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2: J Alzheimers Dis. 2006 Nov;10(2-3):223-53.
Blood-brain barrier flux of aluminum, manganese, iron and other metals suspected
to contribute to metal-induced neurodegeneration.
Yokel RA.
College of Pharmacy and Graduate Center for Toxicology, University of Kentucky
Medical Center, Lexington, KY 40536-0082, USA. ryokel@email.uky.edu
The etiology of many neurodegenerative diseases has been only partly attributed
to acquired traits, suggesting environmental factors may also contribute. Metal
dyshomeostasis causes or has been implicated in many neurodegenerative diseases.
Metal flux across the blood-brain barrier (the primary route of brain metal
uptake) and the choroid plexuses as well as sensory nerve metal uptake from the
nasal cavity are reviewed. Transporters that have been described at the
blood-brain barrier are listed to illustrate the extensive possibilities for
moving substances into and out of the brain. The controversial role of aluminum
in Alzheimer's disease, evidence suggesting brain aluminum uptake by
transferrin-receptor mediated endocytosis and of aluminum citrate by system
Xc;{-} and an organic anion transporter, and results suggesting
transporter-mediated aluminum brain efflux are reviewed. The ability of manganese
to produce a parkinsonism-like syndrome, evidence suggesting manganese uptake by
transferrin- and non-transferrin-dependent mechanisms which may include
store-operated calcium channels, and the lack of transporter-mediated manganese
brain efflux, are discussed. The evidence for transferrin-dependent and
independent mechanisms of brain iron uptake is presented. The copper
transporters, ATP7A and ATP7B, and their roles in Menkes and Wilson's diseases,
are summarized. Brain zinc uptake is facilitated by L- and D-histidine, but a
transporter, if involved, has not been identified. Brain lead uptake may involve
a non-energy-dependent process, store-operated calcium channels, and/or an
ATP-dependent calcium pump. Methyl mercury can form a complex with L-cysteine
that mimics methionine, enabling its transport by the L system. The putative
roles of zinc transporters, ZnT and Zip, in regulating brain zinc are discussed.
Although brain uptake mechanisms for some metals have been identified, metal
efflux from the brain has received little attention, preventing integration of
all processes that contribute to brain metal concentrations.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Review
PMID: 17119290 [PubMed - indexed for MEDLINE]
3: J Alzheimers Dis. 2006 Nov;10(2-3):135-44.
Mechanisms of aluminum-induced neurodegeneration in animals: Implications for
Alzheimer's disease.
Savory J, Herman MM, Ghribi O.
Department of Pathology, University of Virginia, Charlottesville, VA, USA.
For four decades the controversial question concerning a possible role for
aluminum neurotoxicity in contributing to the pathogenesis of Alzheimer's disease
has been debated, and studies by different investigators have yielded
contradictory results. The lack of sensitivity to aluminum neurotoxicity in
transgenic mouse models of Alzheimer's disease has not allowed the system to be
used to explore important aspects of this toxicity. Rabbits are particularly
sensitive to aluminum neurotoxicity and they develop severe neurological changes
that are dependent on dose, age and route of administration. The most prominent
feature induced by aluminum in rabbit brain is a neurofibrillary degeneration
that shares some similarity with the neurofibrillary tangles found in Alzheimer's
disease patients. In the present review we discuss data from our laboratory and
others, on the effects of aluminum on behaviour, neurologic function and
morphology, using aluminum administered to rabbits via different routes. Finally,
we will examine data on the possible cellular mechanisms underlying aluminum
neurotoxicity, and potential neuroprotective strategies against aluminum
toxicity.
Publication Types:
Research Support, U.S. Gov't, Non-P.H.S.
Review
PMID: 17119283 [PubMed - indexed for MEDLINE]
4: Brain Res Rev. 2006 Aug 30;52(1):193-200. Epub 2006 Mar 10.
Some aspects of astroglial functions and aluminum implications for
neurodegeneration.
