Aluminum toxicokinetics regarding infant diet and vaccinations
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Vaccine 20 (2002) S13–S17
Aluminum toxicokinetics regarding infant diet and vaccinations
L.S. Keith∗ , D.E. Jones, C.-H.S.J. Chou
Agency for Toxic Substances and Disease Registry, Division of Toxicology, 1600 Clifton Road, NE, Mailstop E-29, Atlanta, GA 30333, USA
Received 4 June 2001; accepted 7 August 2001
Abstract
Some vaccines contain aluminum adjuvants to enhance the immunological response, and it has been postulated that this aluminum could
contribute to adverse health effects, especially in children who receive a vaccination series starting at birth. The pharmacokinetic properties
and end-point toxicities of aluminum are presented. In assessing the relevance of dietary and medical aluminum exposure to public health,
we estimated infant body burdens during the first year of life for breast milk and formula diets and for a standard vaccination schedule.
We then compared those body burdens with that expected for intake at a level considered safe for intermediate-duration exposure. The
methodology blends intake values and uptake fractions with an aluminum retention function derived from a human injection study using
radioactive 26 Al. The calculated body burden of aluminum from vaccinations exceeds that from dietary sources, however, it is below the
minimal risk level equivalent curve after the brief period following injection. Published by Elsevier Science Ltd.
Keywords: Aluminum; Vaccine; Diet
1. Introduction nations several years before the nodules developed. The
pharmacokinetics and end point toxicity of aluminum are
Aluminum is the third most abundant element in the described below. A method is presented for estimating infant
earth’s crust. This status ensures that the element is present aluminum body burdens associated with dietary intake, vac-
in essentially all air, food, and water. Aluminum is not a cinations, and daily oral intake at a level considered safe by
free metal in nature but is found concentrated in bauxite ore the Agency for Toxic Substances and Disease Registry [2].
deposits that are mined, dissolved in a high temperature and
pressure digestion process, crystallized and calcined to alu-
mina, and then reduced to metallic aluminum. The United 2. Uptake and distribution
States produced 3.7 million metric tons in 1998 for use in
various industries, including building construction, baking 2.1. Uptake
products, and medicine. Historical medical exposures to
Aluminum and its compounds tend to solubilize into
aluminum in renally impaired individuals undergoing dial-
trivalent Al3+ cations in acid environments below pH 5, a
ysis produced a neurological condition in some individuals
phenomenon that makes exterior aluminum surfaces cor-
known as dialysis dementia. Its medical use in vaccines
rodible in acid rain. In the same way, dietary aluminum
occasionally produces adverse reactions (granulomas, per-
compounds dissociate in stomach acid to become unattached
sistent nodules, abscesses, or hypersensitivity) and has stim-
ligands and free aluminum ions that subsequently hydrate
ulated interest by the World Health Organization [1] in the
to form trivalent aluminum hexahydrate. A small portion
toxicity of injected aluminum compounds, especially among
of the aluminum recomplexes with the original or another
the infant population. This follows a similar effort regard-
available ligand in a manner that preferentially favors car-
ing thimerosal (a mercury-containing preservative which
boxylic acids, such as citrate or lactate. Dietary phosphorus
has been eliminated from some vaccine formulations) and
that attaches to the aluminum becomes unavailable for up-
reports of muscle nodules (termed macrophagic myofasci-
take, leading in some cases (large quantity antacid use) to
itis or MMF) observed primarily in immune-compromised
hypophosphatemia with consequent skeletal implications.
Frenchmen who had received aluminum adjuvated vacci-
The majority (>99%) passes unattached into the duodenum
where the increased alkalinity sequentially deprotonates
∗ Corresponding author. Tel.: +1-404-498-0734; fax: +1-404-498-0092. the aluminum hexahydrate ion into insoluble aluminum hy-
E-mail address: skeith@cdc.gov (L.S. Keith). droxide, which is primarily excreted in the feces. A small
0264-410X/02/$ – see front matter. Published by Elsevier Science Ltd.
