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 g/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 g/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 &
    Jaworski, 1986).

         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.


    Biochemical aspects

    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
    (Kortus, 1967).

         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
    al., 1966).

         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 g)
    or vitamin D plus aluminium citrate (136 +/- 70 g) 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
    al., 1970).

         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
    al., 1979).

         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 g
    aluminium/L. The cumulative increase in urinary aluminium excretion
    over 3 days was 123-1,430 g. 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 8 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 g
    aluminium/diet. The reported levels of aluminium in the tibias were
    11.3, 10.40 for the 257, 1075 g/g aluminium diet groups and 4.04
    and 3.13 g aluminium/g for the two control groups. The breaking
    strength of bones from animals fed the 1075 g 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).

    Toxicological Studies

    Acute Toxicity


    Salt        Species   Route   LD50 mg/kg    References
                                  body weight

    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.

    Short-term studies


         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 g/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 g aluminium/g diet accumulated less aluminium
    in their tibias and more aluminium in the kidneys than rats fed 261 or
    268 g 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 l aluminium
    tartrate (saline, 1 M, 2 M, 3 M) 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 M 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 M 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).

    Long-term Studies


         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
    Laboratories, 1973).

         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 mol (10.8 mg) Al/kg, 1 mol Sn/kg, and 50 mol lead/kg or steril
    water; the immature groups received 0, 25, 100, or 400 mol
    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 mol/kg. In rabbits receiving 400 M 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 mol 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 g/g wet weight, but higher levels
    were observed in liver (2.6 g/g), lung (18.2 g/g), lymph nodes 
    (32.5 g/g) and bone (73.4 g/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 g/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 g 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 g/g
    dry weight (control: 2.7 g/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 g/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 g/L serum compared to control levels of 2-19 g/L). Total
    brain aluminium measured in one patient was 2097 g/L, compared to
    normal levels of 2-16 g/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.


    Alfrey, A.C., Le Gendre, G.R. & Kaehney, W.D. (1976). The dialysis
    encephalopathy syndrome.  New Engl. J. Med., 294, 184-188.

    Alfrey, A.C., Hegg, A. & Craswell, P. (1980). Metabolism and toxicity
    of aluminium in renal failure.  Am J. Clin. Nutr., 33, 1509-1516.

    Anthony, J., Fadl, S., Mason, C., Davison, A. & Berry, J. (1986).
    Absorption, deposition and distribution of dietary aluminium in
    immature rats: Effects of dietary vitamin D3 and food-born chelating
    agents.  J. Environ. Sci. Health, B21 (2), 191-205.

    Bailey, R.R., Eastwood, J.B., Clarkson, E.M., Luck, V.A., Hynson,
    W.V., O'Riordan, J.L.H., Woodhead, J.S., Clements, V. & DeWardener,
    H.E. (1971). The effect of aluminium hydroxide on calcium, phosphorous
    and aluminium balances and the plasma parathyroid hormone in patients
    with chronic renal failure.  Clin. Sci. 41, 5P-6P.

    Bennett, R.W., Persaud, T.V.N. & Moore, K.L. (1974). Teratological
    studies with aluminium in the rat.  Teratology, 9(3), A-14.

    Berlyne, G.M., Ben-Ari, J., Pest, D., Weinberger, J., Stern, M.,
    Gilmore, G.R. & Livine, R. (1970). Hyperaluminemia from aluminium
    resins in renal failure.  Lancet, 494-496.

    Berlyne, G.M., Ben-Ari, J., Knopf, E., Yagil, R., Weinberger, G. &
    Danovitch, G.M. (1972).  Lancet, 1, 564-568.

    Bloom, W.L. & Flinchum, D. (1960). Osteomalacia with pseudofractures
    caused by the ingestion of aluminium hydroxide.  J. Amer. Med.
     Assoc., 174, 1327-1330.

    Boegman, R.J. & Bates, L.A. (1984). Neurotoxicity of aluminium. Can.
     J. Physiol. Pharmacol., 60, 1010-1014.

    Bowen, H.J.M. (1979). Environmental Chemistry of the Elements,
    Academic Press, New York, USA.

    Brusewitz, S. (1984). Aluminium, University of Stockholm Institute of
    Physics. Report No. 11-18.

    Camn, J.M., Luck, V.A., Eastwood, J.B. & DeWardener, H.E. (1976). The
    effect of aluminium hydroxide orally on calcium, phosphorous, and
    aluminium metabolism in normal subjects.  Clin. Science and Molecular
     Medicine, 51, 407-416.

