two aspartame toxicity research studies by Resia Pretorius, U. Pretoria, South Africa, debate with JD Fernstrom: Murray 2008.04.04
Rich Murray
Pretoria, South Africa, debate with JD Fernstrom: Murray 2008.04.04
http://rmforall.blogspot.com/2008_04_01_archive.htm
Friday, April 4, 2008
http://groups.yahoo.com/group/aspartameNM/message/1536
____________________________________________________
http://foodqualitynews.com/news/ng.asp?n=84424-aspartame-sweetener
recent news re E Pretorius aspartame and brain review
Direct and indirect cellular effects of aspartame on the brain.
Humphries P, Pretorius E, Naude H, U. Pretoria, South Africa,
Eur J Clin Nutr. 2007 Aug 8: Murray 2007.08.12
http://groups.yahoo.com/group/aspartameNM/message/1463
"The aim of this study was to discuss the direct and indirect
cellular effects of aspartame on the brain,
and we propose that excessive aspartame ingestion
might be involved in the pathogenesis
of certain mental disorders (DSM-IV-TR 2000)
and also in compromised learning and emotional functioning."
Eur J Clin Nutr. 2007 Aug 8; [Epub ahead of print]
Direct and indirect cellular effects of aspartame on the brain.
Humphries P,
Pretorius E, resia.p...@up.ac.za;
Naude H.
[1] Department of Anatomy, University of Pretoria,
Pretoria, Gauteng, South Africa
[2] Department of Anatomy, University of the Limpopo,
South Africa.
The use of the artificial sweetener, aspartame, has long been
contemplated and studied by various researchers, and people are
concerned about its negative effects.
Aspartame is composed of phenylalanine (50%),
aspartic acid (40%) and methanol (10%).
Phenylalanine plays an important role in neurotransmitter regulation,
whereas aspartic acid is also thought to play a role as an excitatory
neurotransmitter in the central nervous system.
Glutamate, asparagines and glutamine are formed from their
precursor, aspartic acid.
Methanol, which forms 10% of the broken down product,
is converted in the body to formate,
which can either be excreted or can give rise to formaldehyde,
diketopiperazine (a carcinogen) and a number of other highly toxic
derivatives.
Previously, it has been reported that consumption of aspartame
could cause neurological and behavioural disturbances in sensitive
individuals.
Headaches, insomnia and seizures are also some of the neurological
effects that have been encountered, and these may be accredited to
changes in regional brain concentrations of catecholamines,
which include norepinephrine, epinephrine and dopamine.
The aim of this study was to discuss the direct and indirect
cellular effects of aspartame on the brain,
and we propose that excessive aspartame ingestion
might be involved in the pathogenesis
of certain mental disorders (DSM-IV-TR 2000)
and also in compromised learning and emotional functioning.
European Journal of Clinical Nutrition advance online publication,
8 August 2007; doi:10.1038/sj.ejcn.1602866.
PMID: 17684524
Keywords: astrocytes; aspartame; neurotransmitters; glutamate;
GABA; serotonin; dopamine; acetylcholine
Received 25 October 2006; revised 26 April 2007;
accepted 27 April 2007
Correspondence: Professor E Pretorius, Department of Anatomy,
University of Pretoria, BMW Building, Dr Savage Street,
PO Box 2034, Pretoria 0001,
Gauteng, South Africa. E-mail: resia.p...@up.ac.za
c 2007 Nature Publishing Group,
All rights reserved 0954-3007/07
$30.00 www.nature.com/ejcn
[ Figures 1-6 not included herein ]
REVIEW
Introduction
The artificial dipeptide sweetener, aspartame (APM;
Laspartyl-L-phenylalanine methyl ester), is present in many
products in the market, especially in unsweetened or sugar free
products.
People trying to lose weight or patients with diabetes, including
children, frequently use these products.
A recent observation indicated that aspartame is slowly making its
way into ordinary products used every day, which do not carry any
indication of being for people on diets or diabetics.
Thus, aspartame is used not only by the above mentioned group of
people, but also by unsuspecting individuals.
Although there is concern and research evidence suggesting possible
adverse neurological and behavioural effects due to aspartame's
metabolic components (phenylalanine, aspartic acid (aspartate),
diketopiperazine and methanol), which are produced during its
breakdown, research suggests that aspartame is not cytotoxic.
This debate still continues 20 years after the FDA had approved the
use of aspartame.
As seen later in the literature study, phenylalanine may cross the
blood-brain barrier and cause severe changes in the production of
very important neurotransmitters.
Methanol breaks down into formate, which in turn is very cytotoxic
and can even cause blindness.
The effects of aspartame have been studied on various species,
including humans, rats, mice and rabbits.
Most studies described in the literature have a macroscopic
approach.
If no adverse effects are visible after a single large administered
dose of aspartame, it is believed that aspartame has no effect.
Further studies are not carried out microscopically to demonstrate
possible adverse effects on the cellular basis.
Thus, results obtained from different studies vary from severe
adverse effects to none observed.
The aim of this study was to investigate the direct and indirect
cellular effects of aspartame on the brain, and we propose that
excessive aspartame ingestion might be involved in the pathogenesis
of certain mental disorders (DSM-IV-TR 2000) and also in
compromised learning and emotional functioning.
Most diet beverages and food products currently in the market
contain aspartame as an artificial sweetener.
However, controversy surrounds the effects of this non-nutritive
artificial sweetener, as it is made up of three components that may
have adverse effects on neural functioning, particularly on
neurotransmitters (Figure 1), neurons and astrocytes.
In light of the possible adverse effects of aspartame, the research
questions directing this study are formulated as follows:
What are the direct and indirect cellular effects of aspartame
on the brain?
How might excessive aspartame ingestion contribute to the
pathogenesis of certain mental disorders?
What are the implications for early brain development,
emotional status and learning following high ingestion
of aspartame?
Aspartame is composed of phenylalanine (50%),
aspartic acid (40%) and methanol (10%).
The first two are known as amino acid isolates.
It has been reported that consumption of aspartame could cause
neurological and behavioural disturbances in sensitive individuals
(Anonymous, 1984; Johns, 1986).
Headaches, insomnia and seizures are some of the neurological
disturbances that have been encountered, and this may be
accredited to changes in regional brain concentrations of
catecholamines, which include
norepinephrine, epinephrine and dopamine (Coulombe and
Sharma, 1986), all important neurotransmitters regulating
life-sustaining functions.
The effects of phenylalanine, aspartic acid and methanol are first
reviewed, followed by a discussion of altered neurotransmitter
functioning, that is dopamine, serotonin, glutamate,
g-aminobutyric acid (GABA), and acetylcholine.
The discussion is concluded with implications for early brain
development, emotional status and learning following high ingestion
of aspartame.
Effects of phenylalanine
Phenylalanine not only plays a role in amino acid metabolism
and protein structuring in all tissues, but is also
a precursor for tyrosine (Hawkins et al., 1988), DOPA,
dopamine, norepinephrine, epinephrine (Ganong, 1997),
phenylethylamine (Young, 1988) and phenylacetate
(as phenylacetate interferes with brain development and
fatty acid metabolism).
Phenylalanine also plays an important role in neurotransmitter
regulation (Caballero and Wurtman, 1988).
Phenylalanine can follow one of the two pathways of
uptake in the body.
A part is converted into tyrosine (a nonessential amino acid)
in the liver (Caballero and Wurtman, 1988)
by the enzyme phenylalanine hydroxylase (Figure 2a)
The remaining portion of phenylalanine (not converted in the liver)
will bind to a large neutral amino acid transporter (NAAT)
to be carried over the blood-brain barrier (BBB) (Figure 2b).
A large number of compounds, including phenylalanine and tyrosine,
compete with each other for a binding site on the NAAT,
because it is the only manner in which they can cross the BBB.
Importantly, tyrosine cannot be synthesized in the brain and
has have to enter the BBB via NAAT (Figure 2c) for production.
Memory loss is thought to be due to aspartic acid and phenylalanine
being neurotoxic without the other amino acids found in protein.
These neurotoxic agents might cross the BBB and deteriorate the
neurons of the brain (Mehl-Madrona, 2005).
NAAT is also a co-transporter for phenylalanine, tryptophan
(an important precursor for synthesis of serotonin),
methionine and the branch-chained amino acids.
All the above-mentioned amino acids (tyrosine, phenylalanine,
tryptophan and methionine) compete for the NAAT transporter,
so a large quantity of one amino acid in the blood stream
will occupy most of this transporter.
This results in a phenylalanine overload in the surrounding areas,
greatly limiting the amount of important amino acids (for example,
tyrosine, tryptophan and methionine) entering the brain
(Figure 2c).
If high concentration of aspartame is taken through the daily diet,
50% of it is broken down to phenylalanine.
Phenylalanine will then be either converted into tyrosine
or cross the BBB as it is.
Tyrosine is converted into dihydroxyphenylalanine (DOPA) once
it is in the brain, by the enzyme tyrosine hydroxylase, with the help
of the co-factors oxygen, iron and tetrahydrobiopterin (THB)
(Figure 2d).
