Re: Regarding aluminum toxicity - what do you think of this study?

[Guest guest]

Try looking at the following study: Domingo JL, Gomez JM, Llobet JM, Corbella

J: Comparative effects of several chelating agents on the toxicity, distribution

and excretion of aluminum. Hum Toxicol 1988;7:259-62. In reveals that malic

forms are able to chelate aluminum. Perhaps you should try magnesium malate.

Leigh Anne Carson <neilcarson@...> wrote: My kids are prone to

constipation/hyperactivity/anxiety so we use a

lot of magnesium citrate. I was looking for possible sources of

aluminum and came across this study. Thoughts?

South Med J. 1994 Sep;87(9):894-8. Related Articles, Links

Aluminum and lead absorption from dietary sources in women ingesting

calcium citrate.

Nolan CR, DeGoes JJ, Alfrey AC.

Department of Medicine, Wilford Hall USAF Medical Center, Lackland

Air Force Base, Tex.

Animal models suggest that citrate-containing compounds augment

absorption of aluminum from food and tap water, causing aluminum

accumulation in bone and brain despite normal renal function. Citrate

also enhances lead absorption in animals. We questioned whether use

of calcium citrate by women as a calcium supplement causes an

increase in aluminum or lead absorption from dietary sources. Changes

in 24-hour urine aluminum and lead excretion, plasma aluminum level,

and whole blood lead level were assessed in 30 healthy women before

and during treatment with calcium citrate (800 mg of elemental

calcium per day). During calcium citrate therapy, urinary aluminum

excretion and plasma aluminum level increased significantly. In

contrast, there were no changes in urine or whole blood lead levels.

We conclude that treatment with calcium citrate significantly

increases absorption of aluminum from dietary sources. Additional

studies are needed to determine whether long-term use of calcium

citrate leads to aluminum accumulation and toxicity.

[Guest guest]

> We questioned whether use

> of calcium citrate by women as a calcium supplement causes an

> increase in aluminum or lead absorption from dietary sources.

This would be bad news. People are taking calcium as a *protection

against lead absorption.

During calcium citrate therapy, urinary aluminum

> excretion and plasma aluminum level increased significantly. In

> contrast, there were no changes in urine or whole blood lead levels.

> We conclude that treatment with calcium citrate significantly

> increases absorption of aluminum from dietary sources.

OK, we need Andy. I'm hoping this is one of those cases he talks about

where the actual paper shows a different conclusion than the precis.

Nell

[Guest guest]

Leigh,

Posted on this earlier, but it must have gotten lost, so trying again.

We had aluminum in the high green to start with. We have always used calcium and

mag citrate and have watched the aluminum levels steadily go down on the hair

tests. We never had much lead, but it has also steadily gone down.

I thought her aluminum came from one of the 3 foods she would eat, macaroni and

cheese, as processed cheese has a lot of aluminum in it. When she quit eating

it, it left.

[ ] Re: Regarding aluminum toxicity - what do you think

of this study?

> We questioned whether use

> of calcium citrate by women as a calcium supplement causes an

> increase in aluminum or lead absorption from dietary sources.

This would be bad news. People are taking calcium as a *protection

against lead absorption.

During calcium citrate therapy, urinary aluminum

> excretion and plasma aluminum level increased significantly. In

> contrast, there were no changes in urine or whole blood lead levels.

> We conclude that treatment with calcium citrate significantly

> increases absorption of aluminum from dietary sources.

OK, we need Andy. I'm hoping this is one of those cases he talks about

where the actual paper shows a different conclusion than the precis.

Nell

[Guest guest]

Maybe taking calcium keeps your body from absorbing aluminum. Thus

the increase in excreting it. Just a thought, but what do I know?

> > We questioned whether use

> > of calcium citrate by women as a calcium supplement causes an

> > increase in aluminum or lead absorption from dietary sources.

>

> This would be bad news. People are taking calcium as a

*protection

> against lead absorption.

>

> During calcium citrate therapy, urinary aluminum

> > excretion and plasma aluminum level increased significantly.

In

> > contrast, there were no changes in urine or whole blood lead

levels.

> > We conclude that treatment with calcium citrate significantly

> > increases absorption of aluminum from dietary sources.

>

> OK, we need Andy. I'm hoping this is one of those cases he talks

about

> where the actual paper shows a different conclusion than the

precis.

>

> Nell

>

>

>

>

>

>

[Guest guest]

At 07:17 PM 8/11/2006, you wrote:

>Try looking at the following study: Domingo JL, Gomez JM, Llobet JM,

>Corbella J: Comparative effects of several chelating agents on the

>toxicity, distribution and excretion of aluminum. Hum Toxicol

>1988;7:259-62. In reveals that malic forms are able to chelate

>aluminum. Perhaps you should try magnesium malate.

I'm not the OP but thanks for posting this....I didn't find the study

but it's enough that I'm going to go find the malate version before

we do another round. We are trying to get rid of my son's aluminum!

and I bump up the magnesium (citrate of course, sigh) during that

time...it could be making the round much less effective.

Are there other supplements I should be looking at for citrate?

Is there a brand of mag. malate that mixes well into juice (comes as

a powder preferably)? My son can take pills but we've been putting

that one in the juice so he doesn't have to take as many.

Stroyan

www.empathic-discipline.com

Click here to email me directly:

<mailto:lstroyan@...>lstroyan@...

[Guest guest]

I don't know the properties of Aluminium BUT another phenomenon could be

happening. Aluminium is perhaps stored somewhere in the body like lead in

bones. We do know that aluminium has been found in the brain of Alzheimers.

So maybe the calcium is MOBILIZING the aluminium and then encouraging

excretion via kidneys in some manner.

Just an idea.

[ ] Re: Regarding aluminum toxicity - what do you

think of this study?

>

>> We questioned whether use

>> of calcium citrate by women as a calcium supplement causes an

>> increase in aluminum or lead absorption from dietary sources.

>

> This would be bad news. People are taking calcium as a *protection

> against lead absorption.

>

> During calcium citrate therapy, urinary aluminum

>> excretion and plasma aluminum level increased significantly. In

>> contrast, there were no changes in urine or whole blood lead levels.

>> We conclude that treatment with calcium citrate significantly

>> increases absorption of aluminum from dietary sources.

>

> OK, we need Andy. I'm hoping this is one of those cases he talks about

> where the actual paper shows a different conclusion than the precis.

>

> Nell

>

>

>

>

>

>

>

>

> =======================================================

>

[Guest guest]

> We are trying to get rid of my son's aluminum!

> and I bump up the magnesium (citrate of course, sigh) during that

> time...it could be making the round much less effective.

We don't really know yet. Often a study will seem to point to a

conclusion that isn't correct.

> Is there a brand of mag. malate that mixes well into juice (comes as

> a powder preferably)?

I used mag malate from Source Naturals for years. At least going by

hair tests, AL is very stubborn.

Nell

[Guest guest]

Hello -- Since you are looking for sources of AL, This article might

help.

Best of luck -

Research

- Related EHP Articles

- PubMed:Related Articles

- PubMed:Citation

- PubMed:References

- Cited in PMC

- Purchase This Issue

The Biological Speciation and Toxicokinetics of Aluminum

DeVoto 1 and A. Yokel 2

1 Department of Environmental Sciences and Engineering, School of

Public Health, University of North Carolina at Chapel Hill

2 Division of Pharmacology and Experimental Therapeutics, College of

Pharmacy and Graduate Center for Toxicology, University of Kentucky,

Lexington, KY 40536-0082 USA

Abstract

This review discusses recent literature on the chemical and

physiological factors that influence the absorption, distribution,

and excretion of aluminum in mammals, with particular regard to

gastrointestinal absorption and speciation in plasma. Humans

encounter aluminum, a ubiquitous yet highly insoluble element in

most forms, in foods, drinking water, and pharmaceuticals. Exposure

also occurs by inhalation of dust and aerosols, particularly in

occupational settings. Absorption from the gut depends largely on pH

and the presence of complexing ligands, particularly carboxylic

acids, with which the metal can form absorbable neutral aluminum

species. Uremic animals and humans experience higher than normal

body burdens of aluminum despite increased urinary clearance of the

metal. In plasma, 80-90% of aluminum binds to transferrin, an iron-

transport protein for which receptors exist in many tissues. The

remaining fraction of plasma aluminum takes the form of small-

molecule hydroxy species and small complexes with carboxylic acids,

phosphate, and, to a much lesser degree, amino acids. Most of these

species have not been observed in vivo but are predicted from

equilibrium models derived from potentiometric methods and NMR

investigations. These models predict that the major small-molecule

aluminum species under plasma conditions are charged and hence

unavailable for uptake into tissues. Key words : absorption,

aluminum, citrate, equilibrium modeling, NMR, pharmacokinetics,

plasma, speciation, transferrin, uremia. Environ Health Perspect

102:940-951 (1994)

http://ehpnet1.niehs.nih.gov/docs/1994/102-11/devoto.html

Address correspondence to E. DeVoto, Department of Epidemiology, CB

7400, UNC-Chapel Hill, Chapel Hill, NC 27599 USA.