    Clarkson, E.M., Luck, V.A., Hynson, W.V., Baily, R.R., Eastwood, J.B.,
    Woodhead, J.S., Clements, V.R., O'Riodan, J.L.H. & DeWardener, H.E.
    (1972). The effect of aluminium hydroxide on calcium, phosphorous, and
    aluminium balances, the serum parathyroid hormone concentration and
    the aluminium content of hone in patients with chronic renal failure.
     Clinical Science, 43, 519-531.

    Cramer, J.M., Wilkins, J.D., Cannon, D.J. & Smith, L. (1986). Fetal
    placental-maternal intake of aluminium in mice following gestational
    exposure: Effect of dose and acute administration.  Neurotoxicology,
    7(2), 601-608.

    Domingo, J.L. & DeWolff, F.A. (1987). The effects of aluminium
    ingestion on reproduction and postnatal survival in rats.  Life
     Sciences, 41, 1127-1131.

    Federation of American Societies for Experimental Biology (FASEB)
    (1975). Life Science Research Office. Evaluation of the health aspects
    of aluminium compound as food ingredients, prepared for the US Food
    and Drug Administration, 26 pp. (Available from the National Technical
    information Service Report No. PB-262 665).

    Food and Drug Research Laboratories, Inc. (1973). Teratologic
    evaluation of FDA 71-45 (sodium silicoaluminate) in mice, rats,
    hamsters, and rabbits. Final reports prepared under DHEW contract
    No. FDA 71-260, Maspeth, N.Y., 56 pp.

    Friberg, L., Nordberg, G.F. & Vouk, V.B. (1986). Handbook on the
    toxicology of metals, 2nd edition, Elsevier Science Publisher,
    Amsterdam, New York, Vol. II.

    Garruto, R.M., Fuatsu, R., Yanagihara, R., Gajdusek, D., Hook, G. &
    Fiori, C.E. (1984). Imaging of calcium and aluminium in neuro-
    fibrillary tangle-bearing neurons in parkinsonism-dementia of
    Guam, Proc. Natl. Acad. Sci., U.S.A.  Neurobiology. 81, 1875-1879.

    Gisselbrecht, H., Baufle, G.H. & Duvernoy, H. (1957).  Annls. Scient.
     Univ. Besancon Med., 44, 29, cited by Kortus, 1967.

    Golub, M.S., Gershwin, M.E., Donald, J.M., Negri, S. & Keen, C.L.
    (1987). Maternal and developmental toxicity of chronic aluminium
    exposure in mice.  Fundamental and Applied Toxicology, 8, 346-357.

    Gomez, M., Domingo, J.L., Llobet, J.M., Tomas, J.M. & Carbella, J.
    (1986). Short-term oral toxicity study of aluminium in rats.  Arch.
     de Farmacol. y Toxicol., XII, 145-151.

    Gorsky, J.E., Dietz, A.A., Spencer, H. & Osis, D. (1979). Metabolic
    balance of aluminium studied in six men.  Clinical Chemistry, 25,

    Greger, J.L. & Baier (1983). Excretion and retention of low or
    moderate levels of aluminium by human subjects.  Fd. Chem. Tox., 21,

    Greger, J.L., Bula, E.N. & Gum, E.T. (1985). Mineral metabolism of
    rats fed moderate levels of various aluminium compounds for short
    periods of time.  J. Nutr. 115, 1708-1716.

    Greger, J.L., Gum, E.T. & Bula, E.N. (1986). Mineral metabolism of
    rats fed various levels of various aluminium hydroxide.  Biological
     Trace Element Research. 9, 67-77.

    Hamilton, E.T., Minsky, M.J. & Cleary, J.J. (1972). The concentration
    and distribution of some stable elements in healthy human tissues from
    the United Kingdom.  Sci. Total. Environ., 1, 341-374.

    Hart, M.M. & Adamson, R.H. (1971). Antitumor activity and toxicity of
    salts of inorganic group IIIa metals: aluminium, gallium and thallium.
     Proc. nat. Acad, Sci. USA, 68, 1623-1626,

    Havas, M. & Jaworski, J.F. (editors) (1986). Aluminium in the Canadian
    Environment, National Research Council of Canada, Ottawa, Canada.

    Hicks, J.S., Zwicker, G.M., Sprague, G.L. & Saunders, D.R. (1986).
    4-Week Dietary Comparative Toxicity Study with Kasal in Rats. Final
    Report T-12644 dated May 7, 1986. Submitted by Stauffer Environmental
    Health Center, Framingham, CT, to WHO.

