
concentration of phosphorous, calcium, magnesium, zinc, iron and
copper in tissues was not affected in the low aluminium dose group,
but some changes were observed at the high aluminium dose level
(Greger et al., 1985).
Salt Species Route LD50 mg/kg References
AlCl3 Mouse Oral 3800 Ondreicka et al., 1966
AlCl3 Rat Oral 3700 Spector, 1956
AlCl3 Rat Oral 1100 Berlyne et al., 1972
AlCl3 Rat i.p. 1500 Berlyne et al., 1972
Al2(SO4)3 Mouse Oral 6200 Ondreicka et al., 1966
Al(NO3)3 Mouse i.p. 320* Hart & Adamson, 1971
Al(NO3)3 Rat i.p. 320* Hart & Adamson, 1971
Al(NO3)3 Rat Oral 4280 Spector, 1956
AlOH Rat i.p. 1100 Berlyne et al., 1972
AlSO4 Rat Oral 1500 Berlyne et al., 1972
AlSO4 Rat i.p. 1100 Berlyne et al., 1972
*Ten daily injections, 30 days observation period.
Groups each of 40 mice equally divided by sex were fed diets
containing bread leavened with aluminium (2.07 or 4.1 g aluminium/
100 g bread) as aluminium phosphate baking powder for a period of four
months. The groups fed bread leavened with aluminium salt developed
serious lesions of the digestive tract. Consumption of very large
doses of the aluminium salts was associated with ovarian lesions and
reproductive failure (Schaeffer et al., 1928).
Aluminium hydroxide was not carcinogenic after daily
intraperitoneal administration to mice for 4 months at dosages up to
about 200 mg aluminium per kg per day (Kay & Thorton, 1955).
Feeding 6-10 mg aluminium/day to a group of six rats for four
weeks caused an impairment of growth at three and four weeks. Animals
supplemented with 0.1% Na2HPO4 showed a normal rate of growth. No
histological abnormalities were found in liver, kidney and heart, but
rachitic changes were observed in animals not supplemented with
phosphorous. In 3/4 out of nephrectomized rats receiving the same
amounts of Al(OH)3, an increase of aluminium in bone was found
(Thurston et al., 1972).
Groups of five rats which were normal or had 5/6 nephrectomy
(total one side, 2/3 other side), were administered drinking water
containing 1 or 2% aluminium sulfate (equivalent to 150-375 mg
aluminium/kg/day), In the case of the nephrectomized animals, all
animals receiving 1% Al2(SO4), died within eight days, and those at
the 2% level within three days. The clinical syndrome included
periorbital bleeding, lethargy and anorexia. None of the normal rats
on the test died during this period, but periorbital bleeding occurred
in 3/5 rats (Berlyne et al., 1972).
Aluminium nitrate was administered in the drinking water of four
groups of 10 female SD rats for one month at the following doses: 0,
375, 750, or 1500 mg/kg bw/day. Food and water consumption and urine
volume were measured daily. Body weight and protein efficiency
coefficients were calculated each week. On days 10, 20, and 30, blood
was analyzed. At necropsy various tissues were sampled, examined
histopathologically, weighed and aluminium content determined by
atomic absorption spectrophotometry. Rats fed 1500 mg aluminium/kg
bw/day excreted less urine (6 ± 2 ml) than control rats (35 ± 14 ml).
There were no significant differences in relative organ weights
between treated and control rats. Blood parameters were unchanged by
aluminium treatment. Although tissue aluminium concentration was
generally higher in treated animals the increases were only
significant for spleen, heart, stomach and small and large intestine
in rats receiving the highest aluminium concentration (Gomez et al.,
The effects of oral ingestion of 5700 ppm aluminium nitrate in
drinking water was examined in male Wistar rats (120-140g) for three
months. Animals were observed for body weight gain, blood chemistry,
organ weights, histopathology and aluminium accumulation (by atomic
absorption spectrophotometry). Aluminium was non-toxic over the period
of this study. Aluminium accumulation was significant in the pancreas,
liver kidney, gall bladder and lung; there was no accumulation in the
brain (Llobet & Domingo, 1985).
Male SD rats (approximately 300 g bw) were maintained for 28 days
on diets containing two formulations of sodium aluminium phosphate or
aluminium hydroxide, or a basal diet. The resultant daily aluminium
doses for respective treated groups were 67, 141, 288 and 302mg/kg/
day. During the study period there was no effect on body weight
gain, and food and water consumption. Hematological and clinical
chemistry parameters showed no compound related effects. At autopsy,
organ weights were smaller, and histopathological findings were
similar in control and test animals. Aluminium deposition was measured
in femurs. Extensive precautions were taken to avoid and contamination
of the tissue at necropsy and during sample preparation. Aluminium
levels were less than or equal to 1 ppm i.e. between the lower limit
of detection and the limit of quantification. There was no effect on
the deposition of aluminium in bones in any of the treated groups
(Hicks et al., 1986).