This work was made possible by EPA ative Agreement 818558. We

acknowledge the advice and assistance of Louise Ball,

McKinney, and Mark Shuman. Although this paper was funded by the

U.S. Environmental Protection Agency and has been submitted to the

agency's peer and policy review, it does not necessarily reflect the

views of the agency, and no official endorsement of any kind should

be inferred.

Received 5 October 1993 ; accepted 3 August 1994.

Aluminum is one of the most abundant elements in the environment.

Some human exposure is unavoidable -- daily intake is largely oral

and averages 30-50 mg ( 1 ). Of this, no more than about 7 mg is

expected to come from water, based on the maximum reported

concentration of aluminum in drinking water ( 2 ) and the average

consumption of 2 l water/day. Inhalation exposure is generally

negligible, though it can be significant in some occupational

settings, as described below. The contrast between widespread

occurrence and relatively low intake underscores the importance of

speciation in determining the bioavailability of aluminum, as this

metal is of limited solubility in its environmentally occurring

forms. Despite generally low exposures, the toxicity of aluminum,

particularly to the nervous system, is of concern. Much research on

aluminum in recent years has focused on its role in the etiology of

Alzheimer's disease (AD), but epidemiologic studies attempting to

link aluminum with AD in drinking water have been inconclusive and

contradictory. This review examines sources of aluminum and the

factors determining its absorption, distribution, and elimination in

the body, with particular reference to the literature and analytical

techniques developed within the last 10 years.

The chemical forms, or species, of aluminum formed in the body have

important implications for the balance between the metal's uptake

into tissues and its excretion. The study of aluminum speciation has

presented a number of major difficulties to researchers. First of

all, tracer studies with the aluminum isotope 26 Al are very

expensive due to the rarity and low activity of the nucleus and also

because of the cost of using accelerator mass spectrometry. Second,

because of aluminum's ubiquity in the environment, contamination of

samples (from dust particles, for example) is difficult to avoid.

Finally, aluminum metal, mineral forms, and some salts are very

insoluble except at extremes of pH or in the presence of chelating

ligands.

Aluminum and Alzheimer's Disease

There has been considerable interest and controversy concerning the

relationship between aluminum in drinking water and AD. A number of

studies ( 3-8 ) found correlations between aluminum concentrations

in drinking water and the incidence of AD, although the relative

risk of AD for those exposed to the highest aluminum concentration,

compared to those exposed to the lowest aluminum concentration, was

less than 2 in each case. Michel et al. ( 9 ) found a relative risk

of about 4 for those exposed to the highest aluminum concentration

(100 µg/l) compared to the lowest (10 µg/l). Studies failing to find

an association were reported by Wood et al. ( 10 ) and Wettstein et

al. ( 11 ). Although drinking water aluminum constitutes only a

small percentage of total daily aluminum intake, Martyn et al. ( 5 )

suggested that aluminum in drinking water " is either dissolved or

readily brought into solution. " The aluminum in drinking water may

therefore exist as species that are more readily absorbed than those

from other sources of aluminum. However, there are no reports on the

oral bioavailability of various aluminum species in water compared

to species found in food or other sources. Continuation of the

Michel et al. ( 9 ) study failed to show an association between

drinking water aluminum and cognitive impairment when water pH was

not considered. They observed a positive association up to pH 7.3,

and a negative association at higher pH ( 12 ), suggesting a pH-

dependent change in the aluminum species composition in water. In a

review of most of the studies of drinking water aluminum and AD,

Doll ( 13 ) pointed out that low pH was reported in several of the

studies showing a positive association between aluminum

concentration and AD; one such study was that of Frecker ( 14 ). In

contrast, the water had a high pH in one of the studies that failed

to show an association ( 11 ).

Odds ratios calculated by Forbes and McAiney ( 8 ), using a logistic

regression model for the association between water pH and impaired

mental functioning, suggest that medium pH, and to a lesser extent

high pH, are protective relative to low pH. However, the authors did

not state what variables were being controlled for in the analysis.

Forbes et al. ( 15 ) and Forbes and McAiney ( 8 ) reported results

suggesting a protective effect of fluoride on aluminum-associated

dementia. This was not substantiated by the results of Jacqmin et

al. ( 12 ). A protective effect of fluoride might be explained by a

fluoride-associated decrease in aluminum bioavailability, as

suggested by the results of Ondreicka et al. ( 16 ).

A number of criticisms of the above studies can be made. First of

all, most do not demonstrate a dose-response relationship. Aluminum

exposure measured over the short-term may not be a good surrogate

for lifetime exposure, which is especially important given that AD

is a chronic disease that may have a long latency period.

Consequently, it is also difficult to establish temporality in the

exposure-disease relationship. Also at issue are the imprecision in

AD diagnosis and the error in measurement and extrapolation of data

on exposure to aluminum in drinking water. Studies with 26 Al to

determine the influence of other chemical species and pH of drinking

water on oral aluminum bioavailability from food and water might

help determine whether enough aluminum is absorbed from water to

impact on aluminum body burden. However, such studies will not

directly address the role of aluminum in AD. Finally, only a small

percentage of total oral daily aluminum intake comes from drinking

water.

Specific Sources of Exposure

The aluminum content of foods has been reviewed by Pennington ( 17 )

and Greger ( 18 ). Common food additives containing aluminum are

acidic sodium aluminum phosphate, a leavening agent, and basic

sodium aluminum phosphate, an emulsifier. Aluminum is also found in

food colorings, and anticaking agents may contain aluminosilicates.

Processed cheese (a 28-g serving, with 297 µg aluminum/g, has 8 mg)

and cornbread (18 mg in a 45-g serving with 400 µg aluminum/g) are

major contributors to high aluminum exposures in the American diet.

The high aluminum content of these foods is largely due to

additives. Another significant dietary source of aluminum is soy-

based milk products, which contribute as much as 2.1 mg

aluminum/day, based on the typical intake of an infant; this

exposure is of particular concern for infants suffering from renal

deficiency ( 18 ).

There has been concern in recent years about leaching of aluminum

from beverage cans and cookware. Aluminum beverage cans are

generally coated with a polymer that prevents leaching. The average

concentration of aluminum in cola drinks was found to be only 0.1

µg/g. Aluminum cookware, however, may leach aluminum into highly

basic or acidic foods. Tomato sauce cooked in aluminum pans was

found to accumulate 3-6 mg aluminum per 100 g serving ( 18 ).

Duplicate portion studies in different populations, in which

subjects submitted for analysis duplicates of the diets they

consumed over a 24-hr period, estimated the following average daily

dietary exposures to aluminum: 3.1 mg [Holland, men and women (

19 )], 2.2-8.1 mg [Japan, men ( 20 )], 13.7 mg (USA, men aged 25-30

( 17 )].

The maximum reported concentration of aluminum in drinking water was

3.5 mg aluminum/l ( 2 ). Aluminum in U.S. groundwaters ranged from

0.014 to 0.29 mg/l and in untreated surface waters from 0.016 to

1.17 mg/l. Aluminum sulfate is often added as a flocculant to

surface waters, resulting in aluminum concentrations in finished

drinking water from 0.014 to 2.67 mg/l. Assuming daily consumption

of 2 l of water with an average concentration of 0.1 mg/l, daily

intake of aluminum from water would be 0.2 mg ( 21 ).

Aluminum in pharmaceuticals has been reviewed by Yokel ( 22 ). Some

over-the-counter pharmaceuticals such as antacids and buffered

aspirin contain sufficient aluminum to increase the daily dose

significantly. Many antacids consist of a mixture of Al(OH) 3 and

other hydroxides, such as magnesium. Maalox Extra Strength tablets,

for instance, contain 400 mg Al(OH) 3 and 400 mg Mg(OH) 2 . The

recommended dose for relief from gastric discomfort is up to eight

tablets per day; that is, 3.2 g Al(OH) 3 , or 1.1 g aluminum, which

is a 30-fold increase over the average exposure from food and

drinking water alone. Patients with renal insufficiency often take

large quantities of aluminum-containing antacids to bind excess

phosphate. The resulting AlPO 4 is insoluble, making the phosphate

more easily excretable via the feces. Other potentially significant

exposures, though likely to be short term, can occur through use of

intravenous solutions: 10% calcium gluconate and 3 M potassium

phosphate were found to contain 5.1 mg aluminum/g and 17 mg/g,

respectively. Diphtheria-pertussis-tetanus vaccine, administered

widely in the United States to children and adults, contains an

aluminum adjuvant ( 18 ).

Dialysis patients can be exposed to large amounts of aluminum via

their dialysis fluid. This exposure has been responsible for notable

episodes of neurotoxicity ( 23,24 ). Toxicity associated with

dialysis fluid can be largely reduced by removing aluminum from the

fluid. Winney et al. ( 25) found that treatment of dialysate water

with reverse osmosis led to decreases in blood aluminum. No new

cases of aluminum toxicity occurred in Scotland over 5 subsequent

years of follow-up among dialysis patients.