    Hicks, J.S., Hackett, D.S. & Sprague, G.L. (1987). Toxicity and
    aluminium concentration in bone following dietary administration of
    two sodium aluminium phosphate formulations in rats.  Fd. Chem.
     Toxic. 25, 533-538.

    Jones, J.H. (1983).  Amer. J. Physiol., 124, 230, cited by Ondreicka
    et al., 1966.

    Kaehney, W.D., Hegs, A.P. & Alfrey, A.C. (1977). Gastrointestinal
    absorption of aluminium from aluminium-containing antacids.  New Eng.
     J. Med. 296, 1389-1390.

    Katz, A.C. (1981). A 6-month subchronic dietary toxicity study with
    Levair (sodium aluminium phosphate, acidic) in beagle dogs.
    Unpublished report by Stauffer Chemical Co., Farmington, Connecticut.
    Submitted to WHO by US FDA, 1982.

    Kay, S. & Thornton, J.L. (1955). Observations on the intraperitoneal
    injection of aluminium hydroxide in mice.  Arch. Pathol. 50, 651-654.

    Kirsner, J.B. (1943).  J. Clin. Invest., 22, 47, cited by Ondreicka
    et al., 1966.

    Kortus, J. (1967). The carbohydrate metabolism accompanying
    intoxication by aluminium in the rat.  Experimentia, 23, 912-913.

    Kratchovil, B., Boyer, S.L. & Hicks, G.P. (1967) Effects of metals on
    the activation and inhibition of isocitric dehydrogenase.  Anal.
     Chem., 39, 45, cited by Sorenson et al., 1974.

    Langenbeck, W. & Schellenberger, A. (1957). Uber die decarboxylierung
    der Benztraubensaure durch Aluminium-ionen,  Arch. Biochem. Biophys.,
    69, 22.

    Litton Bionetic, Inc., (1974). Summary of the mutagenicity screening
    studies, host-mediated assay, cytogenetics, dominant lethal assay on
    compound FDA 71-45 (sodium aluminosilicate). Report prepared for Food
    and Drug Administration by Litton Bionetics, Inc., Kensington, Md, 
    135 pp. Submitted to WHO by US FDA.

    Litton Bionetics, Inc. (1975a). Mutagenic evaluation of sodium
    aluminium sulfate (compound 007784-28-3). Report prepared under DHEW
    contract No. FDA 71-74, Kensington, Md., 33 pp.

    Litton Bionetics, Inc. (1975b). Mutagenic evaluation of aluminium
    ammonium sulfate (compound 007784-26-1). Report prepared under DHEW
    contract No. FDA 75-6, Kensington, Md., 33 pp.

    Litton Bionetics, Inc. (1975c). Mutagenic evaluation of sodium
    aluminium phosphate (acidic) (compound 007785-88-8). Report prepared
    under DHEW contract No. FDA 75-1, Kensington, Md., 40 pp.

    Llobet, J.M. & Domingo, J.L. (1985). Oral toxicity of aluminium over a
    prolonged period.  Rev. San. Hig. Pub., 59, 659-666.

    Lotz, M., Zisman, E. & Bartter, F. (1968). Evidence for a
    phosphorous-depletion syndrome in man.  New Eng. J. Med., 278,

    Lymann, J.F. & Scott, E. (1930). Effects of the ingestion of tartrate
    or sodium aluminium sulfate baking powder upon growth, reproduction
    and kidney structure in the rat.  Amer. J. Hyg., 12, 271-282.

    McCollum, E.V., Rask, O.S. & Becker, E.J. (1928). A study of the
    possible role of aluminium compounds in animal and plant physiology.
    J.  Biol. Chem., 77, 753-769.

    McLachlan, D.R., Krishnan, S.S., & Dalton, A.J. (1973). Brain
    aluminium distribution in Alzheimer's disease and experimental
    neurofibrillary degeneration.  Science, 180, 511-513.

    McLachlan, D.R. & Tomko, G.J. (1975). Neuronal correlates of an
    encephalopathy induced by aluminium neurofibrillary degeneration.
     Brain Research, 97, 253-264.

    McLachlan, D.R., Krishnan, S.S., & Quittkat, S. (1976). Aluminium,
    neurofibrillary degeneration, and Alzheimer's disease.  Brain, 99,

    McLachlan, D.R. & DeBose, U. (1980). Aluminium in human brain disease:
    an overview.  Neurotoxicology, 1, 3-16.