Weanling male SD rats were fed diets containing no added
aluminium, or aluminium lactate, aluminium palmitate, aluminium
phosphate or aluminium hydroxide. The level of aluminium in these
diets was 14, 271, 272, 262 and 268 mg/g diet. In one study the diet
was only marginally adequate in Zn, Cu and Fe. After 18 days on the
test diet, the animals were killed, and the tibia, kidney and brain
prepared for aluminium analysis. Levels of P, Ca, Mg, Fe, Zn, Cu were
also measured in the tibia, liver and kidney. In the first study
(marginal with in respect to dietary zinc, copper and iron), rats
showed an increase in aluminium levels in tibia, brain and kidney, the
effect being most marked in the aluminium hydroxide group. In another
study in which adequate amounts of Zn, Cu and Fe were present the
animals were fed various types and levels of aluminium hydroxide
namely aluminium hydroxide reagent grade (268 µg/g/diet) and aluminium
hydroxide dried gel (at 261 or 205 mg aluminium/g diet). The form of
aluminium hydroxide did not effect accumulation of aluminium in the
tissues. Rats fed 206 µg aluminium/g diet accumulated less aluminium
in their tibias and more aluminium in the kidneys than rats fed 261 or
268 µg aluminium/g diet. The presence of aluminium in the diet had no
effect on tissue levels of calcium, magnesium and iron, and only minor
effects on tissue levels of phosphorous, zinc and copper (Greger
et al., 1985).
Sodium aluminosilicate, used as a desiccant, was tested in a 30
day feeding study to assess the toxic effects of accidental ingestion.
Twenty rats (10 of each sex) were dosed with sodium aluminosilicate at
1, 3, and 10 percent in the diet; controls were a non-treated group
and a group fed 10% of a non-nutritive high salt material. The treated
groups did not differ from the group fed the non-nutritive high salt
diet; these groups differed from the non-treated group in the same
manner indicating changes were a result of lack of nutritive value of
the diet. Primarily these differences were increased water
consumption, urinary volume, and pH, as well as a related decrease in
urine specific gravity, and decreased body weight. In a few rats
(males and females) fed high and intermediate doses of sodium
aluminosilicate, interstitial nephritis and slight urinary bladder
changes (transitional epithelial hyperplasia and grossly yellow
pustules) were observed while changes in the low dose group were minor
(Mellon Institute, 1974).
Ten Harlan-Wistar rats (900-120 g each, sex not given) were
administered a single oral dose of 32 g/kg (the maximum stomach
capacity) of sodium aluminosilicate as a 50% suspension in 0.25%
semi-solid agar by stomach intubation to assess possible deleterious
effects of accidental ingestion of desiccant wafer. There was no
effect on good weight gain. The pathologist considered gross
observations of edema and blanching were not representative of any
specific lesion; there were no remarkable micropathological findings
on tissues taken 14 days after dosing (Mellon Institute, 1974a).
The dietary toxicity and bone aluminium accumulation following
ingestion of 5, 67, 141, 288 mg aluminium/kg bw as basic sodium
aluminium phosphate, or 302 mg aluminium/kg bw as aluminium hydroxide
by male SD rats (25/group) for 28 days was investigated. Animals were
observed for general appearance and behavior, body weight, food and
water consumption throughout the testing period; these parameters were
not altered by aluminium. At the completion of the study 15 rats/group
were necropsied, blood was sampled, organs weighed and examined
histologically. Femurs were collected and analyzed (5 animals/group)
for aluminium content by atomic absorption spectrophotometry; some
rats were allowed to recover for 2 months before femurs were
collected. Aluminium treatment had no effect on hematology, blood
chemistry or tissues sampled. Aluminium levels in the femur at the end
of the study were not altered by dietary treatment and were usually
below the limits of detection. Femurs from "recovered" rats were not
analyzed (Hicks et al., 1987).
Rabbits (2-3 kg each, sex not given, 1/treatment group), fasted
for 24 h, were administered powdered, crystalline, or pelletized
sodium aluminosilicate (32, 16, 5, and 1 g/kg) in semi/solid agar or
in 1 gm gelatin capsules by gastric intubation. Sodium aluminosilicate
caused slight blanching and moderate edema of the inner stomach wall
without remarkable micropathology when examined either 1 or 2 hours
following ingestion (Mellon Institute, 1974a).
Neurotoxicity of intraventricular infusion of 20 µl aluminium
tartrate (saline, 1 µM, 2 µM, 3 µM) was assessed in male and female
2-day old New Zealand white rabbits. Animals were observed for body
weight, behavior (by step-down active avoidance task), anatomical
analysis, electron microscopic analysis, and dendritic analysis.
Rabbits receiving 3 µM aluminium tartrate showed an increase in errors
during retention of the behavioral task; however, only four animals
were tested and testing was performed 6 days earlier than in other
groups due to high mortality in the group. Neurofibrillary tangles
were observed in animals receiving 1 µM aluminium and greater (Petit
et al., 1985).
Sodium aluminosilicate, used as a desiccant, was tested in a 30
day feeding study in dogs to assess the toxic effects of accidental
ingestion. Six dogs (3 of each sex) were dosed with sodium
aluminosilicate at 1, 3, and 10 percent in the diet; controls were a
non-treated group and an equi-ion group fed 10% of a non-nutritive
high salt material. Dogs fed the highest dose exhibited changes
similar to those for the equi-ion control; the degree of change
decreased with the level of the diet. The differences noted were
primarily increased water consumption, urinary volume, and pH, as well
as a related decrease in urine specific gravity. Body weights were
also depressed. Dogs fed the highest dose of sodium aluminosilicate
exhibited some changes that were greater than the comparable equi-ion
control or non-treated control animals. These primarily were:
decreased kidney weight of the females, increased white blood cell
count and blood urea nitrogen of both sexes, increased monocytes and
decreased eosinophils of both sexes (high and intermediate dose groups
affected), decreased body weight change for both sexes. Dogs fed the
lowest sodium aluminosilicate diet showed minor changes; therefore,
the testing facility considered that 0.5% would be without deleterious
effect (Mellon Institute, 1974).