Inhalation exposure of the general population to aluminum in dust is

as high as 0.14 mg/day, based on an upper-bound measurement of 5000

ng/m 3 [in urban air ( 2 )] and typical exposure estimates (1 l

air/breath and 20 breaths/min). In contrast, miners, smelters, and

other metal workers can be exposed to toxic levels of aluminum

through dusts and aerosols. A group of aluminum welders ( 26 ), for

example, was exposed to 2.4 mg/m 3 of aluminum (8-hr time-weighted

average), which results in inhalation of 23 mg over an 8-hr shift.

Miners in northern Ontario between 1944 and 1979 were deliberately

exposed via inhalation to aluminum dust as a proprophylactic measure

against silicosis ( 27 ). Before each shift, miners were exposed to

20,000 to 34,000 ppm aluminum dust in an enclosed area for 10 min,

resulting in estimated average exposures of 375 mg/year. Exposed and

unexposed miners did not differ significantly in incidence of

neurological disorders, but the exposed miners achieved lower scores

on cognitive examinations and were more likely to fall into

the " impaired " range.

Techniques for Analysis of Aluminum and Its Speciation in Biological

Media

Understanding the toxicokinetic behavior of any chemical requires

detailed knowledge of the species it forms in the body, which

determine the extent to which it is absorbed, how it is transported

in the blood, and its bioavailability to tissues susceptible to

toxicity. The study of aluminum has depended largely on equilibrium

modeling of small-molecule species expected to form under various

physiological conditions and on filtration techniques combined with

chromatography to determine the specificity and extent of aluminum's

binding to protein. Nonetheless, it is still not known whether small

aluminum complexes or protein-bound forms contribute more to

aluminum's toxicity. For aluminum to be absorbed directly across

cell membranes, it would have to be in the form of a neutral

species. Alternatively, aluminum could be taken up in the form of a

protein complex by receptor-mediated uptake, such as that occurring

with transferrin (see discussion below). Finally, nonspecific uptake

of aluminum in any form could occur via pinocytosis.

Atomic absorption. Total aluminum concentration in biological media

is typically determined using atomic absorption spectroscopy. This

method alone, however, provides no information about speciation.

Atomic absorption spectroscopy is subject to contamination because

aluminum from dusts is difficult to avoid. Spectral interference

from other metals can be minimized by judicious choice of absorption

lines. The detection limit of flame atomic absorption spectroscopy

for aluminum is 30 ng/ml (1.1 µM). The detection limit for

electrothermal atomic absorption is considerably lower, [0.005 ng/ml

( 28 )].

High-energy accelerator mass spectrometry. Accelerator mass

spectrometry can measure as few as a million atoms of 26 Al ( 29 ).

26 Al is a long-lived radioisotope (half-life of about 10 5 years)

that enables studies of very low doses of isotopic aluminum. Day and

co-workers ( 30 ) and Priest et al. ( 31 ) described the use of 26

Al for tracer studies in humans. A number of investigators performed

similar experiments in rats ( 30,32,33 ); each of these studies is

described below.

Filtration techniques. Gel filtration and ultrafiltration, combined

with atomic absorption spectroscopy, have been used to distinguish

between protein-bound and nonprotein-bound aluminum in serum or

serumlike solutions and, to a degree, among different proteins

binding to aluminum. " Ultrafiltrable " as used here means able to

pass through an ultrafilter and refers to small-molecule species

such as aluminum citrate. Non-ultrafiltrable species are primarily

protein bound but may also include insoluble or colloidal complexes

of, for example, aluminum hydroxide. It is important to recognize

that, at high concentrations, aluminum may precipitate out as a

solid or form a colloid that cannot be distinguished by

ultrafiltration from protein-bound and otherwise non-ultrafiltrable

aluminum.

A number of researchers have attempted to investigate the nature of

aluminum's binding to serum proteins by gel filtration techniques (

34 - 39 ). This approach has been problematic in a number of

respects. Many columns avidly bind aluminum, making recovery

difficult. Favarato et al. ( 37 ) recovered aluminum from different

columns, by washing with buffer containing desferrioxamine, in the

following amounts: TSK-GEL HW-5SS, 75%; Sephadex G-200, 36%;

Sephacryl S-500, 30%; and Bio Gel P-2, 24%.

27 Al-NMR. Recently, nuclear magnetic resonance (NMR) directed at

the 27 Al nucleus has been used to investigate aluminum species in

solution. Unlike 13 C or 1 H, 27 Al has a spin quantum number

greater than 1, resulting in broad signals when bound to

asymmetrically arranged ligands, which makes structural assignments

difficult. Theory and applications of 27 Al-NMR have been thoroughly

reviewed by Akitt ( 40 ). Results of 27 Al-NMR experiments using

citrate are summarized in Table 1. Fatemi et al. ( 41 ) demonstrated

aluminum binding to transferrin, albumin, and citrate. For an

aluminum-citrate solution over the range of pH 6.0-8.4, these

investigators found a double signal in the region from about 0 to 10

ppm shift. At the highest pH, Al(OH) 4 - was detected, as well as

aluminum-citrate complexes. Feng et al. ( 42 ) detected a trinuclear

aluminum-citrate species in solution within a range of intermediate

pH. The identity of this species was confirmed by X-ray

crystallography.

Potentiometric data and equilibrium models. Equilibrium models,

based on potentiometric data, allow a much more complete (although

theoretical) description of species formed in aqueous solutions of

aluminum with its ligands, compared to the analytical techniques

described in earlier sections. In this technique, formation (or

equilibrium) constants are fit to data on change of pH as a function

of acid or base added to a solution. These constants can then be

used, usually with a computer program, to predict equilibrium

concentrations of the postulated species under specified

concentrations of aluminum and its ligands, at different pH values.

A summary of the predominant aluminum species predicted by each

model, in the presence of citrate and range of pH values, is

presented in Table 2.

Berthon and Daydé ( 43 ) described a model of aluminum speciation in

the intestine designed to compare the fraction of neutral aluminum

species formed after administration of either aluminum phosphate or

aluminum hydroxide. This model predicted that Al(OH) 3 would

dissolve better than AlPO 4 in the presence of organic acids and

would complex better with the acids. Aluminum administered orally as

Al(OH) 3 would be better absorbed in the gut than AlPO 4 and thus

lead to the observed increased toxicity. Furthermore, this

dissolution, complexation, and absorption should be higher in the

proximal jejunum (about pH 7) than in the duodenum (pH 3-4).

Öhman ( 44 ) performed a titration study of aluminum-citrate

speciation over time in aqueous solution that followed pH as a

function of added base. Speciation was calculated by curve fitting

using published equilibrium constants. One species, Al(OH)H -1 Cit 2-

[Al(CitH -1 )(OH) 2- , using Öhman's convention] was found at

physiologic pH in fresh (that is, unaged) solutions. A second

species, Al 3 (OH)(H 1- Cit) 3 4- , predominated in somewhat older

solutions.

On the basis of a similar pH-time study, Öhman ( 44 ) first fitted

stability constants for Al(H -1 Cit) - and AlOH(H -1 Cit) 2- at time

0 assuming that the concentration of Al 3 (OH)(H -1 Cit) 3 4- was 0.

He then predicted corresponding concentrations of the trinuclear

species, based on the amount of hydroxide taken up, as evidenced by

the pH, then constructed distribution diagrams over time. In these

models, the trinuclear aluminum species appeared after 1 min at

around pH 6 and then came to predominate over a broader pH range

after a few minutes.

The existence of this trinuclear species, Al 3 (OH)(H -1 Cit) 3 4- ,

was confirmed by Feng et al. ( 42 ) and in our laboratory ( 45 )

through the use of 27 Al-NMR. We found further that the trinuclear

species indeed appeared at an aluminum:citrate ratio close to 1. We

were unable to see this species in solutions where citrate was

increased relative to aluminum, however. Furthermore, the

equilibrium models described below do not support the existence of

this species under high citrate:aluminum ratios such as those found

in blood. The published model found to be in best agreement with the

experimental data generated in our lab was that of Öhman ( 44 ).

When extrapolated to physiologic aluminum and citrate

concentrations, this model predicts the neutral species AlCit° only

below pH 3.5; at higher pH the predominant aluminum species are

AlCitH - (pH 3.5-6.5) and AlOH(H -1 Cit) 2- (pH 6.5-8.5) ( 45 ).

Motekaitis and Martell ( 46 ) examined potentiometrically the

equilibrium between aluminum and a number of organic ligands,

including citric acid, at metal:ligand ratios of 1:1 and 1:2.

Equilibration times between additions of acid or base varied but

were not reported. Only three species were assumed, each of them a

1:1 aluminum:citrate species in a different protonation state.