    McLachlan, D.R. & Van Berkum, M.F.A. (1986). Aluminium: A role in
    degenerative brain disease associated with neurofibrillary
    degeneration. Progress in Brain Research, 70, 339-410.

    McLauglin, I.G., Kazantzis, G., King, E., Teare, D., Porter, R.J. &
    Owen, R. (1962). Pulmonary fibrosis and encephalopathy associated with
    the inhalation of aluminium dust.  Brit. J. Int. Med., 19, 253-263.

    Mellon Institute (1974a). Results of a one month feeding in the diet
    of rats and dogs. Report 37-B. Prepared for Union Carbide Corporation.
    Carnegie-Mellon University, Pittsburgh, PA. 48 pp.

    Mellon Institute (1974b). Molecular sieves in powder, pellet and
    crystal form, single peroral doses to rats and rabbits. Report 34-65.
    Prepared for Union Carbide Corporation. Carnegie-Mellon University,
    Pittsburgh, PA. 5 pp.

    Ministry of Agriculture, Fisheries and Food (1985). Survey of
    aluminium, antimony, chromium, cobalt, indium, nickel, thallium and
    tin in food, HMSO, London.

    Mississippi State University, Undated. Investigation of the toxic and
    teratogenic effects of GRAS substances to the developing chicken
    embryo: sodium aluminosilicate. Report prepared for Food and Drug
    Administration under DHEW contract No. FDA 72-342, 7 pp.

    Nathanson, J.A. & Bloom, F.E. (1976). Heavy metals and adenosine
    cyclic 3',5'-monophosphate metabolism: possible relevance to heavy
    metal toxicity.  Mol. Pharmacol., 12, 390-398.

    Nutrition Reviews (1987). Toxicologic consequences of oral aluminium.
     Nutrition Reviews, 45, 72-74.

    Ondreicka, R., Ginter, E. & Kortus, J. (1966). Chronic toxicity of
    aluminium in rats and mice and its effects on phosphorous metabolism.
     Brit. J. Int. Med., 23, 305-312.

    Perl, D.P. & Brody, A.R. (1980). Alzheimer's disease x-ray
    spectrometric evidence of aluminium accumulation in neurofibrillary
    tangle-bearing neurons.  Science, 208, 297-297.

    Perl, D.P., Gajdi, D.C., Gurruto, R.M., Yanagthara, R.T. & Gibbs, C.J.
    (1982). Intraneuronal aluminium accumulation in amyotrophic lateral
    sclerosis and parkinsonism dementia of Guam.  Science, 217,

    Perl D.P. & Pendlebury, W.W. (1986). Aluminium neurotoxicity-potential
    role in the pathogenesis of neurofibrillary tangle formation.  Can.
     J. Neurol. Sci., 8, 441-445.

    Petit, T.L. (1985). Aluminium in human dementia.  Am. J. Kidney
     Disease, 5, 313-316.

    Petit, T.L., Biederman, G.B., Jonas, P. & LeBartillier, J.C. (1985).
    Neurobehavioural development following aluminium administration in
    infant rabbits.  Exper. Neurol., 88, 650-651.

    Reilly, C. (1980). Metal contamination of food, Applied Science
    Publishers Ltd., Essex, England.

    Ridgway, L.P., & Karnofsky, D.A. (1956). The effects of metals on the
    chick embryo: toxicity and production of abnormalities in development.
     Ann. New York Academy of Sciences, 55, 203-215.

    Santos, F., Chart, J.C.M., Yang, M.S., Savory, J. & Wills, M.R.
    (1987). Aluminium depositing in the central nervous system
    preferential accumulation in the hippocampus in weanling rats.
     Medical Biology, 65, 53-55.

    Schaeffer, G., Fontes, G., LeBreton, E., Oberling, C. & Thivolle, L.
    (1928). The dangers of certain mineral baking powders based on alum,
    when used for human nutrition.  J. Hyg., 28, 92-99.

    Scholtz, C.L., Swash, M., Gray, A., Kogerogos, J. & Marsh, F. (1987).
    Neurofibrillary neuronal degeneration in dialysis dementia: a feature
    of aluminium toxicity.  Clinical Neuropath, 6, 93-97.

    Schroeder, M.A. & Mitchener, M. (1975a). Life-term effects of mercury,
    methylmercury and nine other metals on mice.  J. Nutr., 105, 452-458.

    Schroeder, M.A. & Mitchener, M. (1975b). Life term studies in rats of
    aluminium, beryllium and tungsten.  J. Nutr., 105, 421-427.

