E-mail
from Dr. Philip Rudnick Ph.D.
Professor Emeritus, Chemistry
West Chester University of Pennsylvania
Re:
http://www.altcorp.com/TESTFoundation/thimelililly.htm
Thimerosal is certainly a very
potent neurotoxin. It should never have been used in
vaccines, particularly for infants and children. But
what about aluminum INJECTED into the body not as a
vaccine preservative but as a vaccine adjuvant?
(Aluminum is not readily absorbed from the GI tract.)
Aluminum, also is a neurotoxin. This has been known for
over 100 years. And what safety studies have ever been
done about the possible neurotoxic interaction/synergism
of thimerosal and aluminum?
Sincerely,
Philip Rudnick, PhD
Professor Emeritus, Chemistry
West Chester University of
Pennsylvania
Some Refences:
Redhead K, Quinlan GJ, Das RG,
Gutteridge JM. Pharmacol Toxicol 1992 Apr;70(4):278-80.
Aluminium-adjuvanted
vaccines transiently increase aluminium levels in murine
brain tissue.
Division of Bacteriology, National
Institute for Biological Standards and Control, Herts.,
UK.
Aluminum is widely used as an
adjuvant in human vaccines, and children can often
receive up to 3.75 mg of parenteral aluminum during the
first six months of life. We show that intraperitoneal
injection of aluminum adsorbed vaccines into mice causes
a transient rise in brain tissue aluminum levels peaking
around the second and third day after injection. This
rise is not seen in the saline control group of animals
or with vaccine not containing aluminum. It is likely
that aluminum is transported to the brain by the
iron-binding protein transferrin and enters the brain
via specific transferrin receptors. PMID: 1608913, UI:
92302160
http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=1608913&form=6&db=m&Dopt=b
Gupta RK, Relyveld EH.
Adverse reactions
after injection of adsorbed diphtheria-pertussis-tetanus
(DPT) vaccine are not due only to pertussis organisms or
pertussis components in the vaccine.
Vaccine. 1991 Oct;9(10):699-702.
Review.PMID: 1759487; UI: 92101590
Aluminum compounds such as aluminum
phosphate and aluminum hydroxide are the most commonly
used adjuvants with vaccines for human use. Due to the
increasing concern about the toxicity of aluminum, other
adjuvants like calcium phosphate may be evaluated as an
alternative to aluminum adjuvants. To minimize reactions
after immunization with DPT vaccine due to impurities in
the toxoids, the use of toxoided purified toxins is
suggested.
Neurotoxicology
of the brain barrier system: new implications.
Zheng W.
J Toxicol Clin Toxicol.
2001;39(7):711-9.
College of Physicians and Surgeons,
Columbia University, New York, New York 10032, USA. wz18@columbia.edu
The concept of a barrier system in
the brain has existed for nearly a century. The barrier
that separates the blood from the cerebral interstitial
fluid is defined as the blood-brain barrier, while the
one that discontinues the circulation between the blood
and cerebrospinal fluid is named the blood-cerebrospinal
fluid barrier. Evidence in the past decades suggests
that brain barriers are subject to toxic insults from
neurotoxic chemicals circulating in blood. The aging
process and some disease states render barriers more
vulnerable to insults arising inside and outside the
barriers. The implication of brain barriers in certain
neurodegenerative diseases is compelling, although the
contribution of chemical-induced barrier dysfunction in
the etiology of any of these disorders remains poorly
understood. This review examines what is currently
understood about brain barrier systems in central
nervous system disorders by focusing on chemical-induced
neurotoxicities including those associated with
nitrobenzenes, N-methyl-D-aspartate, cyclosporin A,
pyridostigmine bromide, aluminum, lead, manganese,
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and
3-nitropropionic acid. Contemporary research questions
arising from this growing understanding show enormous
promises for brain researchers, toxicologists, and
clinicians.
Aluminum, NO, and
nerve growth factor neurotoxicity in cholinergic
neurons.
Szutowicz A.
J Neurosci Res. 2001 Dec
1;66(5):1009-18.
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.
Aluminium impairs
the glutamate-nitric oxide-cGMP pathway in cultured
neurons and in rat brain in vivo: molecular mechanisms
and implications for neuropathology.