Gregor and ( 47 ) assumed that citrate's hydroxy proton was

available to complex with aluminum, and used a 5.3- or 6.3-fold

excess of ligand over metal for potentiometric determinations. K + -

Cit 3- ion pairing was taken into account because KOH was used as a

titrating base. Eight aluminum-citrate species were assumed, but no

polynuclear species. 13 C-NMR supported the possibility that the

hydroxy proton was used in bridging.

( 48 ) used adjusted equilibrium constants from the published

literature to model the binding of aluminum citrate (assuming no

polynuclear species), at ionic strengths of 0.1 to 0.16 M, and over

a pH range of 1-9. At physiologic pH and a ratio of 100:1 citrate to

aluminum, the species Al(H -1 Cit) - was predicted to predominate.

Venturini and Berthon ( 49 ) examined the aluminum-citrate

equilibrium at physiologic ionic strength and devised a model

containing seven citrate species, including a trinuclear and a

binuclear aluminum species, and two hydroxy aluminum species. At

physiologic pH and about 60:1 citrate:aluminum, AlCit 2 (OH) 4- [ML

2 H -1 ] by the authors' convention ( 49 )]; Al 3 (OH ) (H -1 Cit) 3

4- [M 3 L 3 H -4 ]; and AlCit 2 (OH) 2 5- [ML 2 H -2 ] were major

species, while the trinuclear aluminum species (stoichiometrically

equivalent to that postulated by Öhman) predominated at

physiological pH at citrate:aluminum ratios of about 5:3 and 6:1.

Two recent studies suggest that aluminum-phosphate species are the

predominant small-molecule forms of aluminum in serum. Daydé et al.

( 50 ) titrated an acidic aluminum chloride/orthophosphoric acid

mixture at different mole ratios over a wide range of pH to produce

formation constants; the aluminum-phosphate species best fitting the

model were AlPO 4 , AlHPO 4 + , AlH 2 PO 4 2+ , Al 2 PO 4 3+ , Al 2

PO 4 (OH) 2 + , and Al 2 PO 4 (OH) 3 o . A model constructed from

these formation constants and those previously determined for

aluminum citrate and hydroxide predicted the predominant low-

molecular-weight species, under physiologic conditions, to be Al(OH)

3 o (51%), AlPO 4 o (41.5%), and Al 2 PO 4 (OH) 2 + (7.2%).

( 51 ) derived a largely different set of equilibrium

constants for the aluminum-phosphate system from linear free-energy

relationships. The two species judged to be most important in serum

were AlPO 4 OH - and AlPO 4 o . This study developed a speciation

model containing all ligands found in serum that are expected to

complex appreciably with aluminum, as well as metal ions (Zn 2+ , Ca

2+ , and Mg 2+ ) that compete with aluminum for binding sites on

transferrin. The model was studied at aluminum and ligand

concentrations typical of normal or uremic plasma and at pH 7.4. The

following assumptions were made: 1) the N-terminal binding site on

transferrin is 60% saturated with iron, which is not displaced by

other metals; 2) aluminum does not bind to albumin; and 3)

trinuclear aluminum citrate [Al 3 Cit 3 (OH) 4 4- ] and aqueous Al

(OH) 3 exist. Concentrations of organic ligands in normal serum were

taken from the Geigy Scientific Tables, and formation constants

(other than for phosphate) were adopted from a number of literature

sources and averaged when more than one was available. The principal

species predicted from the complete model were aluminum-transferrin

(about 81%, which was supported by results obtained with 26 Al (

31 ), AlPO 4 OH - (about 16%), and a few hydrolyzed species.

's work is the first published so far to incorporate citrate

and phosphate in the same equilibrium model and the first to suggest

that phosphate might be a more significant binder of aluminum than

citrate.

Absorption of Inhaled Aluminum

Although inhalation exposure is not likely to be of concern to the

general population, miners, smelters, and other metal workers can be

exposed to toxic levels of aluminum through dusts and aerosols.

Elinder et al. ( 52 ) found that two welders, each with about 20

years of exposure to 3.0-8.9 mg aluminum/m 3 , excreted 107-351 µg/l

aluminum in their urine and had 18-29 µg/g aluminum in their bones.

A group of workers exposed to aluminum-flake powders experienced

higher whole-blood aluminum concentrations (0.33 µM; 8.9 µg/l) than

the comparison group (0.11 µM; 3.0 µg/l) ( 53 ). Welders exposed to

aluminum fumes excreted aluminum in urine at a median concentration

of 82 µg/l (3.0 µM) ( 54 ). Foundry workers exposed to <1 mg

aluminum/m 3 ( 55 ) for a median of 7 years experienced increased

serum aluminum concentrations compared to controls, but urinary

excretion was unchanged. Exposure of rabbits to 0.56 mg aluminum/m 3

over 5 months led to an 15.8-fold increased accumulation of aluminum

in lung (compared to controls), a 2.5-fold increase in brain, and a

1.65-fold increase in kidney ( 56 ). It has been estimated that

about 3% of aluminum is absorbed into the blood from the lung ( 2 ).

Absorption of Aluminum in the Gastrointestinal Tract

The commonly cited estimate of gastrointestinal aluminum absorption

of 0.1-0.3% ( 1,21 ) was based in part on the assumption that

urinary excretion represents absorption, which does not take into

account tissue distribution, as discussed below. Other studies (

2,30 ), one using 26 Al in a human, suggest that 1% is absorbed from

the gastrointestinal tract. However, Schönholtzer et al. ( 57 )

found <0.1% of an oral dose of 26 Al (as hydroxide) in the urine of

normal rats and rats with five-sixths of each kidney surgically

removed ( " 5/6 nephrectomy " ) in the first 300 min after dosing.

Considering the rapid urinary elimination of most aluminum ( 31 ),

these results suggest <0.1% oral absorption of the 26 Al. Jouhanneau

et al. ( 33 ) found only 0.02% of an oral dose of 26 Al, as the

citrate, in urine and another 0.02% of the dose in the liver of

rats, suggesting absorption of only 0.04% from the gastrointestinal

tract.

Some absorption of aluminum may occur in the stomach ( 58 ); the

majority of aluminum absorption, however, is expected to occur in

the intestine. In general, the two-step absorption process in the

gut is 1) lumen * mucosa and 2) mucosa * bloodstream. Aluminum must

be in the form of neutral complexes in order to be absorbed by

diffusion through the plasma membrane of cells. Ionic aluminum may

be absorbed actively by specialized iron-absorption pathways in the

gut, as discussed below.

The most important aspect of the gastrointestinal tract with regard

to its uptake of aluminum is its change in pH, from 2 to 3 in the

stomach to 3 to 8 in the small intestine. The low pH of the stomach

allows for complete dissolution of, for example, Al(OH) 3 in

antacids. This dissolution yields free aluminum (Al 3+ ) that is

thus made available for complexation and possible absorption.

Studies of intestinal uptake that fail to specify or control for pH

must therefore be considered unreliable.

The contents of the gut obviously vary greatly between individuals

and species and have an important impact on absorption of aluminum.

The presence of citric acid and other carboxylic acids have the

potential to form neutral species but may also serve simply to

redistribute aluminum from insoluble to soluble forms, making the

metal more available for active-transport pathways. Silicic acid, a

form of silicon, on the other hand, ties aluminum up as insoluble

complexes that make it less bioavailable, as discussed below.

Animal Studies. Addition of citric acid (0.111 M) to drinking water

containing 0, 100, or 500 mg aluminum/l as the chloride

significantly increased tibial, plasma, urinary, and fecal aluminum

over 12 weeks, suggesting that citrate increases aluminum absorption

( 59 ). The same study found that addition of 0.111 M ascorbic acid

to the water increased urinary and fecal aluminum. Absorption of

aluminum chloride by the in situ rat gut preparation was

significantly increased by addition of equimolar citrate (2.5 * 10 -

3 M) to the perfusate ( 60 ).

Domingo et al. ( 61 ) compared the effect of organic acids

(ascorbic, gluconic, lactic, malic, oxalic, and tartaric) on tissue

and urinary concentrations of aluminum compared to the effect of

citric acid in rats administered aluminum by gastric intubation.

Each of these acids has fewer dissociable protons than citric acid,

which can lose three protons in order to bind to Al 3+ ; for the

most part, administration of these acids resulted in higher tissue

concentrations than did citrate. Ascorbic acid's effect on tissue

accumulation of aluminum after 5 weeks of exposure was similar to

that of citric acid, except for kidney, which had a significantly

higher accumulation of aluminum after ascorbic acid administration.

Organic acid-induced urinary excretion of aluminum would have

provided further evidence of increased gastrointestinal absorption,

but no significant changes in urinary aluminum were found as a

result of administration of the organic acids studied.

Human studies. The effect of gastric pH on absorption of aluminum

was examined by Rodger et al. ( 58 ). These investigators

administered either placebos or ranitidine, a drug that suppresses

production of stomach acids (and would thus elevate gastric pH), to

healthy subjects and to patients with renal disease, followed by Al

(OH) 3 . The subjects who received placebos had higher levels of

urinary excretion of aluminum than those who received ranitidine,

implying that low gastrointestinal pH promotes absorption of

aluminum.