Sodium aluminium phosphate (acidic) was administered to beagle
clogs for 189 consecutive days at dietary levels of 0, 0.3, 1.0 or 3%.
Each dose group consisted of 6 males and 6 females. The food intake of
all female test groups were sporadically lower than the control group,
but no statistically significant differences in weekly mean body
weights were evident between male and female test groups and their
respective controls. There were no treatment-related effects seen in
blood chemistry, haematology, urinalysis, or in ophthalmic and
physical examinations. Gross necropsy and micropathological findings
did not show any significant toxicological effects. There was very
mild renal tubular mineralization in both test and control groups with
no significant difference in the frequency of occurrence or the degree
of mineralization in the various groups (Katz, 1981).
No adverse effects on body weight and longevity were observed in
mice (54 males and females per group, Charles River CD strain)
receiving 0 or 5 ppm aluminium (as potassium sulfate) during lifetime
936 ± 49 days). No details on histopathology are available (Schroeder
& Mitchener, 1975a). A more lengthy final progress report of these
experiments was obtained from the authors of this study. The new
report provided histopathology reports; there was no evidence for an
increase in tumor incidence related to the administration of potassium
aluminium sulfate (US FDA, 1979).
Two groups of rats (Long Evans, 52 of each sex) received 0 and
5 ppm aluminium (as potassium sulfate) in drinking water for 1064 ± 20
days. No effects were found in body weight, average heart weight,
glucose, cholesterol and uric acid level in serum, protein and glucose
content and pH of urine. The life span was not affected. The number of
male rats with tumors was significantly increased (Schroeder &
Mitchener, 1975b). Further evaluation of a more lengthy report
(obtained from the investigators) of these experiments indicates that
there was no evidence for an increase in tumor incidence related to
the administration of potassium aluminium sulfate (US FDA, 1979).
Special Studies on Teratogenicity and Reproduction
Groups each of 40 mice equally divided by sex were fed diets
containing bread leavened with either yeast, or aluminium phosphate or
alum. The presence of aluminium leavened bread in the diet resulted in
a decreased number of offspring, as well as development of ovarian
lesions (Schaeffer et al., 1928). In another study groups mice were
fed bread with yeast plus 4% physiological saline mixture or 13%
saline mixture, or bread with alum phosphate baking powder (4.4%
aluminium plus 4% saline mixture) or bread with alum phosphate powder
(1.3% aluminium) for a period of 4 months. The presence of
aluminium-treated bread resulted in a decreased number of offspring,
as well as increased mortality of offspring during the first week of
life. The ovaries of these animals contained a large number of atritic
follicules, and were greatly reduced in size (Schaeffer et al.,
The maternal and fetal toxicity and tissue aluminium accumulation
resulting from aluminium chloride administered during days 716 of
gestation was assessed in 40 female BALB/c mice. Mice were mated
(pregnancy rate not given) and allocated (no. of mice/group was not
given) to the following groups: saline; 100, 150, or 200 mg aluminium
chloride/kg/day administered intraperitoneally; 200 or 300 mg
aluminium chloride/kg/day administered by oral gavage. Mice were
cervically dislocated on day 18 and maternal liver, fetuses, and
placental tissues were weighed and analyzed for aluminium
concentration by electrothermal atomic absorption spectroscopy on oven
dried samples. All dams given 200 mg/kg/day i.p. died on day 10 of
gestation. Maternal liver aluminium content was significantly elevated
in dams administered 150 mg/kg/day i.p. (the one maternal liver
available in the 100 mg/kg/day group had elevated aluminium content).
Aluminium content in placentas or fetuses from treated dams was
significantly higher than those from control dams when aluminium was
administered IP; however, no dose response was evident. Administration
of oral aluminium had no effect on aluminium content of maternal liver
or fetal or placental weight; aluminium content of placenta or fetus
were slightly elevated and exhibited no dose dependency. The number of
resorptions was increased in all dams given aluminium in a dose
dependent manner (no statistics were performed, the number of animals
and litters were small) (Cramer et al., 1986).
Mice fed aluminium chloride in drinking water at levels averaging
19.3 mg aluminium/kg/day for three generations exhibited no
deleterious effects on reproduction and no histopathologic changes in
the liver, spleen, or kidney in the first litter. No hematologic
effects were detected. However, doubling the dose of aluminium reduced
growth rate in second and third generation offspring (Ondreicka
et al., 1966).
Groups each of 24 rats were maintained on diets containing SAS
powder (a mixture of sodium aluminium sulfate and calcium acid
phosphate) at dietary levels equivalent to approximately 0, 0.15%,
1.8% or 0.44%. Some of the test animals were bred for seven successive
generations. The SAS had no effect on reproductive performance as
measured by number of offspring, average birth weight, average weaning
weight and number weaned. Histopathologic examination of kidneys of
rats that survived 21 months on the diet did not reveal any
significant changes (Lymann & Scott, 1930). No untoward effects were
noted in other rat studies in which diets containing aluminium
chloride or a baking powder containing aluminium sulfate (about
80-500 mg/kg/day) were fed for period of 2 to 8 months (Scott &
Helz, 1932, McCollum et al., 1928).