Aremu DA, Meshitsuka S.
Division of Medical Environmentology, Department of Social Medicine, Graduate
School of Medical Sciences, Tottori University, Yonago 683-8503, Japan.
aremuda@grape.med.tottori-u.ac.jp
The present decade had witnessed an unprecedented attention focused on glial
cells as a result of their unusual physiological roles that are being unraveled.
It is now known that, rather than being a mere supporter of neurons, astroglia
are actively involved in their modulation. The aluminum hypothesis seems to have
been laid to rest, probably due to contradictory epidemiological reports on it as
a causative factor of neurodegenerative diseases. Surprisingly, newer scientific
evidences continue to appear and recent findings have implicated astrocytes as
the principal target of its toxic action. In view of the likely detrimental
effects of the interaction between these two infamous partners in neuroscience on
neurons and nervous system, we have reviewed some aspects of glia-neuron
interaction and discussed the implications of aluminum-impaired astrocytic
functions on neurodegeneration. Because sporadic causes still account for the
majority of the neurodegenerative diseases of which Alzheimer's disease is the
most prominent, it has been suggested that neurotoxicologists should not relent
in screening for the environmental agents, such as aluminum, and that
considerable attention should be given to glial cells in view of the likely
implications of environmental toxicants on their never-imagined newly reported
roles in the central nervous system (CNS).
Publication Types:
Review
PMID: 16529821 [PubMed - indexed for MEDLINE]
5: J Alzheimers Dis. 2005 Nov;8(2):171-82; discussion 209-15.
Effects of aluminum on the nervous system and its possible link with
neurodegenerative diseases.
Kawahara M.
Department of Analytical Chemistry, School of Pharmaceutical Sciences, Kyushu
University of Health and Welfare, Nobeoka-city, Miyazaki, 882-8508, Japan.
kawamasa@phoenix.ac.jp
Aluminum is environmentally abundant, but not an essential element. Aluminum has
been associated with several neurodegenerative diseases, such as dialysis
encephalopathy, amyotrophic lateral sclerosis and Parkinsonism dementia in the
Kii peninsula and Guam, and in particular, Alzheimer's disease. Although this
association remains controversial, there is increasing evidence which suggests
the implication of metal homeostasis in the pathogenesis of Alzheimer's disease.
Aluminum, zinc, copper, and iron cause the conformational changes of Alzheimer's
amyloid-beta protein. Al causes the accumulation of tau protein and amyloid-beta
protein in experimental animals. Aluminum induces neuronal apoptosis in vivo as
well as in vitro. Furthermore, a relationship between aluminum and the
iron-homeostasis or calcium-homeostasis has been suggested. Based on these
findings, the characteristics of aluminum neurotoxicity are reviewed, and the
potential link between aluminum and neurodegenerative diseases is reconsidered.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16308486 [PubMed - indexed for MEDLINE]
6: Curr Opin Pharmacol. 2005 Dec;5(6):637-40. Epub 2005 Sep 28.
Aluminum: new recognition of an old problem.
Klein GL.
Children's Hospital Room 3.270, University of Texas Medical Branch, 301
University Boulevard, Galveston TX 77555-0352, USA. gklein@utmb.edu
The aluminum problem is now over 25 years old, but has remained a neglected
concern. Data indicate that aluminum contaminates much of the raw material used
to manufacture solutions used for intravenous nutritional support of hospitalized
and ambulatory patients, and that pharmaceutical manufacturers have only recently
obtained the technology necessary to detect aluminum contamination of their
products. As a result, aluminum bypassed normal barriers and entered the blood,
accumulating in tissues such as bone, liver and the central nervous system with
toxic consequences. Now that the FDA has finally issued a rule governing aluminum
contamination in these solutions, manufacturers will need to develop methods to
minimize such contamination; scientists should also realize that when data they
obtain indicate a serious problem in the manufacturing sector they should be sure
that the problem is properly addressed.