Canales JJ, Corbalan R, Montoliu C,
Llansola M, Monfort P, Erceg S, Hernandez-Viadel M,
Felipo V.
J Inorg Biochem. 2001
Nov;87(1-2):63-9.
Laboratory of Neurobiology,
Instituto de Investigaciones Citológicas, Fundación
Valenciana de Investigaciones Biomédicas, Amadeo de
Saboya 4, 46010 Valencia, Spain.
Aluminium (Al) is a neurotoxicant
and appears as a possible etiological factor in
Alzheimer's disease and other neurological disorders.
The mechanisms of Al neurotoxicity are presently unclear
but evidence has emerged suggesting that Al accumulation
in the brain can alter neuronal signal transduction
pathways associated with glutamate receptors. In
cerebellar neurons in culture, long term-exposure to Al
added 'in vitro' impaired the glutamate-nitric oxide
(NO)-cyclic GMP (cGMP) pathway, reducing
glutamate-induced activation of NO synthase and
NO-induced activation of the cGMP generating enzyme,
guanylate cyclase. Prenatal exposure to Al also affected
strongly the function of the glutamate-NO-cGMP pathway.
In cultured neurons from rats prenatally exposed to Al,
we found reduced content of NO synthase and of guanylate
cyclase, and a dramatic decrease in the ability of
glutamate to increase cGMP formation. Activation of the
glutamate-NO-cGMP pathway was also strongly impaired in
cerebellum of rats chronically treated with Al, as
assessed by in vivo brain microdialysis in freely moving
rats. These findings suggest that the impairment of the
Glu-NO-cGMP pathway in the brain may be responsible for
some of the neurological alterations induced by Al.
Effects of
aluminium exposure on brain glutamate and GABA systems:
an experimental study in rats.
Nayak P, Chatterjee AK.
Food Chem Toxicol. 2001
Dec;39(12):1285-9.
Biochemistry and Nutrition Research
Laboratory, Department of Physiology, University of
Calcutta, 92 A.P.C. Road, 700 009, Calcutta, India. nprasunpriya@hotmail.com
It has been postulated that the
neurotoxic effects of aluminium could be mediated
through glutamate, an excitatory amino acid. Hence the
effects of aluminium administration (at a dose of
4.2mg/kg body weight daily as aluminium chloride,
hexahydrate, intraperitoneally, for 4 weeks) on
glutamate and gamma-amino butyrate (GABA), an inhibitory
amino acid, and related enzyme activities in different
regions of the brain were studied in albino rats. The
glutamate level increased significantly in the cerebrum,
thalamic area, midbrain-hippocampal region and
cerebellum in response to in vivo aluminium exposure.
The aluminium insult also caused significant increases
in glutamate alpha-decarboxylase activity in all the
brain regions. However, on aluminium insult, the GABA
content was not significantly changed except in the
thalamic area, where it was elevated. On the contrary,
the GABA-T activities of all the regions were reduced
significantly in all regions except the midbrain-hippocampal
region. However, the succinic semi-aldehyde content of
all brain regions increased, often significantly. The
aluminium-induced modification of the enzyme activities
may be either due to the direct impact of aluminium or
due to aluminium-induced changes in the cellular
environment. The aluminium-induced differential regional
accumulation of glutamate or other alterations in
enzymes of the glutamate-GABA system may be one of the
causes of aluminium-induced neurotoxicity.
Dementia in
patients undergoing long-term dialysis: aetiology,
differential diagnoses, epidemiology and management.
Rob PM, Niederstadt C, Reusche E.
CNS Drugs. 2001;15(9):691-9.
Nephrologisches Zentrum am Klinikum
Süd, Kalhlhorststrasse 31, D-23552 Lübeck,
Germany. prof-rob@gmx.de
Dementia in patients undergoing
long-term dialysis has not been clearly defined;
however, four different entities have been described.