Dopamine, a catecholamine, is formed from DOPA by an
aromatic amino acid decarboxylase.
Tyrosine hydroxylase activity is inhibited by high concentrations of
dopamine through its influence on the THB co-factor
(negative feedback, Figure 2d).
This system is very necessary to prevent large amount of dopamine
being produced, as dopamine is an inhibitory neurotransmitter.
However, if phenylalanine, as the main part of aspartame,
competes with tyrosine for NAAT, a compromised dopamine
production will result, because phenylalanine will bind more
frequently and freely than tyrosine, owing to its higher
concentration,
and thus lead to lower concentrations of dopamine in the brain.
After administration of aspartame to humans, the increases in
blood levels of both phenylalanine and tyrosine have been
well documented (Fernstorm, 1988; Filer and Stegink, 1988).
Therefore, phenylalanine (formed by breakdown of aspartame)
will increase in the brain owing to the ingestion of aspartame, and
tyrosine will increase as a breakdown byproduct of phenylalanine
in the liver (Fernstorm, 1988; Filer and Stegink, 1988).
Thus, aspartame and its components could potentially disrupt a
wide range of processes in the body,
including amino acid metabolism, protein structure and metabolism,
nucleic acid integrity, neuronal function and endocrine balances.
Aspartame ingestion directly results in an increase in phenylalanine
and tyrosine levels in the brain, which in turn leads to changes in
the regional brain concentrations of catecholamines
(for example, dopamine) (Fernstorm et al., 1983).
According to Mehl-Madrona (2005) aspartame changes the
dopamine level in the brain, affecting people suffering from
Parkinson's disease.
Bowen and Evangelista (2002) noted a substantial increase in the
levels of plasma phenylalanine and aspartic acid after ingestion of
aspartame.
This increased phenylalanine, thereby causing a PKU
(phenylketonuria) effect.
PKU, also known as phenylpyruvic oligophrenia, is a disorder
characterized by accumulation of phenylalanine and its keto
derivatives in the blood, tissues and urine.
This disorder is a direct result of a hereditarydeficiency or
absence of phenylalanine hydroxylase.
As described previously, this enzyme is necessary for conversion
of phenylalanine into tyrosine.
The enzymes required for the reduction of circulating
phenylalanine are overwhelmed, thus also interfering with other
metabolic reactions that utilize these enzymes,
resulting in the PKU effect.
This causes reduced dopamine and serotonin production as the
enzyme actions controlling numerous types of neurotransmitters
(and their precursor amino acids) are debilitated by overdoses
of the competitive circulating phenylalanine isolates
(and aspartic acid isolates; Bowen and Evangelista, 2002).
Serotonin, an indolamine, causes powerful smooth muscle
contraction (Ganong, 1997).
Physiologically, it is also important for behaviour and control of
sleep, temperature, appetite and neuroendocrine functions.
Tryptophan, independently utilized for synthesis of serotonin in
the brain, is transported across the BBB via NAAT.
Therefore, if NAAT is occupied with phenylalanine, tryptophan
will not be adequately carried across the BBB and serotonin
production can ultimately be compromised (Figure 3).
Aspartame administered orally in mice as single doses gave
contradictory results;
norepinephrine and dopamine (precursor of norepinephrine)
concentrations in various brain regions increased significantly,
and not as observed above.
However, mice have a different metabolism for aspartame and
its breakdown products are different from those of human beings;
this could be the reason for these contradictory results.
Sharma and Coulombe (1987) also analysed different regions for
catecholamine (for example, dopamine) and indoleamine
(for example, serotonin) neurotransmitters
and their major metabolites.
Results from this study indicated that single dose exposure
increased adrenergic chemicals, which were not apparent after
repeated dosing with aspartame.
In contrast to the above observation, decreased serotonin and
its metabolite, 5-hydroxyindoleacetate, was found in several
regions (Sharma and Coulombe, 1987).
The lowered levels of serotonin might cause the following:
A compromised BBB -- due to lower levels of activity of cAMP,
which plays an important role in the complexity of the tight
junctions in the epithelial cells of the capillaries (Figure 3).
Lowered activity of the GABA transporters -- thus GABA is
absorbed at a lower rate into the astrocytes, which results in the
continuous inhibition of depolarization of the postsynaptic membrane
(Figure 4).
Maher and Wurtman (1987) suggested that aspartame
consumption could cause neurological or behavioural reactions
in some people.
When mice were given aspartame in doses that raise plasma
phenylalanine levels more than those of tyrosine (which probably
occurs after any aspartame dose in humans), the frequency of
seizures increased, especially following the administration of the
epileptogenic drug, pentylenetetrazole
Equimolar concentrations of phenylalanine stimulate this effect
and are blocked by synchronized administration of valine,
which blocks phenylalanine's entry into the brain
(Maher and Wurtman, 1987).
Glutamate, the most common neurotransmitter in the brain,
is formed from its precursor a-ketoglutarate from the Kreb's cycle
(Figure 5).
Glutamate is primarily produced in neurons as excitatory
neurotransmitters, owing to an increased flow of positive ions
(sodium and calcium) by opening the ion-channel after binding to
appropriate receptors.
Stimulation of these receptors is terminated by a
chloride-independent membrane transport system, which is used
only for reabsorbing glutamate and aspartate across the
presynaptic membrane.
Glutamate can also be reabsorbed into the neurons for later use.
Excess glutamate released into the synapses is converted into
glutamine (non-excitotoxic molecule)
by nearby astrocytes (glial cells).
Glutamine is safely transported back to neurons, for reconversion
into glutamate.
Swollen astrocytes contribute to the excitotoxicity of glutamate,
owing to their inability to absorb excess glutamate.
Glutamate acts on its postsynaptic N-methyl-Daspartate (NMDA)
and non-NMDA receptors.
The NMDA receptor is an ion channel for calcium, sodium and
potassium ions.
Glutamate and aspartate exert their action through three separate
receptors, characterized by selective interaction with
NMDA, quisqualate and kainate (Hidemitsu et al., 1990).
The glutamate recognition sites might directly be acted upon by
aspartame in the brain synaptic membranes.
This interaction might play a vital role in mediating the potentiation
of hippocampal excitability as reported by Fountain et al. (1988).
As discussed above, aspartame may act on the NMDA
receptors, leading to continuous activation of these receptor sites,
resulting in no binding space for glutamate.
Continuous activation might cause damage to brain neurons,
as suggested by Choi and Rothman (1990).
Thus, aspartame acts as an agonist of glutamate
on the NMDA receptor (Fountain et al., 1988).
GABA is also primarily produced by neurons in the citric acid
cycle from succinate and is inactivated by absorption into
astrocytes (Figure 5).
GABA is secondarily produced in astrocytes from glutamine.
It can be released from the astrocytes as GABA or it can be
reabsorbed into the neuron as glutamine
(for conversion into either glutamate or GABA).
If the neuroenergetics of the cells were compromised by the
presence of aspartame, thus lowering glucose and oxidative
metabolism, this important feedback system of tryptophan
and tyrosine will be inhibited (Ganong, 1997).
Owing to a lowered level of oxidative metabolism and low glucose
levels in the cells, pyruvate would not be converted into
acetyl CoA, necessary for production of acetylcholine in
synapses (Figure 6).
Thus, it could lead to a decreased stimulation of second
messengers (often cyclic AMP) to indirectly open the ion channels.
Since aspartame causes neurodegeneration (destruction of neurons),
the neurons in the Meynert nucleus will also be decreased.
The Meynert nucleus is the primary cholinergic input for the cerebral
cortex, and loss of neurons in this nucleus has been shown in
Alzheimer's patients.
Thus, aspartame might be involved in the cause/mimic of
Alzheimer's disease (Ganong, 1997; Bowen and Evangelista, 2002).
Effects of aspartic acid
One of the largest studies commissioned by the aspartame
manufacturers are of the opinion that: 'in most cases aspartate
concentrations were not significantly affected by aspartame ingestion'
(Stegink et al., 1988; Stegink et al., 1989).
If read in another way, it suggests that in some cases aspartic acid
was, indeed, increased.
Aspartic acid is thought to play a role as an excitatory
neurotransmitter in the central nervous system
(Watkins, 1984; Stone and Burton, 1988).
Glutamate, asparagines and glutamine are formed from their
precursor, aspartic acid (Stegink et al., 1989).
Aspartate is inactivated by reabsorption into the presynaptic
membrane and it opens an ion channel (Olney, 1975).
Aspartate is an excitatory neurotransmitter and has an increased
likelihood for depolarization of the postsynaptic membrane.
Even short-lived increases of a powerful neural stimulator are
enough to induce neuroendocrine disturbances (Olney, 1975).
In addition, Mehl-Madrona (2005) observed that when the
temperature of aspartame exceeds 86 degrees F, the wood
alcohol in aspartame is converted into formaldehyde and
then to formic acid, which in turn causes metabolic acidosis.
The methanol toxicity is thought to mimic the symptoms of
multiple sclerosis.
According to them, symptoms of fibromyalgia, spasms,
shooting pains, numbness in the legs, cramps, vertigo, dizziness,
headaches, tinnitus, joint pain, depression, anxiety, slurred speech,
blurred vision or memory loss have been attributed to aspartame.