Publication Types:
Review
PMID: 16198633 [PubMed - indexed for MEDLINE]
7: Toxicol Ind Health. 2002 Aug;18(7):309-20.
Aluminum as a toxicant.
Becaria A, Campbell A, Bondy SC.
Department of Community and Environmental Medicine, Center for Occupational and
Environmental Health Sciences, Irvine, CA 92697-1820, USA. abecaria@uci.edu
Although aluminum is the most abundant metal in nature, it has no known
biological function. However, it is known that there is a causal role for
aluminum in dialysis encephalopathy, microcytic anemia, and osteomalacia.
Aluminum has also been proposed to play a role in the pathogenesis of Alzheimer's
disease (AD) even though this issue is controversial. The exact mechanism of
aluminum toxicity is not known but accumulating evidence suggests that the metal
can potentiate oxidative and inflammatory events, eventually leading to tissue
damage. This review encompasses the general toxicology of aluminum with emphasis
on the potential mechanisms by which it may accelerate the progression of chronic
age-related neurodegenerative disorders.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 15068131 [PubMed - indexed for MEDLINE]
8: Immunol Allergy Clin North Am. 2003 Nov;23(4):699-712.
Aluminum inclusion macrophagic myofasciitis: a recently identified condition.
Gherardi RK, Authier FJ.
Muscle and Nerve Group, Henri Mondor University Hospital, Créteil, France.
lauret@univ-paris12.fr
The authors conclude that the persistence of aluminum hydroxide at the site of
intramuscular injection is a novel finding which has an exact significance that
remains to be established fully. It seems mandatory to evaluate possible
long-term adverse effects induced by this compound, because this issue has not
been addressed (in the past, aluminum hydroxide was believed to be cleared
quickly from the body). If safety concerns about the long-term effects of
aluminum hydroxide are confirmed, novel and alternative vaccine adjuvants to
rescue vaccine-based strategies should be proposed to ensure the enormous benefit
for public health that these vaccines provide worldwide.
Publication Types:
Review
PMID: 14753387 [PubMed - indexed for MEDLINE]
9: Brain Res Bull. 2003 Nov 15;62(1):15-28.
The role of metals in neurodegenerative processes: aluminum, manganese, and zinc.
Zatta P, Lucchini R, van Rensburg SJ, Taylor A.
CNR-Institute for Biomedical Technologies, Metalloproteins Unit, Department of
Biology, University of Padova, 35121, Padova, Italy. zatta@mail.bio.unipd.it
Until the last decade, little attention was given by the neuroscience community
to the neurometabolism of metals. However, the neurobiology of heavy metals is
now receiving growing interest, since it has been linked to major
neurodegenerative diseases. In the present review some metals that could possibly
be involved in neurodegeneration are discussed. Two of them, manganese and zinc,
are essential metals while aluminum is non-essential. Aluminum has long been
known as a neurotoxic agent. It is an etiopathogenic factor in diseases related
to long-term dialysis treatment, and it has been controversially invoked as an
aggravating factor or cofactor in Alzheimer's disease as well as in other
neurodegenerative diseases. Manganese exposure can play an important role in
causing Parkinsonian disturbances, possibly enhancing physiological aging of the
brain in conjunction with genetic predisposition. An increased environmental
burden of manganese may have deleterious effects on more sensitive subgroups of
the population, with sub-threshold neurodegeneration in the basal ganglia,
generating a pre-Parkinsonian condition. In the case of zinc, there has as yet
been no evidence that it is involved in the etiology of neurodegenerative
diseases in humans. Zinc is redox-inactive and, as a result of efficient
homeostatic control, does not accumulate in excess. However, adverse symptoms in
humans are observed on inhalation of zinc fumes, or accidental ingestion of
unusually large amounts of zinc. Also, high concentrations of zinc have been
found to kill bacteria, viruses, and cultured cells. Some of the possible
mechanisms for cell death are reviewed.
Publication Types:
Review
PMID: 14596888 [PubMed - indexed for MEDLINE]
10: Nutr Rev. 2003 Sep;61(9):306-10.