It has been suggested that patients with AD might have a genetic

tendency to absorb excessive amounts of aluminum. To test this

hypothesis, et al. ( 62 ) administered an aluminum citrate-

containing drink to 20 AD patients and 20 age- and sex-matched

controls, measuring blood aluminum before and after consumption of

the drink. The investigators found a greater increase in blood

aluminum among younger AD subjects than controls, but not among the

older AD subjects compared to their controls. This study could have

been improved by using a study population large enough to allow

sufficient statistical power for stratified analysis or

randomization. Furthermore, as has been reported elsewhere, there

was considerable variability among measured serum aluminum

concentrations, which could have been due to a contamination problem

or the result of confounding by unstratified exposure variables.

The measurement of total aluminum concentration in urine before and

after exposure is the simplest, although probably not the most

accurate, means of assessing absorption. Coburn et al. ( 63 )

administered 950 mg calcium citrate four times daily and/or 2.4 g Al

(OH) 3 daily to eight normal men. Baseline aluminum excretion was

0.24 µg/mmol creatinine. Excretion increased somewhat upon ingestion

of Al(OH) 3 , but was much higher (by a factor of 5.3 to 11.1) when

calcium citrate and Al(OH) 3 were ingested together, compared to Al

(OH) 3 alone. Presumably, soluble citrate becomes available to

complex with aluminum, making it more absorbable, which is

consistent with other studies. et al. ( 64 ) similarly found

that sodium bicarbonate had a lower ability than sodium citrate to

increase aluminum excretion, and Nolan et al. ( 65 ) found that

calcium acetate increased urinary aluminum excretion much less than

did calcium citrate. Maximum urinary excretion of aluminum, after

coadministration with calcium citrate, was 176 ± 103 compared to 6 ±

3 µg/g creatinine/day when only Al(OH) 3 was taken ( 65 ).

House ( 66 ) examined risk factors for elevated serum aluminum in a

group of 71 office workers. Higher serum aluminum was associated

with antacid consumption and with the batch in which the sample was

analyzed, which strongly suggests sample contamination problems.

Consumption of cola drinks from aluminum cans appeared to be

inversely related to serum aluminum, but this was believed, again,

to be an artifactual result of the high variability due to

contamination. Therefore, no conclusions can be drawn from this work

with regard to absorption of aluminum from soda cans.

on et al. ( 67 ) measured uptake of 26 Al dissolved in orange

juice containing no added silicon or 100 µM silicon and found that

silicon reduced the amount of 26 Al measured in serum. It has been

hypothesized that dissolved silicates in drinking water may protect

against aluminum-associated AD by complexing with aluminum and

making it less bioavailable.

Mechanisms of Aluminum Absorption from the Gastrointestinal Tract

Absorption of aluminum from the gastrointestinal tract, if purely

passive, would require that the metal be in some neutral form in

order to diffuse across membranes. Equilibrium models suggest that

this scenario requires very specific conditions of pH and

concentrations of the appropriate complexing ions. If, on the other

hand, active transport mechanisms predominate, it is possible that

transport could occur under a broader range of chemical conditions,

such as the wide variety of pH and chemical compositions found in

the gastrointestinal tract.

Role of active transport and iron absorption pathways. Feinroth et

al. ( 68 ) examined absorption of aluminum using a rat everted gut-

sac, maintained at pH 7.35-7.42. Absorption was inhibited by

dinitrophenol and by the absence of glucose, both of which inhibit

cellular respiration, suggesting that aluminum is actively

transported out of the intestine. As aluminum behaves similarly to

iron in many biological systems (for example, binding to

transferrin, discussed below), Al 3+ may also be taken up via the

specialized iron absorption pathways found in the gut. As evidence

for this hypothesis, iron deficiency has been found to increase the

absorption of aluminum in rats ( 69 ) and in renally impaired humans

( 70 ). Others, in contrast, found that administering extra iron

orally to dialysis patients did not prevent absorption of aluminum

from phosphate binders ( 71 ), which would have implied competition

between aluminum and iron for absorption. Investigators using an

excised gut-section model found that Fe 2+ enhanced disappearance of

aluminum from the intestinal lumen but did not increase systemic or

portal blood aluminum. Fe 3+ had no effect on uptake of aluminum

from the intestinal lumen ( 72 ).

An iron-binding protein has recently been identified in the duodenal

mucosa of rats and humans that may prove to bind to aluminum as well

and may thereby account for part of the mechanism of aluminum's

uptake at the gut. The protein, named mobilferrin after the Alabama

city in which it was discovered, is biochemically and

immunologically distinct from both ferritin and transferrin, the two

major iron-binding proteins in blood, as assessed by molecular size

(56,000 daltons), electrophoretic mobility, and amino acid

composition. The dissociation constant for iron from mobilferrin was

found to be 8.92 * 10 5 ( 73 ). The physiologic role of this protein

is not yet known; to date it has only been isolated from duodenal

homogenates.

Role of citrate. Citrate has been shown in a number of experimental

investigations to increase markedly the gastrointestinal absorption

of aluminum. It is also a common component of human diets. The

polyanion of triprotic citric acid, citrate forms stable complexes

with Al 3+ , possibly resulting in, among other species, a neutral

molecule (AlCi o ) at low pH that can be absorbed into the blood or

make aluminum available to iron-transport pathways. It is possible

that the hydroxy proton of citrate may also be involved in the

citrate-aluminum coordinate bond at physiologic pH, in a proposed

trinuclear aluminum complex. Based on stability constants, (

48 ) predicted that the maximum concentration of the neutral

aluminum-citrate complex, at 1 µM aluminum (about five times greater

than normal), would occur at pH 3 (close to that of the upper

intestine, where much absorption activity takes place) and 10 mM

citrate. Other models predict considerably lower concentrations of

this species, as discussed in the earlier section on equilibrium

modeling.

Citrate-enhanced absorption of aluminum is, however, at least in

part an energy-dependent process. Van der Voet et al. ( 74 ) based

this conclusion on their observation that administration of

dinitrophenol, which inhibits respiration by uncoupling oxidative

phosphorylation, decreased the citrate-mediated disappearance of

aluminum from the intestinal lumen. As mentioned above, citrate

increased absorption of aluminum as the chloride from the in situ

rat gut preparation ( 60 ).

Froment et al. ( 75 ), in an examination of the mechanism of

enhancement of aluminum uptake by citrate, tested the hypothesis

that citrate increases the permeability of the tight junctions

between intestinal epithelial cells. The investigators excised the

duodena of rats, added a solution of ruthenium red, and filled each

gut section with either aluminum chloride or aluminum citrate.

Examination of the isolated duodenal sections by transmission

electron microscopy, in the presence of aluminum citrate, revealed

infiltration of ruthenium red through the tight junctions,

supporting the hypothesis. In addition, aluminum citrate was found

to decrease the transcellular electrical resistance of tight

junctions. The investigators did not examine the effect of citrate

alone, however.

Schönholtzer et al. ( 32 ) found that when 26 Al was administered to

rats as aluminum citrate or aluminum maltolate, 0 to 300-min urinary

26 Al was 0.7 and 0.1% of the dose, respectively. After

administration of the 26 Al citrate with 1 mmol/kg sodium citrate,

5.3% of the 26 Al was found in the urine in the first 300 minutes,

suggesting that citrate increased intestinal permeability to

aluminum citrate.

Aluminum in Blood

Because of the high concentration of potential ligands relative to

the concentration of the metal, aluminum is expected to be entirely

soluble in blood at concentrations up to at least 100 µg/l. Based on

more than 50 literature sources, Ganrot ( 1 ) reported that the most

credible values for serum aluminum are in the range of 1-5 µg/l, or

0.037-0.185 µM; he judged that values much higher than these stem

largely from contamination. More recently, Wang et al. ( 76 )

measured levels of aluminum in 63 Canadians by Zeeman atomic

absorption spectroscopy and found an average of 0.06 ± 0.05 µM (1.62

µg/l) in serum and 0.20 ± 0.10 µM (5.4 µg/l) in urine.

Fulton and Jeffery ( 59 ) examined the effect of dietary citrate or

ascorbate on the absorption of aluminum from drinking water and

subsequent tissue concentrations and excretion. They found a dose-

dependent increase in aluminum concentration in bone, stomach,

intestine, and kidney; liver aluminum was 1.5-fold greater than

controls, but there was no dose response, and no aluminum was

observed in brain. Ascorbate and citrate increased the concentration

of aluminum in tibia, plasma, urine, and feces. Plasma aluminum

(about 0.7 µM) was less than 0.5% of total blood aluminum, which is

inconsistent with other studies and particularly surprising given

that transferrin is a plasma protein. Red blood cell aluminum did

not vary with dose of aluminum, whereas plasma aluminum did, which

is consistent with other work. Plasma aluminum concentrations were

within the range of values reported by other studies ( 1 ).