Uraemic encephalopathy is a complication of uraemia and
responds well to dialysis. Dialysis encephalopathy
syndrome, the result of acute intoxication of aluminium
caused by the use of an aluminium-containing dialysate,
was a common occurrence prior to 1980. However, using
modern techniques of water purification, such acute
intoxication can now be avoided. Dialysis-associated
encephalopathy/dementia (DAE) is always associated with
elevated serum aluminium levels. Pathognomonic
morphological changes in the brain have been described,
but the mechanism for the entry of aluminium into the
CNS is incompletely understood. The mechanisms involved
in the pathogenesis of the neurotoxicity associated with
aluminium are numerous. Although only a very small
fraction of ingested aluminium is absorbed, the
continuous oral aluminium intake from aluminium-based
phosphate binders, and also of dietary or environmental
origin, is responsible for aluminium overload in
dialysis patients. Age-related dementia, especially
vascular dementia, occurs in patients undergoing
long-term dialysis as frequently as it does in the
general population. The differential diagnoses of
dialysis-associated dementias should include
investigation for metabolic encephalopathies, heavy
metal or trace element intoxications, and distinct
structural neurological lesions such as subdural
haematoma, normal pressure hydrocephalus, stroke and,
particularly, hypertensive encephalopathy and
multi-infarct dementia. To prevent DAE, dietary training
programmes should aim to achieve the lowest phosphate
intake and pharmacological tools should be used to keep
serum phosphate levels below 2 mmol/L. To prevent
vascular dementia, lifestyle modification should be
undertaken, including optimal physical activity and fat
intake, nicotine abstinence, and targeting optimal blood
glucose, cholesterol and triglyceride levels, and blood
pressure, to those outlined in current recommendations.
The toxicology of
aluminum in the brain: a review.
Yokel RA.
Neurotoxicology. 2000
Oct;21(5):813-28.
College of Pharmacy and Graduate
Center for Toxicology, University of Kentucky Medical
Center, Lexington, USA. ryokel1@pop.uky.edu
Aluminum is environmentally
ubiquitous, providing human exposure. Usual human
exposure is primarily dietary. The potential for
significant Al absorption from the nasal cavity and
direct distribution into the brain should be further
investigated. Decreased renal function increases human
risk of Al-induced accumulation and toxicity. Brain Al
entry from blood may involve transferrin-receptor
mediated endocytosis and a more rapid process
transporting small molecular weight Al species. There
appears to be Al efflux from the brain, probably as Al
citrate. There is prolonged retention of a fraction of
Al that enters the brain, suggesting the potential for
accumulation with repeated exposure. Al is a
neurotoxicant in animals and humans. It has been
implicated in the etiology of sporadic Alzheimer's
disease (AD) and other neurodegenerative disorders,
although this is highly controversial. This controversy
has not been resolved by epidemiological studies, as
only some found a small association between increased
incidence of dementia and drinking water Al
concentration. Studies of brain Al in AD have not
produced consistent findings and have not resolved the
controversy. Injections of Al to animals produce
behavioral, neuropathological and neurochemical changes
that partially model AD. Aluminum has the ability to
produce neurotoxicity by many mechanisms. Excess,
insoluble amyloid beta protein (A beta) contributes to
AD. Aluminum promotes formation and accumulation of
insoluble A beta and hyperphosphorylated tau. To some
extent, Al mimics the deficit of cortical cholinergic
neurotransmission seen in AD. Al increases Fe-induced
oxidative injury. The toxicity of Al to plants, aquatic
life and humans may share common mechanisms, including
disruption of the inositol phosphate system and Ca
regulation. Facilitation of Fe-induced oxidative injury
and disruption of basic cell processes may mediate
primary molecular mechanisms of Al-induced neurotoxicity.
Avoidance of Al exposure, when practical, seems prudent.
Aluminum
neurotoxicity in preterm infants receiving
intravenous-feeding solutions.
Bishop NJ, Morley R, Day JP, Lucas
A.
N Engl J Med. 1997 May
29;336(22):1557-61.
Comment in:
N Engl J Med. 1997 Oct
9;337(15):1090-1 PMID: 9324646
Medical Research Council (MRC) Dunn
Nutrition Unit, Cambridge, United Kingdom.
BACKGROUND: Aluminum, a contaminant
of commercial intravenous-feeding solutions, is
potentially neurotoxic. We investigated the effect of
perinatal exposure to intravenous aluminum on the
neurologic development of infants born prematurely.