Parenteral nutrition-associated cholestasis in neonates: the role of aluminum.
Arnold CJ, Miller GG, Zello GA.
College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon,
Saskatchewan, Canada S7M 0Z9.
Parenteral nutrition (PN) is an essential component in the care of premature and
ill infants. The incidence of parenteral nutrition-associated cholestasis (PNAC)
ranges from 7.4 to 84%. One substance in PN solutions that has been implicated in
PNAC is aluminum. Aluminum loading in animals and humans causes hepatic
accumulation and damage. The degree of aluminum contamination of PN solutions has
decreased over time, but contamination still significantly exceeds levels that
are safe for human neonates. Further study into the relationship between aluminum
contamination in neonatal PN solutions and the development of PNAC is necessary.
Publication Types:
Review
PMID: 14552065 [PubMed - indexed for MEDLINE]
11: J Inorg Biochem. 2003 Sep 15;97(1):151-4.
Intracellular mechanisms underlying aluminum-induced apoptosis in rabbit brain.
Savory J, Herman MM, Ghribi O.
Department of Pathology, University of Virginia, Charlottesville, VA, USA.
jsr2@virginia.edu
Loss of neurons is a hallmark of neurodegenerative disorders and there is
increasing evidence suggesting that apoptosis is a key mechanism by which neurons
die in these diseases. Mitochondrial dysfunction has been implicated in this
process of neuronal cell death, but there is a growing body of evidence
suggesting also an active role for the endoplasmic reticulum in regulating
apoptosis, either independent of mitochondria, or in concert with
mitochondrial-initiated pathways. Investigations in our laboratory have focused
on neuronal injury resulting from the administration of aluminum maltolate, via
the intracisternal route, to New Zealand white rabbits. This treatment induces
both mitochondrial and endoplasmic reticulum stress. Agents such as lithium or
glial cell-line derived neurotrophic factor (GDNF) have the ability to prevent
aluminum-induced neuronal death by interfering with the mitochondrial and/or the
endoplasmic reticulum-mediated apoptosis cascade. Cytochrome c release from
mitochondria and binding to Apaf-1 initiates the aluminum-induced apoptosis
cascade; this is prevented by lithium treatment. GDNF also protects against
aluminum-induced apoptosis but by upregulation of Bcl-X(L), thereby preventing
the binding of cytochrome c to Apaf-1. This animal model system involving
neurotoxicity induced by an aluminum compound provides new information on
mechanisms of neurodegeneration and neuroprotection.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 14507471 [PubMed - indexed for MEDLINE]
12: Vaccine. 2002 May 31;20 Suppl 3:S18-23.
Erratum in:
Vaccine. 2002 Sep 10;20(27-28):3428.
Aluminum salts in vaccines--US perspective.
Baylor NW, Egan W, Richman P.
Food and Drug Administration, Center for Biologics Evaluation and Research,
Office of Vaccines Research and Review, Bethesda, MD, USA. baylor@cber.fda.gov
Aluminum in the form of aluminum hydroxide, aluminum phosphate or alum has been
commonly used as an adjuvant in many vaccines licensed by the US Food and Drug
Administration. Chapter 21 of the US Code of Federal Regulations [610.15(a)]
limits the amount of aluminum in biological products, including vaccines, to 0.85
mg/dose. The amount of aluminum in vaccines currently licensed in the US ranges
from 0.85-0.125 mg/dose. Clinical studies have demonstrated that aluminum
enhances the antigenicity of some vaccines such as diphtheria and tetanus
toxoids. Moreover, aluminum-adsorbed diphtheria and tetanus toxoids are
distinctly more effective than plain fluid toxoids for primary immunization of
children. There is little difference between plain and adsorbed toxoids for
booster immunization. Aluminum adjuvants have a demonstrated safety profile of
over six decades; however, these adjuvants have been associated with severe local
reactions such as erythema, subcutaneous nodules and contact hypersensitivity.