Effects of methanol
As mentioned previously, aspartame breaks down to form
phenylalanine, aspartic acid and
methanol, which forms 10% of the break down product.
The methanol in the body is converted to formate, which is then
excreted.
It can also give rise to formaldehyde, diketopiperazine (a carcinogen)
and a number of other highly toxic derivatives (Clarke, 2000
The absorption-metabolism sequence of
methanol-formaldehyde-formic acid also results in synergistic
damage (Bowen and Evangelista, 2002).
The accumulation of formate, rather than methanol, is itself
considered to cause methanol toxicity (Stegink et al., 1989), but
research has shown that formaldehyde adducts accumulate in the
tissues, in both proteins and nucleic acids, after aspartame ingestion
(Trocho et al., 1998).
The formed adducts of the metabolic poisons alter both
mitochondrial DNA and nucleic DNA.
Methanol and formaldehyde are also known to be carcinogenic
and mutagenic.
The damaged DNA could cause the cell to function inadequately
or have an unbalanced homoeostasis,
thus initiating disease states (Bowen and Evangelista, 2002).
In addition, it is thought that the methanol is the aspartame
is converted to formaldehyde in the retina of the eye,
causing blindness (Mehl-Madrona, 2005).
As seen from the above discussion, tryptophan, tyrosine
and phenylalanine are precursors for the neurotransmitters
serotonin, dopamine and norepinephrine.
Glutamate (glutamic acid) and aspartate (aspartic acid),
as neurotransmitters, have no direct access to the brain
and have to be synthesized in the neuronal cells of the brain.
Proteins rich in aspartate and glutamate have no effect on the levels
of acidic amino acids in the brain.
If aspartame is ingested in large amounts, it will increase the levels
of acidic amino acids in the brain (Fernstrom, 1994).
Effects of aspartame on the blood brain barrier
A compromised BBB (altered lipid-mediated transport or
active carrier transport) will result in the transport of
excitotoxins (aspartame) across BBB
and within the cerebrospinal fluid,
causing several adverse reactions to occur:
The nerves will be stimulated to fire excessively by the
excitotoxins.
The offset of induced, repeated firing of the neurons mentioned
above will require normal enzymes, which are negated by the
phenylalanine and aspartic acid present in aspartame.
These compulsory enzyme reactions mentioned above require a
normal functioning energy system.
Thus, it could be stated that the neurons become compromised
from (Bowen and Evangelista, 2002):
diminishing intracellular ATP stores;
the presence of formaldehyde;
intracellular calcium uptake been changed (e.g. phenylalanine binds
to NMDA receptor, not glutamate, thus altering calcium channels);
cellular mitochondrial damage;
destruction of the cellular wall; and
subsequent release of free radicals.
These preceding reactions potentiate oxidative stress and
neurodegeneration.
Secondary damage is caused by the toxic by-products, which in
turn will increase capillary permeability,
continuing to destroy the surrounding nerve and glial cells,
thus further obstructing enzyme reactions and
promoting DNA structural defects.
Cellular death occurs over the next 1-12 h
(Bowen and Evangelista, 2002).
Excitotoxic-saturated placental blood flow, caused by maternal
aspartame consumption, could lead to the damage or impairment
of the development of the foetal nervous system, contributing to
cerebral palsy and all-encompassing developmental disorders
(Bowen and Evangelista, 2002).
Mehl-Madrona (2005) also cited findings implicating aspartame
consumption at the time of conception to consequent birth defects,
because the phenylalanine concentrates in the placenta,
causing mental retardation.
Laboratory tests showed that animals developed brain tumours as
a result of aspartame administration. It was also pointed out that
phenylalanine breaks down into 1-deoxy-D-xylulose-5-phosphate
(DXP), a brain tumour agent.
In keeping with these findings, neuronal (brain) damage is also
produced by excitotoxins circulating in the fetal brain areas,
as a result of an incompetent BBB.
This is especially true for those areas adjacent to the brain's
ventricular system.
The methanol components of aspartame are thought to mimic
fetal alcohol syndrome, which is a direct result of the maternal
ingestion of aspartame (Bowen and Evangelista, 2002).
[ See:
methanol impurity in alcohol drinks [ and aspartame ] is turned
into neurotoxic formic acid, prevented by folic acid, re Fetal Alcohol
Syndrome, BM Kapur, DC Lehotay, PL Carlen at U. Toronto,
Alc Clin Exp Res 2007 Dec. plain text: detailed biochemistry,
CL Nie et al. 2007.07.18: Rich Murray 2008.02.24
http://rmforall.blogspot.com/2008_02_01_archive.htm
Sunday, February 24, 2008
http://groups.yahoo.com/group/aspartameNM/message/1524 ]
The amino acids that constitute meat contain a chain of
80-300 amino acids, of which 4% are phenylalanine.
This chain also includes the amino acid valine.
Valine inhibits the transport of phenylalanine into the brain
across the BBB.
In aspartame, phenylalanine makes up 50% of the molecule;
thus, in a can of diet soda, which contains 200 mg aspartame,
100 mg is phenylalanine.
No valine is present in aspartame to block the entry of toxic levels
of phenylalanine into the brain, thus resulting in lowered
concentrations of dopamine and serotonin, owing to NAAT
occupation by phenylalanine.
Thus, it can be concluded that the usage of aspartame should be
carefully considered as it (and its metabolites) causes detrimental
effects, ranging from alterations in concentrations of
neurotransmitters to causing infertility.
Thus, human health at the macroscopic, microscopic and cellular
level is at risk of being destroyed.
Comparison between human and animal reaction to aspartame
Physiologically, the animals tested for phenylalanine toxicity are
approximately 60 times less sensitive than human beings.
Humans are 10 - 20 times more sensitive to methanol
poisoning, both as a subchronic and chronic toxin/carcinogen.
The differences in enzyme concentrations of the species suggest
that animals studied are more sensitive to the more common
ethanol found in alcoholic beverages.
Test animals being used are 8 -10 times less sensitive than humans
to the effects of aspartic acid and glutamates
(Bowen and Evangelista, 2002).
Implications of aspartame consumption for early brain
development and everyday living
Ingestion of aspartame results in a craving for carbohydrates, which
will eventually result in weight gain, especially because the
formaldehyde stores in the fat cells,
particularly in the hips and thighs;
therefore, aspartame is believed to cause problem
in diabetic control.
(Mehl-Madrona, 2005).
In addition, prenatal consumption of aspartame might result in
mental retardation, impaired vision, birth defects and is thought
to play a role in the pathogenesis of Alzheimer's disease;
furthermore, it is implicated in disruption of learning and emotional
functioning due to its involvement in alteration of certain
neurotransmitters.
The earlier research findings show that aspartame consumption
might affect early brain development and neurotransmitter systems,
which might result in specific emotional, behavioural and learning
difficulties as discussed below.
Dopamine involvement in emotional status and learning
In the preceding sections it was noted that when phenylalanine,
one of the main component of aspartame, competes with tyrosine
for NAAT, a compromised dopamine production will result,
because phenylalanine will bind more frequently and freely than
tyrosine owing to its higher concentration.
This will thus lead to lower concentrations of dopamine in the brain.
Dopamine receptors are numbered D1, D2, D3, D4 and D5
receptors, all playing an important role in the dopaminergic system.
The dopaminergic system is active in maintaining normal motor
behaviour, and loss of dopamine is related to Parkinson's disease,
in which the muscles are rigid and movement is difficult
(Kolb and Whishaw, 2003).
Disturbances of the development of the dopaminergic system may
lead to dyskinesia, dystonia, tics, obsessive-compulsive disorders
and abnormal eye movements (Herlenius and Langercrantz, 2004).
This has been observed in DA-depleted rats after 6-hydroxyl
dopamine treatment but with preserved noradrenaline effect
(Zhou and Palmiter, 1995).
D1-receptors are involved in working memory performance
(Williams and Goldman-Rakic (1995)).
A disturbance of the development of the dopaminergic system has
been postulated to contribute to the cause of attention deficit
hyperactivity disorder (ADHD), in which a deficient working
memory is an important component (Dare et al., 2003).
In 2002, Bowen and Evangelista noted a substantial increase in
levels of plasma phenylalanine and aspartic acid after ingestion of
aspartame.
This increased phenylalanine causes PKU effect
as noted earlier in this study.
Infants with phenylketonuria and probably deficient dopaminergic
innervation of the prefrontal cortex have been found to have
(among other symptoms) an impaired working memory
(Diamond et al., 2004).
Serotonin involvement in early brain development, emotional
status and learning
Tryptophan, independently utilized for synthesis of serotonin
in the brain, is transported across the BBB via NAAT.
Therefore, if NAAT is saturated with phenylalanine, tryptophan will
not be adequately carried over the BBB and serotonin production
can ultimately be compromised.
In addition to its role in regulating maturation of terminal areas,
serotonin can set its own terminal density -- a phenomenon
Whitaker-Azmitia (2001) termed autoregulation of development.