In another study, groups each of 24 rats were maintained on diets
containing SAS powder (a mixture of sodium aluminium sulfate and
calcium acid phosphate) at dietary levels equivalent to approximately
0, 0.15%, 1.8% or 0.44%. Some of the test animals were bred for 7
successive generations. The SAS had no effect on reproductive
performance as measured by number of offspring, average birth weight,
average weaning weight and number weaned. Histopathologic examination
of kidneys of rats that survived 21 months on the diet did not reveal
any significant changes (Lymann & Scott, 1930).
SD rats (240-280 g) were dosed with aluminium nitrate nonahydrate
(0, 180, 360, 720 mg/kg/day) intragastrically for 60 days (males) or
14 days (females) prior to mating and then throughout mating,
gestation, delivery and lactation. One half of dams were sacrificed on
day 13 of gestation and examined for number of corpora lutea, total
implantations, viability of fetuses and resorptions. Remaining dams
delivered normally and offspring were sacrificed and organ/body weight
was calculated for the heart, lungs, spleen, liver, kidneys, brain and
testes. Survival of adult rats was unaltered by aluminium ingestion.
Pregnancy rate was similar for all groups. There was a decrease in the
number of corpora lutea in the highest aluminium dose group (14.5 vs
18.2 for control). All other reproductive parameters were not
significantly different. The initial mortality was 18% for rats in the
720 mg/kg/day group and was lower (0-2%) in all other groups.
Mortality increased with aluminium concentration and this effect was
more prominent over time of lactation. The number of dead young/litter
was statistically higher in the highest aluminium group on days 1, 4,
and 21 of lactation. Initially body weight and length and tail length
in the high aluminium group were decreased; however, this was
corrected with time. There was no significant difference between
control and treated groups with respect to organ/body weight ratios
(Domingo et al., 1987).
Orally administered sodium aluminium sulfate was not teratogenic
at levels up to 352 mg/kg in pregnant mice (day 6 through day 15 of
gestation) and up to 191 mg/kg in pregnant rabbits (day 65 through day
18 of gestation). There was no discernable effect of the compound on
implantations, resorptions, fetuses, mortality, body weight,
urogenital tract or congenital abnormalities (Food and Drug Research
Sodium silicoaluminate showed no evidence of teratogenicity after
oral administration at levels up to 1600 mg/kg/day to pregnant mice
(day 6 through 15 of gestation); to pregnant rats (day 6 through 15 of
gestation), or to pregnant rabbits (day 6 through 18 of gestation)
(Food and Drug Research Laboratories, 1973).
No structural defects were found in chick embryos injected with
an aqueous suspension of sodium aluminosilicate into the yolk (up to
97 mg/kg) and into the air cell (up to 210 mg/kg at 0 and 96 h). At
levels of 50 mg/kg or above, there was a significantly higher
mortality rate by both routes of administration, and at 25 mg/kg an
increase in mortality rate was noted when the compound was given at
the start of embryonic development (Mississippi State University,
No effects were found in chick embryos injected with an aqueous
solution of aluminium chloride into the yolk on the fourth day of
incubation or onto the chorioallantoic membrane on the eighth day of
incubation. The LD50 was about 0.3 mg/kg (Ridgway & Karnofsky, 1956).
Aluminium sodium sulfate was considered nonteratogenic when tested by
injection of an aqueous solution into the air cell or yolk of
unincubated fertile eggs or after 96 hours of incubation. Doses ranged
up to 1.0 mg/kg (Verret, 1974).
Special Studies on Mutagenicity
Sodium silicoaluminate did not induce mutations in host mediated
assays with Salmonella typhimurium and Saccharomyces cerevisiae
(non-activated or activated with rat liver homogenate), or in a
dominant lethal assay in which male rats were dosed with up to
425 mg/kg/day by gastric intubation for 5 days prior to mating (Litton
Bionetics, Inc., 1974).
Sodium aluminium sulfate, sodium aluminium phosphate (acidic),
and aluminium ammonium sulfate were tested for genetic activity in a
series of in vivo microbial assays including plate and suspension
test (both non-activated and activated with liver, lung or testicular
homogenates from mice, rats, and monkeys) using Saccharomyces
cerevisiae and Salmonella typhimurium (strains TA-1535, 1537 and
1538) as test organisms. Sodium aluminium phosphate (acidic)
demonstrated marginal (5 fold increase over control) mutagenic
activity in plate tests with Salmonella typhimurium TA-1537
(unactivated) and Salmonella typhimurium TA-1535 (activated with rat
liver). All other tests on acidic sodium aluminium phosphate were
negative. Sodium aluminium sulfate and aluminium ammonium sulfate were
found to exhibit no genetic activity in any of the tests (Litton
Bionetics Inc., 1975, 1975a, 1975b).