Publication Types:
Review
PMID: 12184360 [PubMed - indexed for MEDLINE]
13: Environ Res. 2002 Jun;89(2):101-15.
Aluminum: impacts and disease.
Nayak P.
Department of Physiology, Sikkim Manipal Institute of Medical Sciences, 5th Mile,
Tadong, Gangtok, 737102, Sikkim, India.
Aluminum is the most widely distributed metal in the environment and is
extensively used in modern daily life. Aluminum enters into the body from the
environment and from diet and medication. However, there is no known
physiological role for aluminum within the body and hence this metal may produce
adverse physiological effects. The impact of aluminum on neural tissues is well
reported but studies on extraneural tissues are not well summarized. In this
review, the impacts of aluminum on humans and its impact on major physiological
systems are summarized and discussed. The neuropathologies associated with high
brain aluminum levels, including structural, biochemical, and neurobehavioral
changes, have been summarized. In addition, the impact of aluminum on the
musculoskeletal system, respiratory system, cardiovascular system, hepatobiliary
system, endocrine system, urinary system, and reproductive system are discussed.
Publication Types:
Review
PMID: 12123643 [PubMed - indexed for MEDLINE]
14: J Neurosci Res. 2001 Dec 1;66(5):1009-18.
Aluminum, NO, and nerve growth factor neurotoxicity in cholinergic neurons.
Szutowicz A.
Chair of Clinical Biochemistry, Department of Laboratory Medicine, Medical
University of Gdańsk, Debinki 7, 80-211 Gdańsk, Poland. aszut@amg.gda.pl
Several neurotoxic compounds, including Al, NO, and beta-amyloid may contribute
to the impairment or loss of brain cholinergic neurons in the course of various
neurodegenerative diseases. Genotype and phenotypic modifications of cholinergic
neurons may determine their variable functional competency and susceptibility to
reported neurotoxic insults. Hybrid, immortalized SN56 cholinergic cells from
mouse septum may serve as a model for in vitro cholinotoxicity studies.
Differentiation by various combinations of cAMP, retinoic acid, and nerve growth
factor may provide cells of different morphologic maturity as well as activities
of acetylcholine and acetyl-CoA metabolism. In general, differentiated cells
appear to be more susceptible to neurotoxic signals than the non-differentiated
ones, as evidenced by loss of sprouting and connectivity, decreases in choline
acetyltransferase and pyruvate dehydrogenase activities, disturbances in
acetyl-CoA compartmentation and metabolism, insufficient or excessive
acetylcholine release, as well as increased expression of apoptosis markers. Each
neurotoxin impaired both acetylcholine and acetyl-CoA metabolism of these cells.
Activation of p75 or trkA receptors made either acetyl-CoA or cholinergic
metabolism more susceptible to neurotoxic influences, respectively. Neurotoxins
aggravated detrimental effects of each other, particularly in differentiated
cells. Thus brain cholinergic neurons might display a differential susceptibility
to Al and other neurotoxins depending on their genotype or phenotype-dependent
variability of the cholinergic and acetyl-CoA metabolism. Copyright 2001
Wiley-Liss, Inc.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 11746431 [PubMed - indexed for MEDLINE]
15: Ann N Y Acad Sci. 1997 Oct 15;825:152-66.
Toxin-induced blood vessel inclusions caused by the chronic administration of
aluminum and sodium fluoride and their implications for dementia.
Isaacson RL, Varner JA, Jensen KF.
Department of Psychology, Binghamton University, New York 13902-6000, USA.
isaacson@binghamton.edu
Publication Types:
Review
PMID: 9369984 [PubMed - indexed for MEDLINE]
16: J Toxicol Environ Health. 1996 Aug 30;48(6):667-83.
Prevention and treatment of aluminum toxicity including chelation therapy: status
and research needs.
Yokel RA, Ackrill P, Burgess E, Day JP, Domingo JL, Flaten TP, Savory J.