Serotonin (5-HT), like other monoamine neurotransmitters, has been
shown to play a role in regulating brain development before the time
it assumes its role as a neurotransmitter in the mature brain
(Chubakov et al., 1986, 1993; Lauder, 1990;
Whitaker-Azmitia, 1991; Turlejski, 1996;
Whitaker-Azmitia et al., 1996).
This neurotransmitter is concentrated in the raphe nucleus of the
brain, and is also present in platelets.
Serotonin and serotonergic neurons are localized in the midbrain,
the pineal gland, the substantia nigra, the hypothalamus and the
raphe nuclei of the brain stem (Herlenius and Lagercrantz, 2004).
The 5-HT neurons have widespread projections, making it possible
to coordinate complex sensory and motor behavioural conditions.
Serotonin is also involved in inducing sleep, sensory perception,
temperature regulation and control of mood;
therefore, serotoninergic activity was found to be highest during
waking and arousal and absent during active or rapid
eye-movement sleep (Boutrel et al, 1999).
In addition, serotonin has been reported to affect neuronal
proliferation, differentiation, migration and synaptogenesis
(Gaspar et al., 2003).
In the mammalian brain, all the monoamine neurotransmitter
systems are present relatively early but, in particular, serotonin
is likely to present the earliest in the most terminal regions
(Whitaker-Azmitia, 2001).
These early appearances of serotonergic neurons with their wide
distribution of terminals play a crucial role in programmed
neurogenesis, synaptogenesis and apoptosis.
Serotonergic cells in the raphne are among the earliest to be
generated in the brain (Gaspar et al., 2003).
Therefore, serotonin concentration must be neither too high nor too
low during the critical period of synaptogenesis and formation
of cortical connections.
Serotonergic abnormalities are also associated with abnormalities
of cortical development and thalamocortical connectivity, as
abnormal serotonin transport or synthesis during brain
development may directly affect formation of intracortical and
thalamocortical circuitry (Chugani, 2004).
Furthermore, disruptions of the serotonergic pathways due to
excess or inadequate activation of specific 5-HT receptors
during development are implicated in the pathogenesis of
developmental disorders such as autism (Gaspar et al., 2003).
The relative balance of tryptophan metabolism, regulated by the
serotonin and kynurenine pathways, might therefore be important
in the pathogenesis of pervasive developmental disorders among
children, and aspartame consumption may therefore play a role
in the occurrence of developmental disorders.
GABA involvement in early brain development, emotional status
and learning
The removal of the carboyxl (COOH) group from glutamate
produces GABA, which is the main inhibitory transmitter
(Kolb and Whishaw, 2003), and perhaps 25-40% of all nerve
terminals contain GABA (Herlenius and Lagercrantz, 2004).
In humans, the majority of neocortical GABAergic neurons
arise locally in the ventricular and subventricular zone.
Proportionally fewer GABAergic neurons originate from the
ganglionic eminence of the ventral forebrain (Letinic et al., 2002).
The lowered levels of serotonin due to aspartame
consumption might cause lowered activity of the GABA
transporters, and thus GABA is absorbed at a lower rate into
the astrocytes, which will result in the continuous inhibition
of depolarization of the postsynaptic membrane.
Although GABA is regarded as the main inhibitory
transmitter in the mature animal, it has a different role
during early development (Herlenius and Lagercrantz, 2004).
During early brain development, it acts as a trophic factor to
influence events such as proliferation, migration, differentiation,
synapse maturation and cell death (Owens and Kriegstein, 2002).
Herlenius and Lagercrantz (2004) report that GABA is a crucial
transmitter for the human infant and operates mainly as an
excitatory transmitter on immature neurons.
As GABA has a trophic role during early brain development,
interference with the function of GABAergic transmission during
this period may affect the development of neuronal wiring,
plasticity of neuronal network and also have a profound influence
on neural organization (Herlenius and Lagercrantz, 2004).
Acetylcholine involvement in early brain development, emotional
status and learning
Previously, it was mentioned that aspartame could cause changes
to acetylcholine production.
It is known that at a lowered level of oxidative metabolism and
low glucose levels in the cells, pyruvate would not be converted
acetyl CoA necessary for production of acetylcholine in synapses.
Acetylcholine is one of the major neurotransmitters of
importance in the brain for cortical activation, attention,
reward and pain.
The cholinergic system is thought to play a role in memory and
learning by maintaining neuron excitability.
Death of acetylcholine neurons and decrease in acetylcholine in the
neocortex are thought to be related to Alzheimer's disease
(Kolb and Whishaw, 2003), as it has a major role in the control
motor tone and movement and probably counterbalances the effect
of dopamine (Johnston and Silverstein, 1998; Cooper et al., 2003).
In addition, acetylcholine is of major importance for the
development and the control of autonomic functions, and alterations
to the cholinergic system might result in major changes
in cortical structure.
These changes can be correlated to cognitive deficits but do not
affect motor behaviour (Herlenius and Lagercrantz, 2004).
Norepinephrine involvement in emotional status and learning
Aspartame may also cause a change in norepinephrine.
Compared with dopamine systems, which restrict their outputs
to the reptilian brain (that is, the basal ganglia) and frontal
cortex,
the projections of the caudally situated noradrenaline systems
are more widespread.
The cell bodies of the noradrenergic neurons are concentrated in
the brain stem, particularly in the locus coeruleus within the caudal
pons (Kolb and Whishaw, 2003).
Five major noradrenergic tracts originate from the locus coeruleus
that disperse through the whole brain.
There are also clusters of noradrenergic cell bodies in the nucleus
tractus solitarius and in the lateral ventral tegmental field
(Herlenius and Lagercrantz, 2004).
Fibres from these nuclei intermingle with those from the locus
coeruleus.
The A6 noradrenaline cell group, well known as the locus coeruleus,
controls higher brain activity through the dorsal noradrenaline
pathway.
This group sends inputs to the cortex, hypothalamus, cerebellum,
lower brain stem and spinal cord, thereby exerting control over
cortical arousal and attention, fear and anxiety,
and learning and memory.
The ventral noradrenaline pathway infiltrates the hypothalamus
and the limbic system (Panksepp, 1998).
Noradrenergic neurons appear at an early stage in the
development of the central nervous system.
Sundstrom et al (1993) reported noradrenergic neuronal
development at the 12th to 14th day of gestation in the rat and
within 5-6 weeks in the human, and Sundstrom (1996) later
suggested that noradrenaline is essential
for normal brain development.
In addition, the noradrenergic system regulates the development of
the Cajal-Retzius cells that are the first neurons to be formed in the
cortex (Herlenius and Lagercrantz, 2004).
Wang and Lidow (1997) showed that radial glia participate in key
steps of brain development and cortical neurogenesis, whereas two
independent studies showed glia participation in migration
(Noctor et al., 2001, 2004).
Thus, adrenergic transmission may be involved in regulating the
generation, migration and maturation of cerebral cortical cells.
Herlenius and Lagercrantz (2004) reported that administration of
6-OH-dopamine prevents programmed cell death of these
neurons and delays the formation of cortical layers.
Lesioning of the noradrenergic projections or blocking of
neurotransmission with receptor antagonist prevents astrogliosis
and glial cell proliferation.
During postnatal development, noradrenaline plays an
important role in regulating attention, as noradrenergic cells
are exquisitely sensitive to environmental stimuli, especially
powerful emotional events (Panksepp, 1998).
With low noradrenaline activity, individuals tend to perseverate on
a task despite changes in stimulus contingencies because of
attention deficits.
Such individuals are prone to act impulsively rather than
deliberately.
Depletion of noradrenaline during the perinatal period can also result
in subtle dendritic changes and possibly also alterations in cortical
differentiation that may lead to behavioural changes
(Berger-Sweeney and Hohmann, 1997).
It is also known that noradrenaline dampens the background 'noise'
or cortical neural activity irrelevant to a given task
(Panksepp, 1998).
This makes the influence of specific incoming signals more
prominent in the cortex, namely the ratio of the signal to
background noise is increased.
Thus, it is suspected that with high noradrenaline activity,
individuals
can better process information that already has access to the cortex.
Glutamate involvement in emotional status and learning
The glutamate recognition sites might directly be acted upon by
aspartame in the brain synaptic membranes, and aspartame may
act on the NMDA receptors, leading to continuous activation of
these receptor sites and no binding space for glutamate.
The excitatory amino acid transmitter glutamate and the inhibitory
amino acid transmitter GABA are closely related in the sense that
GABA is formed by a simple modification of glutamate
(Herlenius and Lagercrantz, 2004).
Glutamate is widely distributed in the forebrain and cerebellum
and also in neurons, but it becomes a neurotransmitter only if it is
appropriately packed in vesicles in the axon terminal
(Kolb and Whishaw, 2003).
Glutamate acts on at least five types of receptors, and particularly
the NMDA receptors dominate in the immature brain, when
synaptic transmission is weak and extremely plastic, as the
NMDA receptors permit entry of Naþ and Ca2þ when opened.
NMDA channels seem to be crucially involved in the appearance
of long-term potentiation and synaptic plasticity underlying learning
and memory storage throughout life
(Herlenius and Lagercrantz, 2004).