METHODS: We randomly assigned 227 premature infants with
gestational ages of less than 34 weeks and birth weights
of less than 1850 g who required intravenous feeding
before they could begin enteral feeding to receive
either standard or specially constituted,
aluminum-depleted intravenous-feeding solutions. The
neurologic development of the 182 surviving infants who
could be tested was assessed by using the Bayley Scales
of Infant Development at 18 months of age. RESULTS: The
90 infants who received the standard feeding solutions
had a mean (+/-SD) Bayley Mental Development Index of
95+/-22, as compared with 98+/-20 for the 92 infants who
received the aluminum-depleted solutions (P=0.39). In a
planned subgroup analysis of infants in whom the
duration of intravenous feeding exceeded the median and
who did not have neuromotor impairment, the mean values
for the Bayley Mental Development Index for the 39
infants who received the standard solutions and the 41
infants who received the aluminum-depleted solutions
were 92+/-20 and 102+/-17, respectively (P=0.02). The
former were significantly more likely (39 percent, vs.
17 percent of the latter group; P=0.03) to have a Mental
Development Index of less than 85, increasing their risk
of subsequent educational problems. For all 157 infants
without neuromotor impairment, increasing aluminum
exposure was associated with a reduction in the Mental
Development Index (P=0.03), with an adjusted loss of one
point per day of intravenous feeding for infants
receiving the standard solutions. CONCLUSIONS: In
preterm infants, prolonged intravenous feeding with
solutions containing aluminum is associated with
impaired neurologic development.
Aluminum
neurotoxicity in experimental animals.
Erasmus RT, Savory J, Wills MR,
Herman MM.
Ther Drug Monit. 1993
Dec;15(6):588-92.
Department of Pathology, University
of Virginia Health Sciences Center, Charlottesville
22908.
Neurotoxic effects of aluminum (Al)
were recognized > 100 years ago, but have only
recently been studied in detail. By far, the most
dramatic effect of Al is that of producing intraneuronal
perikaryal neurofilamentous aggregates, which consist of
phosphorylated neurofilaments. Several species have been
used to demonstrate this effect, rabbit being most
common; the effect also is seen in in vitro systems.
Besides its role in producing neurofibrillary pathology,
Al appears to modify the blood-brain barrier and exert
cholinergic and noradrenergic effects. Possible
mechanisms of Al neurotoxicity could be related to cell
damage via free radical production, impairment of
glucose metabolism, and effects on signal transduction.
Effects of metals
on the nervous system of humans and animals.
Carpenter DO.
Int J Occup Med Environ Health.
2001;14(3):209-18.
School of Public Health University
at Albany Rensselaer, NY 12144, USA.
Several metals have toxic actions
on nerve cells and neurobehavorial functioning. These
toxic actions can be expressed either as developmental
effects or as an increased risk of neurodegenerative
diseases in old age. The major metals causing
neurobehavioral effects after developmental exposure are
lead and methylmercury. Lead exposure in young children
results in a permanent loss of IQ of approximately 5 to
7 IQ points, and also results in a shortened attention
span and expression of anti-social behaviors. There is a
critical time period (<2 years of age) for
development of these effects, after which the effects do
not appear to be reversible even if blood lead levels
are lowered with chelation. Methylmercury has also been
found to have effects on cognition at low doses, and
prenatal exposure at higher levels can disrupt brain
development. Metals have also been implicated in
neurodegenerative diseases, although it is unlikely that
they are the sole cause for any of them. Elevated
aluminum levels in blood, usually resulting from kidney
dialysis at home with well water containing high
aluminum, result in dementia that is similar to but
probably different from that of Alzheimer's disease.
However, there is some epidemiological evidence for
elevated risk of Alzheimer's in areas where there is
high concentration of aluminum in drinking water. Other
metals, especially lead, mercury, manganese and copper,
have been implicated in amvotrophic lateral sclerosis
and Parkinson's disease.
RESEARCH
Cancer
in Cats and Dogs
In
pets, researchers have working models for human diseases
The
Scientist
14[11]:18, May. 29, 2000
http://www.the-scientist.com/yr2000/may/research_000529.html
Vaccine-Associated
Feline Sarcoma
All of the above methods could find their ways into
human cancer treatment regimens. But there is one
baffling cancer that is uniquely feline and for which
the specific etiology is unknown: vaccine-associated
feline sarcoma.