Special Studies on Lactation/Suckling and Development
The effects of pre- and postnatal exposure to aluminium in the
diet on neurobehavioural and neuromotor development, overt toxicity,
immunological consequences and possible reproductive and teratologic
effects were assessed in Swiss-Webster mice (9-15 weeks old, number
not given). In one study mice were fed a diet containing aluminium
lactate (500 or 1000 ppm elemental aluminium) or a control diet
(100 ppm aluminium) ad libitum from day 0 of gestation through day
21 of lactation. An additional group was added as a pair-fed control
for the highest dose group. At parturition litters were culled to
8/litter. Pups were observed for viability, weight, length, and overt
toxicity on day 5, 15, and 21 postnatal. On days 8-18 randomly selected
pups were evaluated for neurobehavioural toxicity by the Wahlsten test
battery (an index of neuromotor development). In a second random
subgroup of pups retro-orbital blood was sampled for hematocrit, red
and white blood cell counts and spleen removed for mitogen stimulation
assay. A third random subgroup was evaluated for organ weight (spleen,
testes, thymus, brain, adrenals, liver, kidney, and heart), body
weight and length. Food intake was increased during the postnatal
period in all groups; however, the increase was not as pronounced in
the high aluminium group. Maternal weight was lower in the high
aluminium group compared to ad lib control but not to the pair fed
control. Neurotoxicity (e.g., splaying, dragging of feet, etc.) in
lactating female which received aluminium lactate pre- and postnatally
in the diet was observed in 58% of the 500 ppm group compared to
control. However, pups whose mothers were fed 1000 ppm aluminium were
not different from pups in the pair-fed controls. Neurological
development showed no significant differences between any groups on
days 11-13, 17 and 18. The greatest differences were observed on days
14-16 when both the moderate and high aluminium groups scored lower
than either control (no standard errors were given). Aluminium had no
effect on the immunological parameters measured (Golub et al.,
In the second part of the study, mice were injected
subcutaneously with aluminium lactate (10, 20, 40 mg elemental
aluminium/kg bw or vehicle) on days 3, 5, 6, 9, 11, 13, and 15 of
gestation. Food intake and signs of toxicity were recorded daily. On
day 18 the dams were killed, examined, and organs weighed. Fetuses
were examined for internal malformations (2/litter) and skeletal
development (remaining fetuses, number not given). No maternal
mortality or change in food intake was associated with subcutaneous
aluminium treatment. Necrotic skin lesions were associated with 7% of
the 10 mg dose group, 64% with the 20 mg dose group and in 100% of the
mice in the 40 mg dose group. The percentage of completed pregnancies
in the 40 mg dose group was low (25%), therefore, this group was
discontinued. Aluminium treatment was reported to increase the
absolute and relative spleen size and the relative liver size in the
20 mg/kg bw/day aluminium-treated dams. Subcutaneous aluminium lactate
had no effect on reproductive parameters and caused no fetal
abnormalities (Golub et al., 1987).
Lactating rabbits received aluminium lactate injections (up to
22 mg/day) between day 4 or 29 post-partum. Significant weight loss
and deaths occurred in the does treated at the highest levels. Less
than 2% of the injected aluminium was found in the milk. Offspring
maintained for up to one month after weaning, showed no increased
levels of aluminium in tissues. Some decreased weight gain was
observed in the offspring of does treated with the highest levels of
aluminium, but this effect was probably due to decreased milk
production by the does (Yokel, 1984).
The effects of subcutaneous injection of aluminium lactate during
the first month post partum (neonatal groups) and during the second
postpartum month (immature groups) was assessed on the offspring of
New Zealand white rabbits. Aluminium was administered into rotating
sites on the back times each week. The neonatal group received
400 µmol (10.8 mg) Al/kg, 1 µmol Sn/kg, and 50 µmol lead/kg or steril
water; the immature groups received 0, 25, 100, or 400 µmol
aluminium/kg. Animals were observed for body and organ weights, carpal
joint width, tissue aluminium concentrations, and classical
conditioned learning during and after aluminium treatment.
Additionally weekly milk consumption was measured in the neonatal
groups. After the first week, milk consumption was depressed in the
neonatal group receiving aluminium, Sn, and Pb. At 5 weeks postpartum
body weights were slightly lower in the neonatal group receiving
aluminium but this was not significant by week 12 in mature rabbits
consuming 400 µmol/kg. In rabbits receiving 400 µM aluminium during
the first month postpartum tissue aluminium levels were elevated in
the spinal cord, bone, heart, kidney, liver, and spleen at 9 weeks
postpartum and decreased with time. Tissue aluminium content of
immature rabbits was increased in bone, liver and spleen and a
dose-response was evident; aluminium was also increased in the kidney
but levels decreased with time. There was no effect of aluminium on
the acquisition of, latency to, or retention and extinction of a
conditioned response in neonatal rabbits. In immature rabbits
aluminium affected the latency and retention/extinction in animals
receiving 100 or 400 µmol aluminium when tested at 14.5 weeks (Yokel,
Observations in man
The aluminium concentration in human tissues from different
geographic regions was found to be widely scattered, and probably
reflected the geochemical environment of the individuals and of
locally grown food products (Tipton & Cook, 1965).
In healthy human tissues from the United Kingdom, the aluminium
concentration was usually below 0.5 µg/g wet weight, but higher levels
were observed in liver (2.6 µg/g), lung (18.2 µg/g), lymph nodes
(32.5 µg/g) and bone (73.4 µg/g of ash) (Hamilton et al., 1972).
In two subjects the intake was found to be 18 and 22 mg/day
during a 30-day period. Excretion took place mainly via feces
(respectively 17 and 45 mg/day): 1 mg was found in 24-hour urine. The
mean balances were 0 and 24 mg/day (Tipton et al., 1966).