Cell death resulting from glutamate occurs in two ways:
first, it causes an increase in intracellular calcium
that poisons the cell, and
second, the increase in intracellular calcium can activate genes in
the cell's DNA to produce proteins that kill the cell,
called apoptosis (Kolb and Whishaw, 2003
During critical periods of development and synaptogenesis, NMDA
receptors play an essential role in activity-dependent plasticity and
synaptic refinement
(McDonald and Johnston, 1990; Qu et al., 2003).
Thus, either too much or too little NMDA receptor activity can be
life-threatening to developing neurons (Lipton and Nakanishi, 1999).
Conclusion
It was seen that aspartame disturbs amino acid metabolism, protein
structure and metabolism, integrity of nucleic acids, neuronal
function, endocrine balances and changes in the brain
concentrations of catecholamines.
It was also reported that aspartame and its breakdown products
cause nerves to fire excessively,
which indirectly causes a very high rate of neuron depolarization.
The energy systems for certain required enzyme reactions become
compromised, thus indirectly leading to the inability of enzymes to
function optimally.
The ATP stores in the cells are depleted, indicating that low
concentrations of glucose are present in the cells, and this in turn
will indirectly decrease the synthesis of acetylcholine, glutamate
and GABA.
The intracellular calcium uptake has been altered, thus the
functioning of glutamate as an excitatory neurotransmitter is
inhibited.
Mitochondria are damaged, which could lead to apoptosis of cells
and infertility in men and also a lowered rate of oxidative
metabolism are present, thus lowering concentrations of the
transmitters glutamate and production of GABA.
The cellular walls are destroyed; thus, the cells (endothelium of the
capillaries) are more permeable, leading to a compromised BBB.
Thus, overall oxidative stress and neurodegeneration are present.
From all the adverse effects caused by this product, it is
suggested that serious further testing and research be undertaken to
eliminate any and all controversies surrounding this product.
www.alwayson.co.za/resia/ Resia Pretorius
Current Position:
Associate Professor in the Department of Anatomy,
University of Pretoria, South Africa.
Research Focus Areas:
* Cell Biology
* The Link Between Neuroanatomy and Learning Difficulties
* Geometric Morphometrics
Email: resia.p...@up.ac.za
Tel: +27 12 319 2533 Fax: +27 12 319 2240
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____________________________________________________
phenylalanine and aspartic acid from low dose aspartame in rabbits
interfere with blood coagulation, Pretorius E and Humphries P,
U. of Pretoria, Ultrastruct Pathol 2007 March: Murray 2007.07.14
http://groups.yahoo.com/group/aspartameNMmessage/1452
" The authors conclude by suggesting that aspartame usage
may interfere with the coagulation process
and might cause delayed fibrin breakup after clot formation.
They suggest this,
as the fibrin networks from aspartame-exposed rabbits
are more complex and dense,
due to the netlike appearance of the minor, thin fibers.
Aspartame usage should possibly be limited
by people on anti-clotting medicine
or those with prone to clot formation. "
Ultrastruct Pathol. 2007 Mar-Apr; 31(2): 77-83.
Ultrastructural changes to rabbit fibrin and platelets
due to aspartame.
Pretorius E,
Humphries P.
Department of Anatomy, Faculty of Medicine,
University of Pretoria, South Africa.
[ Humphries P also at
Department of Anatomy, University of Limpopo.
Medunsa Campus, Garankuwa. South Africa ]
email: E. Pretorius resia.p...@up.ac.za
*Correspondence to E. Pretorius,
BMW Building, PO Box 2034,
Faculty of Health Sciences,
University of Pretoria, Pretoria 0001, South Africa
The coagulation process, including thrombin, fibrin,
as well as platelets,
plays an important role in hemostasis,
contributing to the general well-being of humans.
Fibrin formation and platelet activation are delicate processes
that are under the control of many small physiological events.
Any one of these many processes
may be influenced or changed by external factors,
including pharmaceutical or nutritional products, e.g.,
the sweetener aspartame (L-aspartyl-L-phenylalanine methyl ester).
It is known that phenylalanine is present at position P(9)
and aspartate at position P(10)
of the alpha-chain of human fibrinogen,
and plays an important role in the conversion of fibrinogen
to fibrin by the catalyst alpha-thrombin.
The authors investigate the effect of aspartame
on platelet and fibrin ultrastructure,
by using the rabbit animal model
and the scanning electron microscope.
Animals were exposed to 34 mg/kg of aspartame
26x during a 2-month period.
Aspartame-exposed fibrin networks appeared denser,
with a thick matted fine fiber network
covering thick major fibers.
Also, the platelet aggregates appeared more granular
than the globular control platelet aggregates.
The authors conclude by suggesting that aspartame usage
may interfere with the coagulation process
and might cause delayed fibrin breakup after clot formation.
They suggest this,
as the fibrin networks from aspartame-exposed rabbits
are more complex and dense,
due to the netlike appearance of the minor, thin fibers.
Aspartame usage should possibly be limited
by people on anti-clotting medicine
or those with prone to clot formation.
PMID: 17613990
____________________________________________________
http://www.nature.com/ejcn/journal/vaop/ncurrent/full/ejcn20085a.html
Journal home > Advance online publication > 30 January 2008
> Full text
Letter to the Editor
European Journal of Clinical Nutrition
advance online publication 30 January 2008
doi: 10.1038/ejcn.2008.5
Aspartame effects on the brain
J D Fernstrom 1
1 Department of Psychiatry and Pharmacology,
University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Correspondence: JD Fernstrom, E-mail: ferns...@upmc.edu;
The following comments relate to the review by
Humphries et al. (2007).
The premise of the review, that the high-intensity sweetener
aspartame is neurotoxic, ignores a very large scientific literature to
the contrary, recently comprehensively summarized
(Butchko et al., 2002; Magnuson et al., 2007).
The key point about aspartame is that very little is consumed.
Because it is 180 times sweeter than sugar,
relatively little shows up in products.
For example, a 355 ml can of diet soda
contains 180 mg of aspartame, which for a
70 kg human is a 2.5 mg kg-1 dose
(1.25 mg kg-1 phenylalanine).
After its introduction, its use was monitored for years,
revealing that average daily dosing is barely 5 mg kg-1 day-1
(2.5 mg kg-1 day-1 phenylalanine), not much.
As a comparison, the amount of phenylalanine in a quarter-pound
hamburger is about 1000 mg, or 14 mg kg-1 phenylalanine
(70 kg individual), or much more.
It is important to keep this fact in mind when considering the
authors' arguments, which relate to studies in animals involving
extremely high aspartame doses
(for example, up to 2000 mg kg-1 in rats, a huge dose).
Such studies have no relevance to human use.
And, for aspartame to have effects in animals, blood levels of
aspartame constituents (aspartate, phenylalanine, methanol)
must increase to very high values.
At the levels ingested by humans, such increases in blood do not
occur, even at high levels of intake
(Butchko et al., 2002; Magnuson et al., 2007).
The errors in this article are too numerous to enumerate
in a letter of limited length.
I note those most obvious to me.
(a) Formate is not converted to diketopiperazine (abstract).
(b) The authors are incorrect in stating that tyrosine cannot be
synthesized in brain from phenylalanine.
(c) Despite the authors' statement, even very large increases in
phenylalanine levels produced by aspartame administration to rats
do not suppress catecholamine synthesis rate
(Fernstrom et al., 1991).
(d) Contrary to the authors' statement, my 1983 Life Sciences
paper did not find changes in regional brain catecholamine
concentrations following aspartame dosing of rats.
(e) Maher and Wurtman gave rats aspartame up to 2000 mg kg-1,
a huge dose. And their results could not be confirmed
(see Butchko et al., 2002; Magnuson et al., 2007).
(f) Aspartame does not enter the blood from the gut,
and thus does not get into brain.
Hence, brain glutamate receptors cannot be engaged directly by
aspartame, despite the authors' assertions.
(g) Despite the authors' statement, my 1994
Journal of the American Dietetic Association article does not state
that aspartame increases brain levels of acidic amino acids.
(h) There is no such thing as
'excitotoxic-saturated placental blood flow'
caused by maternal aspartame consumption.
(i) Finally, many erroneous statements have been obtained from
two websites, one cited as Mehl-Madrona
and the other as Bowen and Evangelista.
These seem to me to be inappropriate references,
as their contents have not been subjected to peer review,
and contain unsupported speculation.
While I recognize the need for a continuing dialog on any issue
relevant to human nutrition and health, here in relation to
aspartame, in my view, the article by Humphries
does not make an informed contribution.
References
Butchko HH, Stargel WW, Comer CP, Mayhew DA,
Benninger C, Blackburn GL et al. (2002).
Aspartame: review of safety.
Regul Toxicol Pharmacol 35, S1-S93.
| Article | PubMed |
Fernstrom JD, Fernstrom MH, Massoudi MS (1991).
In vivo tyrosine hydroxylation in rat retina:
effect of aspartame ingestion in rats
pretreated with p-chlorophenylalanine.
Am J Clin Nutr 53, 923-929. | PubMed | ChemPort |
Humphries P, Pretorius E, Naude H (2007).