PII: S 0 2 6 4 - 4 1 0 X ( 0 2 ) 0 0 1 6 5 - 2S14 L.S. Keith et al. / Vaccine 20 (2002) S13–S17
fraction of the aluminum becomes systemic through pro- of aluminum adjuvant for each vaccine type. Varying the
cesses that have not yet been elucidated but are believed to aluminum between initial and subsequent injections in a se-
involve passive paracellular or transcellular diffusion. An ries could be considered.
additional and unique carboxylic acid-mediated mechanism
enhances gastrointestinal tract absorption by more than an 2.4. Distribution pattern
order of magnitude. The resulting human uptake factors
range from 0.01% for the hydroxide to a maximum of around Once aluminum is in the bloodstream, it distributes widely
1%, with lactate being measured at 0.78% [3–6]. Yokel and to the various body tissues in a pattern that may parallel the
McNamara [7] found the following similar relative uptake density of transferrin receptors within those tissues. Intra-
of aluminum compounds in the rat: citrate > lactate > muscularly injected aluminum hydroxide in rabbits had the
sucrose sulfate > chloride > hydroxide > glycinate > following pattern of tissue redistribution: kidney > spleen >
borate. Trivalent aluminum cations can block the uptake of liver > heart > lymph > brain [13]. The rat model followed
bioessential trivalent phosphorus or phosphate anions [8] so the same pattern, and the addition of bone analysis showed
effectively that a low aluminum diet and restricted antacid that skeletal deposition greatly exceeds that of kidney, with
use are recommended for hypophosphatemic individuals. a value that doubled in uremic rats [14]. Based on these
studies, bone is the primary long-term reservoir for systemic
2.2. Transfer rate from blood aluminum following either ingestion or injection in humans.
Systemic aluminum binds to serum proteins or anions and
is distributed rapidly to other tissues throughout the body. 3. Retention
Approximately, 89% of the aluminum reaching the blood
binds with transferrin, and the rest mainly attaches to cit- 3.1. Elimination rates
rate [9]. The transfer rate from blood has been measured in
various studies. Sutherland and Greger [10] found an initial The retention of aluminum is directly affected by excre-
half-time of 102–119 min, and transfer rates ranging from tion, which has been studied in both rats and humans. Xu
0.003 h−1 for a central compartment (which is likely bone) et al. [15] found 66–70% of injected aluminum was excreted
up to 9 h−1 for three peripheral compartments. In a more sen- in 24 h. In a human study, Priest et al. [11] injected a volun-
sitive study by Priest et al. [11], radioactive 26 Al citrate was teer with 0.7 g of radioactive 26 Al as citrate and followed
injected into a human volunteer and blood aluminum levels blood levels and body elimination. They found that over 50%
were found to decrease by >50% in 15 min and by >99% in of the aluminum distributed from blood to other body tissues
2 days. The advantages of using this accelerator-produced in 15 min. Long-term observation using excreta and whole
radioisotope are high sensitivity using a small mass of alu- body monitoring found excretions of >50% in 24 h, 85%
minum and noninterference by the naturally present 27 Al. at 13 days, and 96% by 1178 days. Elimination followed a
power function featuring a rapid initial release followed by
2.3. Release from injection site successively longer-term components. The result is an over-
all slow buildup of aluminum in the body over a lifetime.
Aluminum adjuvants injected intramuscularly or subcuta-
neously in vaccines can experience some delay in entering 3.2. Retention functions
the bloodstream. Heimlich et al. [12] adsorbed a mock anti-
gen and each of several interstitial and serum proteins onto Mature human tissue can contain aluminum concen-
an aluminum adjuvant. During an in vitro exchange reac- trations of 20 mg/kg in lung, 5–10 mg/kg in bone, and
tion test, free interstitial proteins were found to separate an 0.3–0.8 mg/kg in soft tissue. The body burden late in life
aluminum adjuvant from the mock antigen to which it was can be estimated to reach 20 mg in lung, 25–50 mg in bone,
bound. However, the free mock antigen could not separate and 9–24 mg in soft tissue, with the body burden totalling
the interstitial protein-aluminum adjuvant complexes. Over approximately 50–100 mg Al. The Priest et al. [11] formulae
50% of the adjuvant transferred from the antigen to the in- provide a method for assessing the fate of either injected or
terstitial or serum protein within 15 min. This indicates that dietary aluminum. The body burden from a single injection
the aluminum in vaccines may be readily mobilized from followed a power function of the form,
the injection site. This rapid dissociation raises two distinct R = 0.354dt−0.32 , (1)
but opposing possibilities: (1) that a smaller amount of ad-
juvant may be appropriate for some vaccines, or (2) that a where R is the retained fraction, d the uptake dose in mg Al,
larger amount of aluminum may be needed to achieve max- and t the time in days following uptake.