As any cat owner knows, cats receive two or three
combination vaccinations during their first year of life
and then, depending on the vaccine and the
recommendation of the veterinarian, annual vaccination
against some infections and triennial vaccination
against others. This works out to a lot of vaccinations
during the approximately 12-year lifespan of the average
cat. In 1991, University of Pennsylvania School of
Veterinary Medicine pathologist Mattie Hendrick
coauthored a letter to the editor in the Journal of
the American Veterinary Medical Association1
describing increased numbers of fibrosarcomas in the
interscapular area in cats seen by her service at the
university. Cats usually are vaccinated over their
shoulder blades.
"She was finding increased inflammatory reaction
at the sites and also found foreign material,"
notes James R. Richards, director of the Cornell
Feline Health Center at Cornell's College of Veterinary
Medicine. He is one of 10 members of a group organized
to aid in investigating and preventing these
malignancies and educating veterinarians and the public
about them: the Vaccine-Associated Feline Sarcoma Task
Force (VAFSTF). "This was indeed a foreign
substance that contained aluminum and oxygen," says
Richards. Aluminum is a common adjuvant in vaccines.
But, Richards adds, it's not known "if this is a
cause-and-effect situation or whether the adjuvant was
there and showed up" but did not cause the tumors.
Veterinary oncologist Barbara E. Kitchell of
the University of Illinois College of Veterinary
Medicine in Urbana, who has been studying the
etiopathogenesis of these tumors, notes that they have
been reported to occur "as close as one month after
vaccination and after 10 years. Ninety percent of cats
who develop tumors do so within four years of vaccine;
59 percent developed within one year."
There have been a number of theories about what is
causing these tumors, from macrophage ingestion of
aluminum resulting in fibroblast production to
activation of exogenous or endogenous (within the feline
genome) retroviral elements, to mutations of the p53
gene predisposing some cats to develop these tumors.
Kass has been studying the epidemiology of the tumors
with financial support from VAFSTF. (VAFSTF awards
grants for research from money donated by vaccine
companies, especially Pfizer Animal Health, veterinary
associations such as the American Animal Hospital
Association Foundation, and research groups such as the
Cornell Feline Health Center.) Although he has not yet
analyzed the data--supplied by several hundred
veterinarians who have reported on the numbers, types,
and brands of vaccines used; their vaccination
technique; and any adverse effects--he estimates that
between one and three cats per 10,000 develop
vaccine-associated sarcoma per year. One of the problems
in even estimating the extent of the problem is
"the underreporting is just vast."
In 1994, the U.S. Pharmacopeia (USP), Rockville, Md.,
a nonprofit public health organization, launched the
Veterinary Practitioners' Reporting Program to which
veterinarians could report adverse events and other
problems associated with the use of vaccines, drugs, and
pesticides in animals. Reporting is purely voluntary,
and the information veterinarians supply on
vaccine-associated sarcomas to the USP is limited to the
last vaccine given at the site of sarcoma development,
notes veterinarian E. Kathryn Meyer, who
coordinates the program. From April 30, 1996, through
May 8, 2000, veterinarians reported 586 cases of
vaccine-associated sarcomas in cats to the USP, says
Meyer. "Not every sarcoma that develops is
reported," she says. But 190 veterinarians
reporting these sarcomas to USP in 1998 and early 1999
were invited to enroll in Kass' epidemiological study,
and 72 participated.
"Cats," Kass observes, "are totally
different organisms than dogs. They just react strangely
to chemicals," differently from dogs, horses, other
animals, and humans. Yet the desire to find cures to
human disease is a big motivator for veterinary
oncologists. Says MacEwen: "They [the dog and the
cat] provide an opportunity for enhancing the
effectiveness of treatment in humans. That's why I went
into the field in the first place."
Myrna E. Watanabe is editor of Cornell
University's newsletters for pet owners, CatWatch
and DogWatch.
1. M. Hendrick and M.H. Goldschmidt, "Do
injection site reactions induce fibrosarcomas in
cats?" Journal of the American Veterinary
Medical Association, 199:968, 1991.
Dental
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