Direct and indirect cellular effects of aspartame on the brain.
Eur J Clin Nutr; e-pub ahead of print 8 August 2007
doi: 10.1038/sj.ejcn.1602866.
Magnuson BA, Burdock GA, Doull J, Kroes RM, Marsh GM,
Pariza MW et al. (2007).
Aspartame: a safety evaluation based on current use levels,
regulations, and toxicological and epidemiological studies.
Crit Rev Toxicol 37, 629-727. | Article | PubMed | ChemPort |
____________________________________________________
http://www.nature.com/ejcn/journal/vaop/ncurrent/full/ejcn20084a.html
13 February 2008 > Full text
Letter to the Editor
European Journal of Clinical Nutrition
advance online publication 13 February 2008
doi: 10.1038/ejcn.2008.4
Addressing comments by JD Fernstrom
P Humphries1 and E Pretorius1
1 Department of Anatomy, University of Pretoria,
Gauteng, South Africa
Correspondence: Professor E Pretorius, Department of Anatomy,
University of Pretoria, BMW building, Dr Savage street,
Pretoria, Gauteng 1, South Africa.
E-mail: resia.p...@up.ac.za
Received 21 December 2007; Accepted 27 December 2007;
Published online 13 February 2008.
The issue of aspartame safety has been controversial since
approval by FDA, many years ago.
It seems as if there are two points of views,
either supporting the use of aspartame, or suggesting its dangers.
Numerous research articles raised concerns regarding the adverse
effects and particularly related to the metabolic components.
The comments of JD Fernstrom will now be addressed in Box 1.
Box 1.
http://mail.google.com/mail/?hl=en&tab=wm#compose
Box 1.
Figure and tables index
Comments of JD Fernstrom Our comments
JDF: The article ignores scientific literature that reviews literature
that supports aspartame use.
PH, EP: Although the article Magnuson et al. (2007) was available
only online well after submission of the article
Humphries et al. (2007), and we acknowledge the fact that there
are articles that propagate the fact that aspartame is safe, it was
the
focus of the article to discuss possible adverse effects of the
consumption of aspartame.
JDF: Formate is not converted to diketopiperazine (abstract)
PH, EP: Sentence in the abstract of Humphries et al. (2007)
is as follows:
Methanol, which forms 10% of the broken down product,
is converted in the body to formate, which can either be excreted
or can give rise to formaldehyde, diketopiperazine (a carcinogen)
and a number of other highly toxic derivatives.
This sentence does not imply that formate is converted to
diketopiperazine, but that diketopiperazine is a breakdown product
of methanol. (Prodolliet and Bruelhart, 1993; Lin and Cheng, 2000).
JDF: The authors are incorrect in stating that tyrosine cannot be
synthesized in brain from phenylalanine.
PH, EP: This statement is not true; under the heading 'Effects of
phenylalanine', the sentence reads
'A large number of compounds, including phenylalanine and
tyrosine, compete with each other for a binding site on the NAAT,
seeing that it is the only manner in which these compounds
can cross the BBB.
Importantly, tyrosine cannot be synthesised in the brain, thus have
to enter the BBB via NAAT (Figure 2c) for production'.
For more clarity, the sentence could also have read
'Importantly, dopamine cannot be synthesized in the brain unless
tyrosine is carried over the BBB via NAAT for production'.
JDF: Despite the authors' statement, even very large increases in
phenylalanine levels produced by aspartame administration to rats
do not suppress catecholamine synthesis rate
(Dow-Edwards et al., 1989)
PH, EP: Reference:
There are papers that disagree with the statement of JD Fernstrom:
Yokogoshi and Wurtman (1986), which states
'Phenylalanine has been described as both a substrate
(Kaufman S, personal communication) and an inhibitor
(McKean, 1972; Gibson and Wurtman, 1977)
of tyrosine hydroxylase, the enzyme that catalyzes the rate-limiting
step in converting tyrosine to catecholamines'.
'The effect of TPT (tryptophan, phenylalanine and tyrosine)
depletion on the ratio between the monoamine precursors
and other LNAA that compete for active transport into the brain
correspond to an 87-90% decrease.
Neuro-imaging, cerebrospinal fluid, microdialysis
and post-mortem tissue punch studies indicate that this magnitude
of decline decreases brain 5-HT (serotonin)
and catecholamine synthesis'
(Palmour et al., 1998; McTavish, Cowen and Sharp, 1999;
Leyton et al., 2003, 2004).
JDF: Contrary to the authors' statement, my 1983 Life Sciences
paper did not find changes in regional brain catecholamine
concentrations following aspartame dosing of rats
PH, EP: The sentence should have read as follows:
Aspartame ingestion directly results in an increase in brain
phenylalanine and tyrosine levels (Fernstrom et al., 1983).
This may lead to changes in the regional brain concentrations of
catecholamines (e.g. Dopamine) (Coulombe and Sharma, 1986).
JDF: Maher and Wurtman gave rats aspartame up to
2000 mg/kg, a huge dose.
Also, their results could not be confirmed
(see Coulombe and Sharma, 1986; Christian et al., 2004).
PH, EP: Professor Wurtman from MIT is a renowned researcher
with more than 1000 articles that include more that 50 Science and
Nature articles.
There is also research with much lower doses that did see changes
due to aspartame.
References include the following:
Dow-Edwards et al. (1989) administered 500 mg/kg aspartame
to pregnant guinea pigs and found that this aspartame exposure
throughout gestation disrupts odor-associative learning
in 15-day-old guinea pigs.
Christian et al. (2004) used a dosage of 250 mg/kg per day
for 4 months, and the authors demonstrated that chronic aspartame
consumption in rats can leads to altered T-maze performance and
increased muscarinic cholinergic receptordensities
in certain brain regions.
Mead (2006) wrote
'Aspartame-fed females showed significant evidence of
lymphomas/leukemias and of carcinomas of the renal pelvis
and ureter.
The effect on the renal pelvis was much more evident when
carcinomas were combined with atypical preneoplastic lesions.
The researchers also observed an insignificant increase in incidence
of malignant schwannomas of the peripheral nerves in males,
as well as hyperplasia of the olfactory epithelium
in males and females.
Lesions of the kidney and olfactory epithelium are extremely rare
in this strain of rats and therefore merit special attention'.
Also:
Mead (2007) and Soffritti et al. (2006) wrote
'The carcinogenic effects were evident at daily doses as low as
400 parts per million, equivalent to an assumed daily human intake
of 20 milligrams per kilogram body weight (mg/kg).
This dosage is much less than the acceptable daily intake for
humans, with current limits set at 50 mg/kg in the United States
and 40 mg/kg in Europe.
Surveys of aspartame intake in the United States and Europe
from 1984 to 1992 showed that consumers typically consumed
2-3 mg/kg daily, with small children and women of child-bearing age
consuming slightly more, at 2-5 mg/kg daily'.
JDF: Aspartame does not enter the blood from the gut, and
thus does not get into the brain. Hence, brain glutamate receptors
cannot be engaged directly by aspartame,
despite the authors' assertions.
PH, EP: We did not say that aspartame enters from the gut.
We mention that aspartame's metabolic components
enter the blood via the gut.
But:
We referenced Fountain et al. (1988), who mentioned the above.
Also, Pan-Hou et al. (1990) suggested that
'aspartame may act directly on the NMDA glutamate recognition
sites in the brain synaptic membranes'.
Also:
'The safety of two flavour enhancers monosodium glutamate
and aspartame has been examined extensively, and concerns
have been expressed over their excitotoxic effects,
i.e. their potential for destroying central neurons by excessive
stimulation of postsynaptic excitatory membrane receptors,
predominantly the NMDA subtype of the glutamate receptor'
(Olney, 1988; Rothman and Olney, 1995).
JDF: Despite the authors' statement, my
1994 Journal of the American Dietetic Association article does
not state that aspartame increases brain levels of acidic amino acids.
PH, EP: Here is the sentence that we referenced directly from the
1994 article (in the abstract):
'Nevertheless, the food additives monosodium glutamate and
aspartame (which contains aspartate) have been reputed to raise
the level of acidic amino acid in the brain
(when ingested in enormous amounts), to modify brain function,
and even to cause neuronal damage'.
'Several studies have shown that these excitotoxins
(monosodium glutamate and aspartame),
when administered to neonatal animals,
produce acute neuronal degeneration in the retina
and in specialized regions of the brain:
the circumventricula organs that lack the blood brain barriers'
(Olney, 1969a; Olney and Ho, 1970; Olney et al., 1972;
Lau et al., 2006)
JDF: There is no such thing as 'excitotoxic-saturated placental
blood flow' caused by maternal aspartame consumption.
PH, EP: There is research that suggests that phenylalanine
is concentrated in the foetal side of the placenta.
Aspartate does not readily cross the placenta; however, the other
metabolic
compounds may do so.
Phenylalanine:
Rouse et al. (2000) performed a study on woman with PKU to
determine the effects of phenylalanine on offspring.
Women presented with babies that had congenital heart defects
and microcephaly.
These results were confirmed by Matalon et al. (2003).