The aluminium concentration in muscle, bone and brain of patients
maintained on a phosphorous binding aluminium gel for at least two
years was respectively 14.8, 95.5 and 6.5 µg/g dry weight in control
subjects. Patients on dialysis, who died of a neurologic syndrome of
unknown cause (dialysis encephalopathy syndrome) had brain grey matter
concentrations of 25 mg aluminium/kg dry weight, while in controls
2.2 mg/kg was measured (Alfrey et al., 1976).
Oral administration of Al(OH)3 in doses of 15-40 mg aluminium/kg
body weight daily to patients under dialysis is effective in lowering
the predialysis Ca-P product. Systematic use of Al(OH)3 over nearly
four years in more than 70 patients did not result in the appearance
of a particular clinical picture suggesting intoxication and was
compatible with a survival rate of more than 85% after three years.
The development of metastatic calciferations was prevented, and
existing non-vascular and in a few cases vascular metastatic
calciferations disappeared (Verberckmoes, 1972).
Raised serum aluminium levels were found in about 1/3 of
non-dialysed patients with advanced renal failure receiving 45 g
aluminium resin/day or more or 3-6 g Al(OH)3/day for 7-14 days
(Berlyne et al., 1970).
Eight patients with chronic renal failure were given 1.5-3.4 g
aluminium (as Al(OH)3/day for 20-37 days). In all patients there was
a decrease in plasma phosphorous. The balance became more negative in
four and less positive in one, remained unchanged in two and became
positive in one. Patients absorbed 100-568 mg aluminium daily.
Aluminium administration may decrease parathyroid over-activity since
in three patients a normalization of serum parathyroid hormone is
found when serum Ca is increased and serum phosphorous is lowered
(Clarkson et al., 1972).
Men were fed biscuits containing alum phosphate baking powder
(ca. 8%) in addition to normal dietary items, and blood and urine
samples were collected 2, 4, 6 and 8 hours after the meal. Aluminium
was frequently found in the blood of control men (trace - 0.1 mg/
100 ml), and ingestion of the aluminium-rich diets caused occasional
slight increases of levels of aluminium in the blood. Urine of man,
before and after ingestion of the aluminium-rich diets only contained
small amounts of aluminium (less than 0.5 µg excreted in 26 hours)
(Underhill et al., 1929).
Long-term administration to humans of aluminium-containing
antacids such as aluminium hydroxide results in decreased plasma
concentration of phosphorous because of decreased plasma concentration
of phosphorous because of decreased phosphorous absorption or
increased deposition of phosphorous in bone as aluminium phosphate
(Bloom & Finchum, 1960; Lotz et al., 1968; Bailey et al., 1971).
Aluminium antacids may cause an inhibition of intestinal
absorption of phosphorous and this may be followed by an increase in
calcium loss. Large amounts of antacids have been reported to induce
phosphorous depletion (Spencer et al., 1975). Relatively small doses
(16 to 51 mg aluminium per kg per day) of proprietary antacids caused
inhibition of intestinal absorption of phosphorous followed by an
increase in calcium loss in 11 patients. The effect is probably due to
the binding of dietary phosphorous in the intestine by the aluminium.
This effect was not observed when phosphorous-containing aluminium
salts were used (Spencer & Lender, 1979).
Neurotoxicity of Aluminium
There are large numbers of published reports on the neurotoxicity
of aluminium. Aluminium has been implicated in the development of an
encephalopathy in patients receiving dialyses (Alfrey et al., 1976,
1980) in Alzheimer's disease (McLachlan & DeBose, 1980; Pearl & Brody,
1980) and in Parkinsonism-dementia in Guam. This latter disease
occurred in populations living in a calcium and magnesium-deficient
environment and in areas where the surface soil is rich in aluminium
and iron (Garruto et al., 1984).
Aluminium levels in some regions of the brain of patients, who
suffered from the Alzheimer's disease were in the range of 6-12 µg/g
dry weight (control: 2.7 µg/g dry weight). Involvement of aluminium in
the pathogenesis of the Alzheimer's disease is suggested (McLachlan
et al., 1973).
The aluminium content of brain in Alzheimer's disease, in which
the diagnosis was based on histological appearances, revealed an
elevated (0.4-107.0 µg/g) aluminium content (McLachlan et al.,
The brain of an aluminium ball mill worker with progressive
encephalopathy accompanied by dementia and convulsions was found to
contain 5 ppm aluminium (wet weight) which is 20 times the normal
concentration (McLaughlin et al., 1962).
When aluminium gains access to the central nervous system of
certain animal species it acts as a potent neurotoxin. Aluminium salts
inoculated into the intrathecal space or cerebral cortex of
experimental animals have variable effects depending on species used,
developmental age, time and dose of aluminium exposure as well as
route of exposure. Aluminium must bypass the blood brain barrier
before it is neurotoxic in laboratory animals (Petit, 1985); oral
aluminium has not been associated with aluminium-induced
encephalopathy. Rats do not develop aluminium-induced encephalopathy
even after brain aluminium concentrations have reached 6 times the
levels necessary to elicit encephalopathy in cats, rabbits and dogs
(Boegman & Bates, 1984). Learning, memory and behavioural deficits and
electrophysiologic (seizures) and neurochemical alterations are
observed in experimental animals with elevated brain aluminium
concentrations resulting from exposure to high aluminium via brain
infusion or injection. The neurotoxicity of aluminium-induced
encephalopathy is progressive in nature ultimately cumulating in death
of the animal (Petit, 1985).