imum efficacy for some vaccines. Experiments to measure Eq. (1) applies to a single oral dose or a single vaccination
antibody titers (as an indicator of vaccine efficacy) could be injection, and may be summed for repetitive dietary intakes
devised using varying and precisely measured ratios of adju- or a multiple vaccination regimen. The body burden from
vant to antigen in order to identify an optimal concentration uniform daily dosing, such as may be assumed for adultL.S. Keith et al. / Vaccine 20 (2002) S13–S17 S15
dietary sources, is obtained by integrating Eq. (1), resulting to the daily aluminum intake, with the resulting dietary
in, curves shown in Fig. 1.
B = 0.52d(t 0.68 − 1), (2)
where B is the body burden based on constant uptake. 4. Toxicity summary
Uptake following injections is taken as 100%; dietary con-
4.1. Historical toxicity observations
tribution is considered to be the product of dietary intake
and the gastrointestinal tract uptake factor. Vaccinations typ-
ATSDR has summarized the pharmacokinetics and end-
ically begin early in infancy and are repeated several times
point toxicity of aluminum in its Toxicological Profile for
over the course of the first year of life, making this the focus
Aluminum [2]. The mechanism of aluminum toxic action is
period of this article.
currently unknown. The element may affect the phospho-
inositide second messenger-producing system, which mod-
3.3. Infant dietary body burden ulates intracellular calcium concentrations [22]. It strongly
binds in a largely irreversible manner to large proteins, such
An infant’s general fluid consumption increases from as nuclear components, which may relate to an inhibition
670 ml per day at birth to 900 ml per day at 6 months, with of neuronal microtubule formation. Neurotoxicity has been
aluminum intake depending on the dietary source. Breast identified as the most sensitive health end point for ingested
milk measurements cover the range of 5–380 g Al/l with aluminum. Its effect on the nervous system was first recog-
a central value around 40 g/l [16–20]; the high value is nized in past decades in cases involving renal failure. The
associated with Croatian women, but the cause has not yet dialysate solution for renal patients was made from tap wa-
been elucidated. Formula concentrations average around ter, which naturally contained some aluminum. It was subse-
225 g Al/l with a maximum of 1150 g/l. The higher lev- quently introduced into systemic circulation where it bound
els in formula over breast milk may be a result of food in- with transferrin. This molecule was not filterable by the dial-
dustry practices using aluminum components in processing ysis equipment, resulting in an ever-increasing aluminum
facilities and adding aluminum-containing compounds to body burden that was enhanced by elevated tap water lev-
food ingredients to improve their blending and anti-caking els. A neurological disorder was produced in some patients
properties. The daily fluid volume coupled with the source that was termed dialysis dementia. Investigation found ele-
concentration gives the daily aluminum intake through 6 vated serum aluminum levels, a condition that is now known
months of age. During the second 6 months, introduction of to be preventable by using water with low aluminum con-
semisolid food increases the aluminum intake to an average tent. Other more subtle neurological effects that have been
0.7 mg per day [21]. An estimate of infant aluminum body induced in animal models or associated with human occu-
burden during year 1 was developed using a 0.78% uptake pational exposure include memory loss, fatigue, depression,
factor and applying the Priest et al. [11] retention function behavioral modifications, and learning impairment.