Paolini et al. (2001a, 2001b) stated
'That in human pregnancy the in vivo placental transport of amino
acids that preferentially use exchange transporters
(leucine and phenylalanine) is much more rapid
than of amino acids that do not (glycine and proline)'.
'Previous in vivo studies have demonstrated that amino acids
with the most rapid flux from mother to foetus use
exchange transporters located on the
foetal surface of the trophoblast that have properties
similar to the sodium-independent 1 system
(Jozwik et al., 1998; Paolini et al., 2001a, 2001b).
Both branched chain amino acids and phenylalanine have been
shown to use this exchange transporter'
(Battaglia and Regnault, 2001).
Sturtevant (1985) (abstract):
'Phenylalanine is concentrated on the foetal side of the placenta'.
Methanol:
'Transplacental methanol toxicokinetics has been demonstrated;
methanol appears to decrease uteroplacental perfusion in a
concentration-dependant fashion in both rats and mice,
limiting the ability of methanol to diffuse into the conceptual
department' (Ward and Pollack, 1996b).
JDF: Finally, many erroneous statements have been obtained
from two web sites, one cited as Mehl-Madrona,
the other as Bowen and Evangelista.
These seem to me to be inappropriate references,
as their contents have not been subjected to peer review,
and contain unsupported speculation.
PH, EP: The research mentioned in the web site of Mehl-Madrona
is substantiated by peer-reviewed articles:
Memory loss is thought to be due to aspartic acid and phenylalanine
being neurotoxic without the other amino acids found in protein.
These neurotoxic agents may go past the BBB
and deteriorate the neurons of the brain (Mehl-Madrona, 2005).
Two references to confirm this statement:
Maher and Wurtman (1987) (abstract):
'If mice are given aspartame in doses that elevate plasma
phenylalanine levels more than those of tyrosine
(which probably occurs after any aspartame dose in humans),
the frequency of seizures following the administration of an
epileptogenic drug, pentylenetetrazole, is enhanced.
This effect is simulated by equimolar phenylalanine
and blocked by concurrent administration of valine,
which blocks phenylalanine's entry into the brain'.
Also, Lau et al. (2006) mentioned that aspartame
could produce acute neuronal degeneration in the retina
and in specialized regions of the brain.
In addition, Mehl-Madrona (2005) states that when the
temperature of aspartame exceeds 86 degrees F,
the wood alcohol in aspartame converts to formaldehyde
and then to formic acid, which in turn causes metabolic acidosis.
Reference to confirm this statement:
Lim (2007): metabolic acidosis can occur as a result of either the
accumulation of endogenous acids that consume bicarbonate
(high anion gap metabolic acidosis)
or the loss of bicarbonate from the gastrointestinal tract
or the kidney
(hyperchloremic or normal anion gap metabolic acidosis).
The cause of high anion gap metabolic acidosis includes
lactic acidosis, ketoacidosis, renal failure
and intoxication with ethylene glycol, methanol, salicyclate
and less commonly with pyroglutamic acid, propylene glycole or
djenkol bean.
In addition, it is thought that the methanol in the aspartame
converts to formaldehyde in the retina of the eye,
causing blindness (Mehl-Madrona, 2005).
Reference to confirm this statement:
Hayasaka et al. (2001) reported that rabbits 1 month after
receiving 0.1% formaldehyde showed retinal vessel dilation,
and the rabbits that received 1% formaldehyde showed
mild posterior subcapsular cataract
and retinal vessel dilatation and haemorrhages.
These same animals, 1 month after treatment
developed mild posterior subcapsular cataract and retinal lesions.
Also, histologically disorganized retina and optic nerve
were seen in eyes that received 0.1 or 1% formaldehyde.
Mehl-Madrona (2005) also cited research findings implicating
aspartame consumption at the time of conception to consequent
birth defects, because the phenylalanine concentrates in the placenta,
causing mental retardation.
Peer-reviewed articles that confirm this statement are
Rouse et al. (2000); Matalon et al. (2003);
and Paolini et al. (2001a, 2001b).
Ingestion of aspartame results in a craving for carbohydrates,
which will eventually result in weight gain,
especially because the formaldehyde stores in the fat cells,
particularly in the hips and thighs; therefore, aspartame
is thought to make diabetic control especially problematic
(Mehl-Madrona, 2005).
This is a statement that was made by a Dr Dr HJ Roberts,
diabetic specialist, in the Congressional record
(Congressional Record SID835: 131 (August 1, l985)).
Bowen and Evangelista: their 2002 web site makes use of many
peer-reviewed articles, and it is noteworthy that AM Evangelista
is a former FDA investigator.
[ End of Box 1 ]
From the comments made by JD Fernstrom, it appears that he
does not trust research suggesting that
aspartame may be detrimental to human health.
We believe that there are numerous well-researched papers
by key researchers that prove the negative effects of this sweetener.
Can we as researchers really take the responsibility of the health of
millions of consumers by ignoring research?
Can we sit back and close our eyes to even one paper
that suggests that a product may influence the health
of innocent consumers and unborn babies?
What if it is indeed true that the health of only one person
is negatively influenced by aspartame consumption?
Is it not our responsibility as researchers to prevent this?
Millions of people use this product, not necessarily at abuse doses,
but every day of their lives, Dr Fernstrom, what if....
References
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Placental transport and metabolism of amino acids.
Placenta 22, 145-161. | Article | PubMed | ChemPort |
Christian B, McConnaughey K, Bethea E, Brantley S, Coffey A,
Hammond L et al. (2004).
Chronic aspartame affects T-mase performance,
brain cholinergic receptors and Na+, K+-ATPase in rats.
Pharmacol Biochem Behav 78, 121-127.
| Article | PubMed | ChemPort |
Coulombe Jr RA, Sharma RP (1986).
Neurobiochemical alterations induced
by the artificial sweetener aspartame (NutraSweet).
Toxicol Appl Pharmacol 83, 79-85.
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Dow-Edwards DL, Scribani LA, Riley EP (1989).
Impaired performance on odor-aversion testing following prenatal
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Fountain SB, Hennes SK, Teyler TJ (1988).
Aspartame exposure and in vitro hippocampal slice excitability
and plasticity.
Fundam Appl Toxicol 11, 221-228.
| Article | PubMed | ISI | ChemPort |
Gibson CJ, Wurtman RJ (1977).
Physiological control of brain catechol synthesis by brain tyrosine
concentrations.
Biochem Pharmacol 26, 1137-1142.
| Article | PubMed | ChemPort |
Hayasaka Y, Hayasaka S, Nagaki Y (2001).
Ocular changes after intavitreal injection of methanol,
formaldehyde, or formate in rabbits.
Pharmacol Toxicol 89, 74-78.
| Article | PubMed | ChemPort |
Jozwik M, Teng C, Timmerman M, Chung M,
Meschia G, Battaglia FC (1998).
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nonmetabolizable amino acids
with different transport system affinities.
Placenta 19, 531-538. | Article | PubMed | ChemPort |
Lau K, McLean WG, Williams DP, Howard CV (2006).
Synergistic interactions between commonly used food additives
in a developmental neurotoxicity test.
Toxicol Sci 90, 178-187. | Article | PubMed | ChemPort |
Leyton M, Dagher A, Boileau I, Casey K, Baker GB,
Diksic M et al. (2004).
Decreasing amphetamine-induced dopamine release
by acute phenylalanine/tyrosine depletion:
A PET/[11C]raclopride study in healthy men.
Neuropsychopharmacology 29, 427-432.
| Article | PubMed | ChemPort |
Leyton M, Kwai Pun V, Benkelfat C, Young SN (2003).
A new method for rapidly and simultaneously decreasing serotonin
and catecholamine synthesis in humans.
Rev Psychiatr Neurosci 28, 464-467.
Lim S (2007). Metabolic acidosis.
Acta Med Indones 39, 145-150. | PubMed |
Lin SY, Cheng YD (2000).
Simultaneous formation and detection of the reaction product
of solid-state aspartame sweetener
by FT-IR/DSC microscopic system.
Food Addit Contam 17, 821-827.
| Article | PubMed | ChemPort |
Maher TJ, Wurtman RJ (1987).
Possible neurologic effects of aspartame,
a widely used food additive.
Environ Health Perspect 75, 53-57.
| Article | PubMed | ISI | ChemPort |
Matalon KM, Acosta PB, Azen C (2003).
Role of nutrition in pregnancy with phenylketonuria
and birth defects.
Pediatrics 112 (6 Part 2), 1534-1536. | PubMed |
McKean CM (1972). The effects of high phenylalanine
concentrations on serotonin and catecholamine metabolism
in the human brain.
Brain Res 47, 469-476. | Article | PubMed | ChemPort |
McTavish SF, Cowen PJ, Sharp T (1999).
Effect of a tyrosine-free amino acid mixture on regional brain
catecholamine synthesis and release.
Psychopharmacology (Berl) 141, 182-188.
| Article | PubMed | ChemPort |
Mead MN (2006).
Sour finding on popular sweetener.
Environ Health Perspect 114, A176. | PubMed |
Mead MN (2007).