Nature and amounts of carrier molecules. Although many of the

ligands found in the gut are also found in the blood (Table 3), the

major plasma binder of aluminum is transferrin, an iron-transport

protein that also binds other metals, including aluminum, at two

specific binding sites. Some nonspecific aluminum binding may also

take place with albumin, and at least two other aluminum-binding

proteins, an 8 kDa component ( 38,77 ) and an 18 kDa component,

albindin ( 38 ).

Transferrin, which appears to be the major ligand for aluminum in

serum, is a protein of 76-80 kDa ( 78 ). It is similar in size and

amino-acid sequence to albumin, but binds metals (particularly iron)

with high specificity at two independent binding sites with similar

metal-binding affinities. Binding of a metal ion to transferrin

involves deprotonation of three tyrosine residues and concomitant

binding of a bicarbonate ion (whose concentration is not limiting in

serum). Transferrin is normally 30% saturated with iron ( 79 ).

Although its usual concentration in serum is 37 µM ( 51 ), lower

levels have been found in dialysis patients, about 30 µM ( 79 ).

Bertsch and ( 80 ) studied the speciation of the aluminum-

citrate system using ion chromatography. They found that only two

peaks were eluted, one containing hexaaquo (fully hydrated) aluminum

and the other apparently containing neutral aluminum citrate and

AlHCit 1+ . Other singly charged species were not distinguishable

from the second peak and, presumably, more highly charged species

were undetectable. Citrate complexes were highly sensitive to

changes in ionic strength.

Binding to serum proteins. Parajón et al. ( 81 ) evaluated two

ultrafiltration methodologies: conventional ultrafiltration, using

Amicon Diaflo YM10 and DDS GR61PP membranes, and

ultramicrofiltration, using the Amicon MPS-1 system with a 30 kDa

YMT membrane, for in vitro fractionation of aluminum. Contamination

was a large problem in both systems. These investigators found,

using the Amicon MPS-1 system, that 8.3% of serum aluminum from

normal subjects and 13.3% of that from patients with lower than

normal renal function (i.e., uremic) was ultrafiltrable.

Yokel and McNamara ( 82 ), using the MPS-1 system, found that a

greater proportion of aluminum was ultrafiltrable in the serum of

renally impaired rabbits than in serum from renally competent

animals. These results were obtained after incubation of aluminum

with rabbit serum in vitro and after an intravenous dose of 100

µmol/kg. These investigators also compared the ultrafiltrability of

different aluminum salts in bicarbonate buffer and found that the

citrate salt of aluminum remained completely ultrafiltrable up to a

total aluminum concentration of 1 mg/ml, while aluminum chloride,

nitrate, and lactate salts decreased in ultrafiltrability when total

aluminum exceeded 0.01 mg/ml. The concentrations at which aluminum

was not totally ultrafiltrable were above the high end of the

expected range of serum concentrations. Two of the rabbits in this

study died prematurely, possibly (according to the authors) from

kidney stones, which could conceivably have consisted of

precipitated aluminum.

The similar sizes of transferrin and albumin make it difficult to

separate these proteins chromatographically, and failure to add

bicarbonate to the elution buffer can decrease or prevent binding of

aluminum to transferrin. Many authors have assumed that aluminum

binds to both proteins, although evidence discussed below suggests

that binding to albumin is insignificant. et al. ( 83 ),

based on the weak binding of aluminum to albumin in vitro , the high

competition in vivo for albumin binding sites, and the generally low

affinity of metal ions for albumin, argued against significant in

vivo binding of aluminum to albumin. This would be particularly true

under uremic conditions, where potential binding sites on albumin

are likely to be occupied by other ligands that accumulate in serum.

Day et al. ( 30 ) administered an oral dose of 100 ng 26 Al and

about 1 µg 27 Al (natural aluminum) in sodium citrate solution to a

human volunteer. The highest plasma 26 Al concentration measured was

0.3 ng/l at 6 hr after ingestion, which suggests that at least 1% of

the administered dose (assuming a plasma volume of 3 l) was absorbed

(that is, this concentration does not account for aluminum that has

already been distributed to tissues or eliminated). The study

confirmed, by gel permeation chromatography and anion exchange

chromatography at pH 7.4, that 80% of aluminum in plasma was

associated with transferrin, 15% existed as other high molecular

weight (>5 kDa) complexes (including albumin), and 5% as low

molecular weight species. Ion-exchange chromatography, however, may

cause redistribution of ionic aluminum among proteins, so the

findings of protein-specific binding are not reliable.

Favarato et al. ( 38 ) compared the protein binding of aluminum in

serum among renally competent workers exposed and unexposed to

aluminum and detected a novel protein, dubbed " albindin. " This

protein picked up more than 40% of serum aluminum after treatment of

the serum with desferrioxamine, a powerful chelator of trivalent

metallic cations. The amino-acid composition of albindin was

distinct from that of transferrin or albumin ( 38 ). The protein-

binding profile of aluminum was most complex in the more highly

exposed group of workers (classified on the basis of total serum

aluminum content). Proteins were identified by polyacrylamide gel

electrophoresis (SDS-PAGE), but transferrin and albumin could not be

resolved chromatographically ( 38 ).

Cochran et al. ( 39 ) eluted plasma (which had been spiked with

aluminum) from uremic patients on Sephacryl S-300 and assessed the

reproducibility of the aluminum/transferrin and aluminum/albumin

molar ratios in adjacent elution fractions. They found that the

aluminum: transferrin ratio remained at about 0.12, whereas

aluminum/albumin varied from 0.002 to 0.024. These results provided

evidence for an association between aluminum and transferrin but not

albumin. Transferrin and albumin concentrations were assessed by

immunodiffusion, but the methods used were neither described nor

referenced. The overall recovery of aluminum was not reported for

this experiment, so the significance of the results is uncertain.

Dialysis of purified albumin against aluminum solution resulted in

the association of 10% of the aluminum with albumin, but when

calcium and phosphate were added, no association of aluminum with

albumin was detectable. There was no evidence of association of

aluminum with either the Sephacryl S-300 or Sephadex G-50 gel used

by Cochran et al. ( 39 ).

Role of transferrin. Evidence for transferrin's role as an aluminum

carrier is strengthened by a study by Cannata et al. ( 69 ) that

showed increased aluminum levels in the urine and brain of rats

depleted of iron and exposed orally to aluminum). This phenomenon

may occur because reduced iron stores lead to increased production

of transferrin ( 84 , 85 ), a central concept in iron homeostasis.

Cannata et al. also found that iron-depleted rat intestinal

epithelial cells in vitro contained significantly more aluminum when

exposed to transferrin-bound aluminum than did normal cells ( 69 ).

Although these results, which show aluminum retention, may reflect

aluminum uptake into tissues in general, this evidence is not

specifically relevant to the intestine because transferrin is not

found in the intestinal lumen.

In vitro analytical chemical methods such as titration have been

used to estimate the affinity of aluminum (and other metals) for

transferrin and other potential chelators found in serum.

Transferrin's affinity for iron is considerably higher than for

aluminum [e.g., log K 1 = 22.7 and log K 2 = 22.1 for Fe 3+ ( 83 )

compared to log K 1 = 13.72 and log K 2 = 12.72 for Al 3+ ( 51 ).

Because aluminum is present in small amounts in the blood relative

to iron concentrations and the capacity of transferrin to bind

aluminum (as discussed above), and because iron normally occupies

only 30% of available sites on transferrin, aluminum binding to

transferrin is not expected to be limited by either the

concentration in blood of transferrin (37 µM) ( 51 ) or of iron.

Kinetics of Aluminum Uptake by Cells

As in the gastrointestinal tract, aluminum may be taken up into

cells by mechanisms similar to those used to take up iron. Foremost

among such mechanisms is receptor-mediated uptake of transferrin-

bound metal, which is saturable. Small-molecular forms of aluminum

may be taken up via diffusion of ions or via pinocytotic uptake of

small amounts of extracellular fluid.

Several investigators have examined the uptake kinetics of

transferrin and iron by cells. Cole and Glass ( 86 ) found binding

of iron to transferrin was not saturated at iron concentrations up

to 50 µM. Iron uptake by mouse hepatocytes increased with increasing

transferrin concentrations, but nonspecific uptake (pinocytosis

and/or diffusion) accounted for 10-20% of uptake. Dissociation

constants of 0.081 µM (for suspended cells) and 0.29 µM (for plated

cells) were reported for the dissociation of transferrin from cells.