Aluminium injected into the brains of experimental animals has
been suggested as a model for the role of aluminium in human
dementias; the development of histopathology characteristics of
Alzheimer's disease (e.g., neurofibrillary tangle-bearing neurons) and
behavioural alterations following parenteral aluminium exposure
suggests aluminium may cause human dementia (Petit, 1985). The most
important and consistent findings of aluminium-induced neurotoxicity
in experimental animals appears to be neurofibrillary tangles (NFT)
and elevated brain aluminium content. Neurofibrillary tangles,
sometimes associated with elevated aluminium content, have been
reported to be a manifestation of human neurotoxicity (e.g.,
Alzheimer's disease and amyotrophic lateral sclerosis or parkinsonism
dementia found in isolated geographic regions). Although neuro-
fibrillary changes occur in aluminium-induced encephalopathy in
animals and in human dementias, the histopathologies are distinct
(Wishniewski et al., 1985). Aluminium induction of neurofibrillary
degeneration in laboratory animals is unrelated to the site of
injection; NFT's are predominantly located in the brain stem and
spinal cord (Boegman & Bates, 1984). In human dementias NFT's are not
found in the spinal cord. In Alzheimer's diseased brain NFT's are
composed of paired filaments, 10-13 nM in diameter, helically twisted
with a periodicity of 80 nM and appear to be similar to cytoskeletal
proteins (protofilaments); NFT's in the brains of animals with
aluminium-induced encephalopathy are smaller (100 A), composed of
neurofilament polypeptides, and not associated in a double helix,
(Boegman & Bates, 1984; Wishniewski et al., 1985; Perl & Pendlebury,
1985). Neurofibrillary tangles in Alzheimer's diseased brains and not
the animal model are associated with neuritic plaques.
Evidence of neurotoxicity associated with aluminium is strongest
in patients exposed to high aluminium concentrations intravenously
through hemodialysis, total parenteral nutrition, or ingestion of
aluminium-based phosphate binding gels by renally impaired patients
(Alfrey et al., 1976). In these patients aluminium is strongly
indicated as the cause of osteodystrophy and encephalopathy (dialysis
dementia). The aluminium content of brain, cerebrospinal fluid, serum,
and hair is elevated in patients with dialysis dementia unlike
patients with Alzheimer's disease (Shore & Wyatt, 1983). No specific
histopathology (i.e., NFT's) has been routinely found in the brains of
patients exhibiting dialysis dementia despite an elevated aluminium
content of the brain several times higher than in Alzheimer's diseased
brains (Alfrey et al., 1976). The symptomatology pattern and rate of
progression of dialysis dementia is different from that of Alzheimer's
disease. Dialysis dementia, like aluminium-induced encephalopathy in
experimental animals, is characterized by seizures, behavioural
changes which are quick in onset and is frequently fatal. The
mechanism of aluminium induced neurotoxicity in dialysis dementia is
unknown but may be a result of aluminium overload brought about by
changes in the permeability of the blood brain barrier as a result of
renal failure (Wishniewski et al., 1985).
It has been proposed that aluminium neurotoxicity becomes
manifest when the brain concentration exceeds 10-20 times the normal
value. The authors believe a correlation between location of areas of
high aluminium content and NFT's may suggest a role for aluminium in
Alzheimer's disease (McLachlan & Debose, 1980). Estimates of brain
aluminium content based on bulk analysis have been highly variable;
generally regions of high aluminium content correlated with density of
NFT-bearing neurons (Wishniewski et al., 1985). Perl & Brody (1985)
found the aluminium within individual neurons of brain tissue from
three cases of Alzheimer's disease and three nondemented controls was
frequently present in the nuclei of neurons with NFT's. This occurred
both in the absence and presence of Alzheimer's although neurons with
NFT's were found more often in the Alzheimer patients.
When scanning electron microscopy with X-rays spectrometry was
used, intraneuronal accumulation of aluminium was detected within the
NFT-bearing neurons in the hippocampus of Alzheimer's diseased brains;
adjecent HFT-free brain areas or age matched controls did not show the
same degree of aluminium accumulation. Similar accumulation of
aluminium was found in the brains of individuals from Guam suffering
from amyotrophic lateral sclerosis or parkinsonism with dementia (Perl
& Pendlebury, 1986). In some case aluminium brain accumulation was not
different between elderly normal controls and those with dementia
(Shore & Wyatt, 1983). Brain aluminium measured in 10 patients with
Alzheimer's disease and in 9 control patients were highly variable and
showed no differences and there was no correlation between mean
aluminium concentration and density of NFT (US Department of Health
and Human Services, 1985) of 12 Alzheimer's patients (74 brain
samples) and 28 nondemented controls (166 brain samples) there was no
difference in aluminium content and no correlation with density of
NFT's. Aluminium brain concentration is typically much higher in
dialysis dementia than in other human dementias (Petit, 1985), yet
neurofibrillary-like degeneration has been found in the brains of only
two cases (see below). Aluminium accumulation in brains from
experimental animals or dialysis dementia victims is cytoplasmic while
aluminium accumulation and NFT's are localized to the nuclear region
in Alzheimer's diseased brains (Shore & Wyatt, 1983) and the cytoplasm
and nuclear regions in cases of geographically occurring dementia
(Wishniewski et al., 1985).