Fig. 1. Aluminum body burden contributions from diet and vaccines relative to MRL level intake.S16 L.S. Keith et al. / Vaccine 20 (2002) S13–S17
4.2. Inhalation exposure experienced spontaneous motor activity interference with a
no-observed-adverse-effect level (NOAEL) of 62 mg Al/kg
Inhaled aluminum can be a respiratory toxicant causing per day [31]. Applying uncertainty factors of 3 for extrapo-
irritation and, ultimately, pulmonary fibrosis [23]. Such fi- lation to humans and 10 for human variability produced an
brosis has been produced by a pyrotechnic powder in com- MRL of 2 mg Al/kg per day.
bination with a nonpolar oil, but has not been observed
since the manufacturing process adjusted to use another
type of lubricant. Steinhagen et al. [24] noted an increase 5. MRL body burden
in the number of pulmonary macrophages following alu-
minum exposure. This outcome can also be induced by a The MRL curves in Fig. 1 are based on low and average
range of other inhaled species, and a review of the overall weight infants consuming aluminum at an amount equiva-
inhalation database indicates that the effects are consistent lent to the MRL each day starting from birth. The curves
with pulmonary overload associated with diverse inorganic are adjusted for increasing daily body mass and food intake
dust. using an intestinal uptake factor of 0.78% and excretion ac-
cording to Eq. (1). Since the MRL is a function of body
4.3. Dermal exposure weight, which significantly changes during year 1 for the in-
fant, it was necessary to first modify Eq. (1) by an appropri-
Aluminum compounds can also cause dermal irritation ate body weight function before integration. Functions were
or an immunologic response. Antiperspirants containing derived for standard 5th and 50th percentile females using a
aluminum chlorhydrate can cause a localized underarm standard chart of monthly infant body weights [32], and are
irritation in some individuals [25]. Aluminum adjuvated of the form,
vaccines have produced a permanent and decentralized sen-
sitivity in those individuals who experience injection site BW(5th percentile female) = 2.36 + 10(1 − e−0.0023×A )
granulomatous nodules that last more than several weeks,
and
a phenomenon that is reportedly quite rare [26]. Similar le-
sions have been observed in hilar and peribronchial lymph BW(50th percentile female) = 3.23 + 10(1 − e−0.0028×A ),
nodes following inhalation exposure.
(3)
4.4. Oral exposure where BW is the body weight (kg) and A is age (days).
The MRL curves are the upper two on Fig. 1, and the
Musculoskeletal toxicity is atypical among those with curve for 5th percentile infants is below that for the 50th
normal renal function. However, trivalent aluminum ions percentile group. The dietary curves for ingested breast milk
have been found to pharmacokinetically compete with di- and formula are the lower two in Fig. 1, and fall well below
valent magnesium and calcium ions during hydroxyapatite both MRL curves.
osteogenic formation. This occurs despite the ionic valence
disparity that makes aluminum an unexpected competitor
based on valence considerations alone. Osteomalacia in ure- 6. Vaccine body burden
mic individuals involves systemic aluminum buildup that
correlates with aluminum content of bone [27,28]. Con-
The systemic aluminum body burden from vaccine injec-
versely, osteomalacia and rickets in otherwise healthy indi-
tions can be estimated using the previous Priest equation
viduals involve phosphate depletion rather than aluminum
and the injection dose and schedule information presented in
buildup in bone. These effects are observed among chronic
Table 1. A simplified dosing schedule was used that reduced
antacid users in whom the aluminum binds with intestinal
the CDC-recommended time windows [33] to specific time
phosphorus and prevents its uptake [29,30]. Either can ulti-
mately lead to pathological fractures.
Table 1
4.5. Minimal risk level (MRL) Vaccination schedule [33]
Age Vaccination(s)a Aluminum content (mg) [34]
ATSDR reviewed a large body of literature and con-
Birth Hep B 0.25
cluded that neurotoxicity is the most sensitive health end
2 months Hep B + DTP 0.50–1.10
point for ingested aluminum compounds. The agency 4 months DTP 0.25–0.85
used this end point in developing an oral MRL, or 6 months Hep B + DTP 0.50–1.10
dose which is expected to be safe for human exposure. 12 months DTP 0.25–0.85
The basis was an intermediate-duration study in which a Hep B: hepatitis B; DTP: diphtheria + tetanus toxoids + acellular
mice were fed a diet containing aluminum lactate. They pertussis.L.S. Keith et al. / Vaccine 20 (2002) S13–S17 S17
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