Page et al. ( 87 ) found similar results using cultured rat

hepatocytes. Cochran et al. ( 88 ) examined the competition between

aluminum and iron for transferrin binding and uptake in

reticulocytes (immature red blood cells). Binding was significantly

less strong in these cells ( K d = 3 µM) than Cole and Glass ( 86 )

reported for hepatocytes. Furthermore, aluminum + radiolabeled

transferrin (5 µM) was taken up 1.8 times faster than labeled iron-

transferrin. Iron uptake reached a plateau by 40 min; aluminum

uptake, in contrast, continued to increase after 40 min. In

addition, uptake of radiolabeled iron-transferrin was inhibited to a

greater extent by addition of unlabeled iron-transferrin than by

addition of aluminum-transferrin. The authors postulated a post-

uptake feedback mechanism to regulate uptake of iron, which does not

appear to have an effect on uptake of aluminum ( 88 ). McGregor et

al. ( 89 ) reported that aluminum in the form of an AlCl 3 solution

became associated with cells (probably nonspecifically) more than

did aluminum in a citrate solution. This may occur because, at

physiologic pH, aluminum from AlCl 3 would be expected to be

hydrolyzed to colloidal Al(OH) 3 o , in contrast to aluminum

citrate, which forms only charged species at intermediate pH.

Interestingly, in contrast to the results of Cochran et al. ( 88 ),

transferrin-bound aluminum downregulated the number of cell-surface

transferrin receptors on human erythroleukemia K562 cells to a

greater degree than iron did ( 90 ). It is possible that hepatocytes

possess a regulatory mechanism for transferrin receptors that is

different from that in cultured leukemia cells. Alternatively, there

may be an interspecies difference, as Cochran et al. used rat

hepatocytes, but the differences may also be due largely to the

different study designs.

Pharmacologic Behavior of Aluminum: Distribution and Excretion

After gastrointestinal absorption (or intraperitoneal injection),

aluminum travels via the portal circulation into the liver, where it

is thought to undergo a first-pass clearance; that is, much is

removed from the bloodstream ( 91 ).

A 41-year-old male volunteer given 26 Al intravenously as aluminum

citrate excreted all but 10-15% of the aluminum during the first day

( 31 ). However, 7% of the aluminum remained 170 days after the

injection, at which time the authors estimated the clearance half-

time to be >1 year. Analysis of their results by RSTRIP ( 92 ), a

program for pharmacokinetic analysis, showed that the terminal

elimination half-lives of 26 Al that could be estimated in blood and

the whole body were about 7 and 300 days, respectively. However, the

confidence in this estimate of a 300-day half-life, based on samples

collected to only 170 days, is not great. Further analysis of these

results suggests that the whole-body aluminum elimination half-life

increases with time after exposure. This phenomenon might be

explained by the retention of aluminum in a chemical species

different from that administered. This species may represent a depot

of aluminum that might serve as an aluminum source within the body

as it is slowly eliminated from its site of distribution. The whole-

body retention of 7% of the administered aluminum 6 months after

dosing suggests the prolonged residence of a significant fraction of

the administered aluminum. With continued exposure the aluminum

depot would be expected to increase. The result would be an increase

in aluminum over the human life span, as reported for brain aluminum

( 93 ).

Much of the work conducted thus far on aluminum speciation and

distribution has looked at exposures other than ingestion, such as

intravenous injection, which can bypass the first-pass effect of the

liver. Exposure to dialysis fluid can be considered analogous to

intravenous injection because the bloodstream is directly exposed,

without being filtered first by the liver.

Implications of speciation for aluminum excretion and aluminum in

uremia. The ionic milieu and speciation of aluminum in various body

fluids are important to the nature and rate of aluminum elimination

by various routes. Aluminum is excreted primarily in the urine, as

described above, and to a small degree in the feces (largely as

insoluble aluminum phosphate) by way of the portal circulation,

liver, and bile. Xu et al. ( 94 ) found that biliary excretion

accounted for <1% of the aluminum administered as the sulfate to

rats, whereas urinary elimination accounted for 9-17%. Greater than

80% of an intravenous dose of 26 Al citrate was eliminated in the

urine of a human within 2 weeks, whereas <2% appeared in the feces (

31 ). The relative contributions of each route of excretion depend

in part on such factors as the solubility of aluminum species,

presence of complexing ions in serum, renal competence, and aluminum

dose. Under normal renal conditions, aluminum should be excreted in

urine in the form of small, charged, and thus water-soluble ions or

complexes with anions such as citrate and phosphate. Renal

dysfunction could result in the excretion of protein-bound aluminum

as well.

Uremic animals and humans seem to be more susceptible to aluminum

accumulation and toxicity than renally competent subjects, even in

the absence of dialysis. Alfrey et al. ( 95 ) found that nondialyzed

uremic patients experienced aluminum burdens in liver 6.3 times,

spleen 12 times, bone 6.2 times, and brain 1.7 times higher than

renally competent patients. Dialyzed uremics and, in particular,

dialyzed uremics suffering from encephalopathy, had tissue burdens

many times higher than nondialyzed uremics.

Hosokawa and Yoshida ( 96 ) performed 5/6 nephrectomy on rats and

collected serum 3 months later, without administering additional

aluminum above the normal dietary exposure. They found that the

average concentration of aluminum in serum was more than 10 times

that seen in renally intact rats, and the concentration in kidneys

was about 10 times higher. Arieff et al. ( 97 ) obtained results

similar to Alfrey's human data for concentrations of aluminum in

liver of nonuremic dogs and uremic rats but, in contrast, they found

that brain aluminum was higher in nondialyzed than dialyzed chronic

renal failure patients. No information was given on the aluminum

content of the water used in dialysis. It is possible that, if water

containing little or no aluminum was used to prepare the dialysis

fluid, dialysis could have cleared the blood of small-molecule

aluminum, although most aluminum is not in this form. Another

explanation could be dietary or therapeutic differences between

dialyzed and nondialyzed individuals that would result in the

administration or gastrointestinal absorption of different total

quantities of aluminum.

There are a number of possible reasons for the observation that

uremia leads to an increased body burden of aluminum. The simplest

explanation is that, in having lower excretory capacity, uremics

might simply not be able to rid themselves of aluminum efficiently,

allowing it more time to be distributed to peripheral tissues. Yokel

and McNamara ( 82 ) found that the systemic clearance was

significantly lower in renally impaired animals than renally intact

(39 compared to 53 ml/kg-hr), whereas Meirav et al. ( 29 ) compared

the systemic clearance of aluminum in a renally impaired rat to that

in two normal rats and found that the renal clearance was similar.

Ittel et al. ( 98 ) found that urinary excretion of aluminum was

greater in uremic than in control rats, but ascribed their results

to greater absorption of aluminum rather than greater clearance. A

mechanism postulated for an increase in absorption was secondary

hyperparathyroidism.

The aluminum toxicity experienced by uremics may also be iatrogenic,

through exposure to aluminum in dialysis fluid. This possibility has

already been addressed in the clinical setting: dialysis fluid is

now made from low-aluminum water, and patients appear to suffer less

aluminum toxicity as a result ( 1 ).

An alternative explanation for Ittel's observation of increased

excretion of aluminum in uremia is that the free, or ultrafiltrable,

fraction is increased relative to the protein-bound fraction. One

study found that a greater percentage of the aluminum added to serum

from renally impaired rabbits was free than in serum from normal

rabbits ( 82 ). However, Graf et al. ( 99 ) found a negative

relationship between plasma aluminum concentration and percent

ultrafilterable aluminum in 24 dialysis patients. Another study (

36 ) found 46% of the aluminum in serum ultrafiltrate from 30 normal

patients and 33% of the aluminum in the ultrafiltrate from 30 uremic

patients, with an increase in non-ultrafiltrate aluminum as serum

aluminum increased.

Alternatively, it is plausible that, in uremia, potential aluminum-

binding sites on transferrin (and possibly albumin or some other

protein) are occupied by competing ligand molecules that accumulate

in the blood. Excretion of aluminum would thus be expected to

increase with time after onset of uremia, as competing ligands

accumulate, but this hypothesis has not been investigated. Cochran

et al. ( 79 ) reported that the serum transferrin concentration in

dialysis patients is about 30 µM. Given that serum aluminum

concentrations are higher than normal in these patients, this

reduction in aluminum-binding capacity may have implications for

aluminum speciation.

As uremics also experience higher aluminum tissue burden and

toxicity ( 95 ), it may be that this fraction is more available to

tissues than the protein-bound fraction, although tissue burden may

reflect selective retention rather than increased bioavailability.

Another explanation that has not been examined is that tubular

reabsorption of aluminum occurs to a greater degree in uremics.

Distribution of Aluminum to the Central Nervous System

The brain appears to be one of the most important target sites for

aluminum toxicity. The blood-brain barrier is normally permeable

only to small molecules, or larger molecules, such as proteins, by

active-transport mechanisms. Because of this low permeability, it is

important to understand the mechanisms by which aluminum permeates

the barrier. Aluminum-protein complexes are unlikely to permeate the

blood-brain barrier directly because of their size, although

transferrin-receptor-mediated uptake is a possible mechanism (

100 ). Transferrin receptors are found in a number of CNS cell

types, including neurons, oligodendrocytes, astrocytes, ependymal

cells (found in the spinal cord), and choroid plexus cells ( 101 ).