In a recent study, Scholtz and coworkers (1986) examined the
brains of two patients suffering from dialysis encephalopathy
associated with excessive amounts of aluminium in tap water used for
dialysis. These patients had chronic renal failure and exhibited
outward signs of dialysis dementia before their deaths. Both
individuals had high levels of aluminium in the hair and serum
(155-340 µg/L serum compared to control levels of 2-19 µg/L). Total
brain aluminium measured in one patient was 2097 µg/L, compared to
normal levels of 2-16 µg/L. The authors reported the finding of
"neurofibrillary material in the cytoplasm of cortical neurons"; this
finding was not qualified. The observed neurofibrillary degeneration
more closely resembled NFT's seen in animal models of aluminium-
induced encephalopathy; aluminium increases were associated with
cytoplasm and filaments were unpaired.
Studies are currently being conducted to evaluate the effect of
aluminium chelators on the progression of Alzheimer's disease
(McLachlan & Van Berkum, 1986). Deferoxamine (an aluminium chelator)
has been beneficial in treating victims of dialysis dementia; studies
in Alzheimer's disease patients are not yet completed.
The neurotoxicity associated with high brain aluminium
concentrations may involve effects on axonal transport,
neurotransmitter, receptor activation, dendritic morphology, and
behavioural effects. Aluminium has been suggested to affect brain
enzyme activity (acetylcholinesterase, catecholamine balance) and
microsomal and ribosomal protein synthesis (Boegman & Bates, 1984).
The activities of choline acetyltransferase and acetylcholine esterase
are decreased in Alzheimer's disease but are unchanged in brains from
animals with aluminium-induced encephalopathy. Aluminium inhibits
these enzymes in vitro by 30% at 500 times the aluminium
concentration present in Alzheimer's diseased brains (Wishniewski
et al., 1985). Aluminium is suggested to be neurotoxic by
interfering with calcium-calmodulin (McLachlan & Van Berkum, 1986);
however, given the ubiquitous nature of calcium-calmodulin this theory
does not account for selective accumulation of brain aluminium and
accompanying neuronal toxicity in Alzheimer's disease.
Excess aluminium intake and absorption by a normal individual is
excreted (Tipton, 1985; Cambell & Kehoe, 1957).
Aluminium that is absorbed is readily excreted by the normal
human kidney. However, elevated serum aluminium levels are recorded in
patients with chronic renal failure, particularly after ingestion of
35 mg aluminium/kg per day as aluminium hydroxide (Berlyne et al.,
1970). The effects of hyperaluminemia are not fully known, the use of
aluminium compounds in patients with advanced renal failure should be
regarded with some concern. A study in man has confirmed the possible
deleterious interaction of aluminium salts in phosphorous metabolism,
especially during long-term ingestion of aluminium containing antacids
(Loot et al., 1968).
Patients with renal failure are at greater risk of aluminium
overload, since administered aluminium may be retained because of the
functional impairment of the kidney (Alfrey et al., 1976). Dialysis
encephalopathy has been associated with exposure of dialysis patients
to excess aluminium (Schteeder, 1979). The possible relationship
between increased brain aluminium and Alzheimer's disease has not been
established (McLachlan et al., 1976).
A report of the Secretary's Task force on Alzheimer's Disease by
the US Department of Health and Human Services stated: "Evidence of
excess accumulation of aluminium within the neurons harbouring the
classic neurofibrillary tangles of Alzheimer's disease has led some
scientists to speculate that aluminium and other trace metals may
somehow play a role in the development of the disease. The role of
aluminium, however, is far from clear, since those with the greatest
exposure to aluminium, such as aluminium workers and individuals on
renal dialysis, do not develop neurofibrillary tangles nor Alzheimer's
disease. Scientists are still uncertain as to how aluminium actually
gains access to the brain. The etiological role of environmental
toxins in the pathogenesis of Alzheimer's disease remains unproven and
controversial" (US Department of Health and Human Services, 1984).
The general population is principally exposed to aluminium from
food and water. Aluminium intake from foods, particularly those
containing aluminium compounds used as food additives, represents the
major route of aluminium exposure excluding persons who regularly
ingest aluminium-containing drugs. Previous evaluations by the
Committee dealt with sodium aluminium phosphate, a primary sources of
dietary aluminium intake.
Recent estimates of aluminium intake from food based on newer
methods of analysis and improved quality control are considerably less
than previously estimated. Current estimates of aluminium intake range
from about 2-6 mg/day for children and 6-14 mg/day for teenagers and
adults. Low total body burdens of aluminium coupled with urinary
excretion suggest to the Committee that even at high levels of
consumption, only a small amount of aluminium is absorbed. Aluminium
which is absorbed is located primarily in the heart, spleen, and bone
but its presence in these sites was without histopathologic lesions.
Studies are adequate to set a provisional tolerable weekly intake
of aluminium from 0-7.0 mg/kg b.w. It was concluded that there was no
need to set a separate ADI for sodium aluminium phosphate, basic or
acid, as the provisional tolerable weekly intake included aluminium
intake occurring from food additive uses.
Level causing no toxicological effect
Dog: 3% sodium aluminium phosphate (acidic) in the diet,
equivalent to 1250 mg/kg bw, equivalent to approximately 110 mg/kg bw
Estimate of provisional tolerable weekly intake
7.0 mg/kg bw*
*Includes intake of aluminium from food additive uses.
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