College of Pharmacy, University of Kentucky Medical Center, Lexington 40536-0082,
USA. ryokel1@pop.uky.edu
The prevention and treatment of aluminum (Al) accumulation and toxicity are
reviewed. Recommendations to further our understanding of desferrioxamine
(deferoxamine, DFO) treatment and to develop more effective chelation approaches
are provided. Reduction of Al accumulation and toxicity may benefit end-stage
renal disease (ESRD) patients and perhaps those suffering from specific
neurodegenerative disorders as well as workers with Al-induced neurocognitive
disorders. The clearance of Al may be increased by extracorporeal chelation,
renal transplantation, perhaps complexation with simple ligands such as silicon
(Si), and systemic chelation therapy. The abilities of extracorporeal chelation
and Si to reduce Al accumulation require further evaluation. Although it may not
be possible to design Al-specific chelators, chelators with greater Al
selectivity are desired. Aluminum-selective chelation might be achieved by
targeted chelator distribution or by the use of adjuvants with the chelator. The
ability of carboxylic acids to facilitate Al elimination, under specific
conditions, warrants further study. Desferrioxamine does not produce significant
biliary Al excretion. A chelator with this property may be useful in ESRD
patients. The necessity for an Al chelator to distribute extravascularly to be
effective is unknown and should be determined to guide the selection of
alternatives to DFO. The lack of oral efficacy and occasional side effects of DFO
encourage identification of orally effective, safer Al chelators. The bidentate
3-hydroxypyridin-4-ones are currently the most encouraging alternatives to DFO.
They have been shown to increase urinary Al excretion in rats and rabbits, but to
have toxicity comparable to, or greater than, DFO. Their toxicity may relate to
incomplete metal complexation. The ability of orally effective chelators to
increase absorption of chelated metal from the gastrointestinal (Gl) tract needs
to be evaluated. Orally effective, safe Al chelators would be of benefit to
peritoneal dialysis patients and those with neurodegenerative disorders, if Al
chelation therapy is indicated. The reduction of Alzheimer's disease (AD)
progression and the reversal of Al-induced behavioral deficits and
neurofibrillary tangles by DFO encourage further study of Al chelation therapy
for selected neurodegenerative disorders.
Publication Types:
Review
PMID: 8772805 [PubMed - indexed for MEDLINE]
17: J Toxicol Environ Health. 1996 Aug 30;48(6):649-65.
Systemic aluminum toxicity: effects on bone, hematopoietic tissue, and kidney.
Jeffery EH, Abreo K, Burgess E, Cannata J, Greger JL.
Institute for Environmental Studies, University of Illinois, Urbana-Champaign
61801, USA. jeffery@ux1.cso.uiuc.edu
Although the full mechanisms are not yet elucidated, research into the mechanism
of toxicity of aluminum (Al) on bone formation and remodeling and on
hematopoietic tissue is ongoing. In contrast little information exists on the
interactive effects of systemic Al and the kidney. In bone, both clinically and
experimentally, high doses of Al inhibit remodeling, slowing both osteoblast and
osteoclast activities and producing osteomalacia and adynamic bone disease. In
contrast, while very low levels of Al are mitogenic in bones of experimental
animals, the effect of low levels of Al in humans is unknown. Aluminum has been
shown to have its mitogenic action at the osteoblast, but whether the effect on
resorption is viz osteoblast-directed changes in osteoclast activity has not yet
been determined. Parathyroid hormone (PTH) levels are disrupted by Al in humans
and animals. Whether altered PTH levels play a major or even a minor role in
Al-dependent osteotoxicity requires clarification. In hematopoietic tissue, Al
causes a microcytic anemia, not reversible by iron. Friend leukemia cells treated
with Al have been reported to accumulate excess iron, without incorporating it
into ferritin or heme. It is not yet known which steps in iron metabolism are
disrupted by Al, if they involve a single mechanism of action, or even if this
disruption in iron metabolism accounts for the anemia seen in Al toxicosis. In
kidney, research is needed to evaluate Al nephrotoxicity; there are almost no
studies in this area. Furthermore, research is needed to evaluate mechanisms of
renal Al excretion, presently shown by one study to occur at the distal tubule.