    Scott, E. & Helz, M.K. (1932). A microscopic study of the tissues of
    the albino rat following the ingestion of aluminium salts.  Amer. J.
     Hyg., 16, 865-869.

    Shore, D. & Wyatt, R.S. (1983). Aluminium and Alzheimer's disease.
     J. Nerv. Mental Dis., 171, 553-558.

    Skalsky, H.L. & Carchman, R.A. (1983). Aluminium homeostasis in man.
     J. Amer. Col. Toxicol., 6, 405-423.

    Slanina, P., Falkeborn, Y., Frech, W. & Cedergren, A. (1984).
    Aluminium concentration in the brain and bone of rats fed citric acid,
    aluminium citrate or aluminium hydroxide.  Fd. Chem. Toxic., 22,

    Slanina, P., Frech, W., Bernhardson, A. Cedergrem, A., & Mettsson, P.
    (1985). Influence of dietary factors on aluminium absorption and
    retention in the brain and bone of rats.  Acta Pharmacol. et.
     Toxicol., 56, 331-336.

    Sorensen, J.R.J., Cambell, I.R., Tepper, L.B. & Lingg, R.D. (1974).
    Aluminium in the environment and human health.  Env. Health Persp.,
    8, 395.

    Spector W.S. (1956). Handbook of toxicology. I. Acute toxicities,
    Philadelphia, p. 16.

    Spencer, H. & Lender, M. (1979). Adverse effects of aluminium-
    containing antacids on mineral metabolism.  Gastroenterology, 
    76, 603-606.

    Spencer, H., Norris, C., Coffey, J. & Wiatrowski, E. (1975). Effect of
    small amounts of antacids on calcium, phosphorous, and fluoride
    metabolism. American Gastroenterology Society. Abstracts, May 1975

    Thurston, H., Gilmore, G.R. & Swales, J.P. (1972). Aluminium retention
    and toxicity in chronic renal failure,  Lancet. I, 881-883.

    Tipton, I.H. & Cook, M.J. (1965). Trace elements in human tissues.
    III. Subjects from Africa, the Near and Far East and Europe.  Health
     Phys., 11, 403.

    Tipton, I.H., Stewart, P.L. & Martin, P.G. (1966). Trace elements in
    diets and excreta.  Health Phys., 1683-1689.

    Underhill, F.P., Peterman, F.I. & Sperandeo (1929). Studies on the
    metabolism of aluminium. VII. A note on the toxic effects produced by
    subcutaneous injection of aluminium salts.  Am. J. Physiol., 90, 76.

    US Department of Health and Human Services (1984). Alzheimer's
    Disease: DHHS Task Force Report, US Government Printing Office,
    Washington, D.C., September 1984.

    US Department of Health and Human Services (1985). Hypophosphatemia
    and hyperphosphatemia: Drug products for over-the-counter human use.
     Federal Register, 1-15-85, 3, 2160-2166.

    US FDA (1979). Unpublished memos on aluminium salts, dated August 21,
    1979 and December 11, 1979

    US FDA (1982). Digestive aid drug products for over-the-counter human
    use.  Federal Register, 1-5-82, 3: 454-487.

    Van Der Voet, G.B. & DeWolff, F.A. (1987). The effect of di- and
    trivalent iron on the intestinal absorption of aluminium in Rats.
     Toxicology and Applied Pharmacology. 90, 190-197.

    Verberckmoes, R. (1972). Aluminium toxicity in rats.  Lancet, I, 750.

    Verrett, J.M. (1974). Investigation of the toxic and teratogenic
    effects of GRAS substances to the developing chicken embryo: sodium
    aluminium sulfate. Report prepared for DHEW at IDA Washington, D.C.,
    6 pp (unpublished).

    Wishniewski, H.M., Sturman, J.A., Shek, J.W. & Iqubal, K. (1985).
    Aluminium and the central nervous system.  J. Environ. Pathol.
     Toxicol. Oncol., 1, 1-8.

    Yokel, R.A. (1984). Toxicity of aluminium exposure during lactation to
    the maternal and suckling rabbit.  Tox. and Appl. Pharm., 75, 35-43.

    Yokel, R.A. (1987). Toxicity of aluminium exposure to the neonatal and
    immature rat.  Fundamental and Applied Toxicology, 9, 795-806.

    See Also:
       Toxicological Abbreviations
       Aluminium (EHC 194, 1997)
       Aluminium (WHO Food Additives Series 12)
       ALUMINIUM (JECFA Evaluation)