Transferrin is believed to play a role in the development of

myelinated cells. In the presence of other, smaller complexes,

however, aluminum could cross the blood-brain barrier. A case study

was reported of several renal dialysis patients suffering from bone

aluminum toxicity who were treated with desferrioxamine, an iron-

chelating drug that also efficiently chelates aluminum. The subjects

experienced neurological symptoms resembling dialysis dementia;

several of them died. The investigators conjectured that the

resulting desferrioxamine-aluminum complex, which is much smaller

and more soluble than aluminum-protein complexes, had distributed

into the brain ( 102 ). Yokel et al. ( 103 ) supported this

hypothesis in a rat study using microdialysis probes to monitor

aluminum-desferrioxamine distribution into various tissues,

including the brain.

and Yokel ( 104 ) used in vivo microdialysis to compare the

permeabilities of aluminum and gallium through the blood-brain

barrier with a view to using gallium as a model for aluminum. They

found aluminum and gallium permeation to be dissimilar. Gallium,

although attractive because it possesses usable radioisotopes,

therefore does not seem an appropriate model for aluminum

penetration into the brain. Specifically, these investigators found

that aluminum permeates the brain primarily at the cerebral

capillaries, whereas gallium permeates equally at the cerebral

capillaries and at the choroid plexuses. The permeation of aluminum

was nonsaturable, suggesting a nonspecific process such as diffusion

or pinocytosis of small-molecule aluminum rather than binding of

aluminum-transferrin to cell-surface receptors. The permeation of

aluminum into the brain could, however, be a combination of specific

and nonspecific processes and still appear nonsaturable overall, so

there still may be a role for transferrin.

Farrar et al. ( 105 ) used HPLC and gel electrophoresis to study the

binding of radioactive gallium (which they presumed to be analogous

to aluminum) to transferrin. Binding was lower in people with either

AD or Down's syndrome than in normal subjects. The authors postulate

that reduced binding of gallium, and presumably aluminum, to

transferrin could lead to increased uptake of the metal across the

blood-brain barrier as a neutral citrate complex. As discussed

above, aluminum appears to be taken up in a nonsaturable fashion

(i.e., nonspecifically), at least at the cerebral capillaries (

104 ).

Roskams and Connor ( 100 ) examined the binding of aluminum-

transferrin and iron-transferrin to homogenized rat brain and found

evidence of a receptor that binds both. Dissociation constants ( K

d ) were 5.7 nM for iron-transferrin and 13.1 nM for aluminum-

transferrin. The affinity of this receptor for aluminum-transferrin,

although lower than that for iron-transferrin, is still higher than

the affinity of receptors in other cells (such as hepatocytes and

lymphocytes) for iron-transferrin. Unfortunately, homogenized rat

brain is probably not a good model for the blood-brain barrier.

These authors suggested that aluminum's toxicity in the brain might

involve, at least in part, disruption of normal iron homeostasis and

iron-dependent cellular processes. Fleming and Joshi ( 106 ) found

that aluminum can interfere with the rate of binding of iron to

ferritin, an iron-storage protein, in support of Roskams and

Connor's suggestion ( 100 ).

Summary and Conclusions

A small fraction (0.1-1%) of aluminum appears to be absorbed

gastrointestinally from the diet, possibly by iron-absorption

pathways. Upon reaching the serum, 80-90% of aluminum binds to the

iron-transport protein transferrin and, possibly, to albumin;

another aluminum-binding protein that has not yet been well

characterized has also been tentatively identified. The remaining 10-

20% of aluminum forms soluble (operationally defined as

ultrafiltrable), small-molecular complexes, particularly with

citrate and phosphate, some of them hydrolyzed. Aluminum is expected

to be entirely soluble in serum due to large excesses of complexing

ligands. Existing analytical techniques are, however, inadequate to

establish definitively the nature of the aluminum species present in

biological fluids. Equilibrium modeling and nuclear magnetic

resonance indicate that most of the major species at physiologic pH

are charged. The only neutral species postulated is Al(OH) 3 o (aq),

whose existence has not been established and which, in any case,

appears, based on modeling data, not to constitute a large fraction

of soluble aluminum species in serum.

The charged, soluble aluminum species are unavailable for diffusion

into tissues, but are presumably readily excretable. Receptors for

transferrin, on the other hand, exist in many cells, including at

the blood-brain barrier, and provide a means for uptake of

transferrin-bound aluminum into tissues. Radionuclides of aluminum

are expensive, making tracer studies difficult; atomic absorption

spectroscopy is the usual means of quantitating aluminum in

biological samples. Radioactive gallium has been used as a model for

aluminum uptake, but its behavior does not appear to be strictly

comparable. Uptake of aluminum into brain and bone lead to toxicity.

Aluminum toxicity is of particular concern to individuals with

kidney impairment, in whom aluminum concentrations are higher.

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Last Update: June 18, 1998

In , " Leigh Anne Carson "

<neilcarson@...> wrote:

>

> My kids are prone to constipation/hyperactivity/anxiety so we use

a

> lot of magnesium citrate. I was looking for possible sources of

> aluminum and came across this study. Thoughts?

>

> South Med J. 1994 Sep;87(9):894-8. Related Articles, Links

>

>

> Aluminum and lead absorption from dietary sources in women

ingesting

> calcium citrate.

>

> Nolan CR, DeGoes JJ, Alfrey AC.

>

> Department of Medicine, Wilford Hall USAF Medical Center, Lackland

> Air Force Base, Tex.

>

> Animal models suggest that citrate-containing compounds augment

> absorption of aluminum from food and tap water, causing aluminum

> accumulation in bone and brain despite normal renal function.

Citrate

> also enhances lead absorption in animals. We questioned whether

use

> of calcium citrate by women as a calcium supplement causes an

> increase in aluminum or lead absorption from dietary sources.

Changes

> in 24-hour urine aluminum and lead excretion, plasma aluminum

level,

> and whole blood lead level were assessed in 30 healthy women

before

> and during treatment with calcium citrate (800 mg of elemental

> calcium per day). During calcium citrate therapy, urinary aluminum

> excretion and plasma aluminum level increased significantly. In

> contrast, there were no changes in urine or whole blood lead

levels.

> We conclude that treatment with calcium citrate significantly

> increases absorption of aluminum from dietary sources. Additional

> studies are needed to determine whether long-term use of calcium

> citrate leads to aluminum accumulation and toxicity.

>

[Guest guest]

Regarding aluminum toxicity and malic acid, see posts:

http://onibasu.com/archives/am/178148.html

http://onibasu.com/archives/am/129181.html

http://onibasu.com/archives/am/115764.html

Re: [ ] Re: Regarding aluminum toxicity - what do you

think of this study?

Magnesium malate from Source Naturals is also what I use - the malic acid in

it is suppose to chelate aluminum.

lanellici <lanellici@...> wrote:

> We are trying to get rid of my son's aluminum!

> and I bump up the magnesium (citrate of course, sigh) during that

> time...it could be making the round much less effective.

We don't really know yet. Often a study will seem to point to a

conclusion that isn't correct.

> Is there a brand of mag. malate that mixes well into juice (comes as

> a powder preferably)?

I used mag malate from Source Naturals for years. At least going by

hair tests, AL is very stubborn.

Nell

[Guest guest]

One thing to note is that a lot of Source Naturals products now

contain wheat. I recently purchased some things and they had added

stickers to the bottles saying so. Worth checking into if wheat is a

problem.

René

>

> Magnesium malate from Source Naturals is also what I use - the malic

acid in it is suppose to chelate aluminum.

>

[Guest guest]

Regarding these posts, I was wondering if you could use aluminum as a marker for

knowing when the mercury was mostly gone. Our mercury, first hair test was

nonexistant, went to the high green and stayed there for two hair tests and is

now down to low, low green, although the cadmium was elevated to the lowest

yellow value.

The aluminum started 3/4 in the green and has steadily gone down to very low.

Have always had a suspicion that we did not have that much of a problem with

mercury, more with Bismuth that started in the red, (now in the low green

value). Bismuth can cause all the neurological and physiological problems that

mercury can i.e. binds to sulfhydrl enzymes, neurological problems, etc,

anorexia, etc. Always wondered if that was the reason she has never ever met

the counting rules.

Re: [ ] Re: Regarding aluminum toxicity - what do you

think of this study?

Magnesium malate from Source Naturals is also what I use - the malic acid in

it is suppose to chelate aluminum.

lanellici <lanellici@...> wrote:

> We are trying to get rid of my son's aluminum!

> and I bump up the magnesium (citrate of course, sigh) during that

> time...it could be making the round much less effective.

We don't really know yet. Often a study will seem to point to a

conclusion that isn't correct.

> Is there a brand of mag. malate that mixes well into juice (comes as

> a powder preferably)?

I used mag malate from Source Naturals for years. At least going by

hair tests, AL is very stubborn.

Nell