Such studies might well throw light on whether Al plays a role in aggravating
renal insufficiency, or whether the role of the kidney in Al toxicosis is limited
to the causative effect of renal compromise on Al accumulation. In summary, while
a number of mechanisms have been proposed for the toxic action of Al, no single
mechanism emerges to explain these diverse effects of systemic Al.
Recommendations for future research are presented and summarized in Table 1.
Publication Types:
Review
PMID: 8772804 [PubMed - indexed for MEDLINE]
18: J Toxicol Environ Health. 1996 Aug 30;48(6):585-97.
What we know and what we need to know about developmental aluminum toxicity.
Golub MS, Domingo JL.
Department of Internal Medicine, University of California, Davis 95616, USA.
Information concerning developmental aluminum (Al) toxicity is available from
clinical studies and from animal testing. An Al toxicity syndrome including
encephalopathy, osteomalacia, and anemia has been reported in uremic children
receiving dialysis. In addition, some components of the syndrome, particularly
osteomalacia, have been reported in non-dialyzed uremic children receiving
Al-based phosphate binders, nonuremic infants receiving parenteral nutrition with
Al-containing fluids, and nonuremic infants given high doses of Al antacids. The
number of children in clinical populations that are at risk of Al toxicity is not
known and needs to be determined. Work in animal models (rats, mice, and rabbits)
demonstrates that Al is distributed transplacentally and is present in milk. Oral
Al administration during pregnancy produces a syndrome including growth
retardation, delayed ossification, and malformations at doses that also lead to
reduced maternal weight gain. The severity of the effects is highly dependent on
the form of Al administered. In the postnatal period, reduced pup weight gain and
effects on neuromotor development have been described as a result of
developmental exposures. The significance of these findings for human health
requires better understanding of the amount and bioavailability of Al in food,
drinking water, and medications and from sources unique to infants and children
such as breast milk, soil ingestion, and medications used specifically by
pregnant women and children. We also need a better understanding of the unique
biological actions of Al that may occur during developmental periods, and unique
aspects of the developing organism that make it more or less susceptible to Al
toxicity.
Publication Types:
Review
PMID: 8772800 [PubMed - indexed for MEDLINE]
19: J Toxicol Environ Health. 1996 Aug 30;48(6):569-84.
Aluminum toxicokinetics.
Exley C, Burgess E, Day JP, Jeffery EH, Melethil S, Yokel RA.
Department of Chemistry, Keele University, Staffordshire, United Kingdom.
cha38@keele.ac.uk
In this study of the toxicokinetics of aluminum we have examined some of the
fundamental issues that currently define our understanding of the toxicology of
aluminum in humans. There is a vast literature on this subject, and it was not
our aim to review this literature but to use it to develop our understanding of
the toxicokinetics of aluminum and to identify critical and unresolved issues
related to its toxicity. In undertaking this task we have chosen to define the
term toxicokinetics to encompass those factors that influence both the lability
of aluminum in a body and the sites at which aluminum is known to accumulate,
with or without consequent biological effect. We have approached our objective
from the classical pharmacological approach of ADME: the absorption,
distribution, metabolism, and excretion of aluminum. This approach was successful
in identifying several key deficits in our understanding of aluminum
toxicokinetics. For example, we need to determine the mechanisms by which
aluminum crosses epithelia, such as those of the gastrointestinal tract and the
central nervous system, and how these mechanisms influence both the subsequent
transport and fate of the absorbed aluminum and the concomitant nature and
severity of the biological response to the accumulation of aluminum. Our hope in
highlighting these unresolved issues (summarized in Table 1) is that they will be
addressed in future research.
Publication Types:
Review PMID: 8772799 [PubMed - indexed for MEDLINE]
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