Aspartame cancer risks revisited: prenatal exposure
may be greatest concern.
Environ Health Perspect 115, A460.
Olney JW, Ho OL (1970).
Brain damage in infant mice following oral intake
of glutamate, aspartate or cysteine.
Nature 227, 609-611. | Article | PubMed | ISI | ChemPort |
Olney JW, Sharpe LG, Feigin RD (1972).
Glutamate-induced brain damage in infant primates.
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Olney JW (1969a).
Brain lesions, obesity, and other disturbances
in mice treated with monosodium glutamate.
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Olney JW (1988).
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Prog Brain Res 73, 283-294. | PubMed | ChemPort |
Palmour RM, Ervin FR, Baker GB, Young SN (1998).
An amino acid mixture deficient in phenylalanine and tyrosine
reduces cerebrospinal fluid catecholamine metabolites
and alcohol consumption in vervet monkeys.
Psychopharmacology (Berl) 136, 1-7.
| Article | PubMed | ChemPort |
Pan-Hou H, Suda Y, Ohe Y, Sumi M, Yoshioka M (1990).
Effect of aspartame on N-methyl-D-aspartate-sensitive
L-[3H]glutamate binding sites in rat brain synaptic membranes.
Brain Res 520, 351-353. | Article | PubMed | ChemPort |
Paolini CL, Marconi AM, Ronzoni S, Di Noio M, Fennessey PV,
Pardi G et al. (2001a).
Placental transport of leucine, phenylalanine, glycine, and proline
in intrauterine growth-restricted pregnancies.
J Clin Endrocrinol Metab 86, 5427-5432. | Article | ChemPort |
Paolini CL, Meschia G, Fennessey PV, Pike AW, Teng C,
Battaglia FC et al. (2001b).
An in vivo study of ovine placental transport of essential amino
acids.
Am J Physiol 280, E31-E39. | ChemPort |
Prodolliet J, Bruelhart M (1993).
Determination of aspartame
and its major decomposition products in foods.
JAOAC Int 76, 275-282. | PubMed | ChemPort |
Rothman SM, Olney JW (1995).
Excitotoxicity and the NMDA receptor -- still lethal after eight
years.
Trends Neurosci 18, 57-58. | Article | PubMed | ISI | ChemPort |
Rouse B, Matalon R, Koch R, Azen C, Levy H,
Hanley W et al. (2000).
Maternal phenylketonuria syndrome:
congenital heart defects, micocephaly, and developmental outcomes.
J Pediatr 136, 57-61. | Article | PubMed | ChemPort |
Soffritti E, Belpoggi F, Espasti DD, Lambertini L, Tibaldi E,
Rigano A (2006).
First experimental demonstration of the multipotential carcinogenic
effects of aspartame administered in the feed
to Sprague-Dawley rats.
Environ Health Perspect 114, 379-385. | PubMed | ChemPort |
Sturtevant FM (1985).
Use of aspartame in pregnancy.
Int J Fertil 30, 85-87. | PubMed | ChemPort |
Ward KW, Pollack GM (1996b).
Use of intrauterine microdialysis to investigate methanol induced
alterations in uteroplacental blood flow.
Toxicol Appl Pharmacol 140, 203-210. | Article | ChemPort |
Yokogoshi H, Wurtman RJ (1986).
Acute effects of oral or parenteral aspartame on catecholamine
metabolism in various regions of rat brain.
J Nutr 116, 356-364. | PubMed | ChemPort |
____________________________________________________
http://groups.yahoo.com/group/aspartameNMmessage/1452
phenylalanine and aspartic acid from low dose aspartame in rabbits
interfere with blood coagulation, Pretorius E and Humphries P,
U. of Pretoria, Ultrastruct Pathol 2007 March: Murray 2007.07.14
" The authors conclude by suggesting that aspartame usage
may interfere with the coagulation process
and might cause delayed fibrin breakup after clot formation.
They suggest this,
as the fibrin networks from aspartame-exposed rabbits
are more complex and dense,
due to the netlike appearance of the minor, thin fibers.
Aspartame usage should possibly be limited
by people on anti-clotting medicine
or those with prone to clot formation. "
Ultrastruct Pathol. 2007 Mar-Apr; 31(2): 77-83.
Ultrastructural changes to rabbit fibrin and platelets
due to aspartame.
Pretorius E,
Humphries P.
Department of Anatomy, Faculty of Medicine,
University of Pretoria, South Africa.
[ Humphries P also at
Department of Anatomy, University of Limpopo.
Medunsa Campus, Garankuwa. South Africa ]
email: E. Pretorius resia.p...@up.ac.za
*Correspondence to E. Pretorius,
BMW Building, PO Box 2034,
Faculty of Health Sciences,
University of Pretoria, Pretoria 0001, South Africa
The coagulation process, including thrombin, fibrin,
as well as platelets,
plays an important role in hemostasis,
contributing to the general well-being of humans.
Fibrin formation and platelet activation are delicate processes
that are under the control of many small physiological events.
Any one of these many processes
may be influenced or changed by external factors,
including pharmaceutical or nutritional products, e.g.,
the sweetener aspartame (L-aspartyl-L-phenylalanine methyl ester).
It is known that phenylalanine is present at position P(9)
and aspartate at position P(10)
of the alpha-chain of human fibrinogen,
and plays an important role in the conversion of fibrinogen to fibrin
by the catalyst alpha-thrombin.
The authors investigate the effect of aspartame
on platelet and fibrin ultrastructure,
by using the rabbit animal model
and the scanning electron microscope.
Animals were exposed to 34 mg/kg of aspartame
26x during a 2-month period.
Aspartame-exposed fibrin networks appeared denser,
with a thick matted fine fiber network
covering thick major fibers.
Also, the platelet aggregates appeared more granular
than the globular control platelet aggregates.
The authors conclude by suggesting that aspartame usage
may interfere with the coagulation process
and might cause delayed fibrin breakup after clot formation.
They suggest this,
as the fibrin networks from aspartame-exposed rabbits
are more complex and dense,
due to the netlike appearance of the minor, thin fibers.
Aspartame usage should possibly be limited
by people on anti-clotting medicine
or those with prone to clot formation.
PMID: 17613990
____________________________________________________
two detailed critiques of industry affiliations and biased science in
99
page review with 415 references by BA Magnuson, GA Burdock
and 8 more, Critical Reviews in Toxicology, 2007 Sept.: Mark D
Gold 13 page: also Rich Murray 2007.09.15: 2008.03.24
http://rmforall.blogspot.com/2008_03_01_archive.htm
Monday, March 24, 2008
http://groups.yahoo.com/group/aspartameNM/message/1531
"Nearly every section of the Magnuson (2007) review has research
that is misrepresented
and/or crucial pieces of information are left out.
In addition to the misrepresentation of the research,
readers (including medical professionals) are often not told that
this review was funded by the aspartame manufacturer, Ajinomoto,
and the reviewers had enormous conflicts of interest."
[ See also:
http://groups.yahoo.com/group/aspartameNM/message/1453
Souring on fake sugar (aspartame), Jennifer Couzin,
Science 2007.07.06: 4 page letter to FDA from 12 eminent
USA toxicologists re two Ramazzini Foundation cancer studies
2007.06.25: Murray 2007.07.18
http://groups.yahoo.com/group/aspartameNM/message/957
safety of aspartame Part 1/2 12.4.2: EC HCPD-G SCF:
Murray 2003.01.12 EU Scientific Committee on Food, a whitewash
http://groups.yahoo.com/group/aspartameNM/message/1045
http://www.holisticmed.com/aspartame/scf2002-response.htm
Mark Gold exhaustively critiques European Commission Scientific
Committee on Food re aspartame ( 2002.12.04 ):
59 pages, 230 references
bias, omissions, incuriosity = opportunity, aspartame safety
evaluation, Magnuson BA, Burdock GA, Williams GM, 7 more,
2007 Sept, Ajinomoto funded 98 pages html [ $ 32 pdf ]:
Murray 2007.09.15
http://rmforall.blogspot.com/2007_09_01_archive.htm
Saturday, September 15, 2007 ]
"Of course, everyone chooses, as a natural priority, to enjoy
peace, joy, and love by helping to find, quickly share, and positively
act upon evidence about healthy and safe food, drink, and
environment."
Rich Murray, MA Room For All rmfo...@comcast.net
505-501-2298 1943 Otowi Road, Santa Fe, New Mexico 87505
http://RMForAll.blogspot.com new primary archive
http://groups.yahoo.com/group/aspartameNM/messages
group with 120 members, 1,536 posts in a public archive
http://groups.yahoo.com/group/aspartame/messages
group with 1,090 members, 22,545 posts in a public archive
Hawaii Senate Health Committee will consider resolution SCR191
by Sen. Suzanne Chun Oakland, and 10 other of 25 Senators,
to have FDA ban aspartame
and for National Academy of Sciences to review research:
Murray 2008.03.14
http://rmforall.blogspot.com/2008_03_01_archive.htm
Friday, March 14, 2008
http://groups.yahoo.com/group/aspartameNM/message/1527
http://groups.yahoo.com/group/aspartameNM/message/1525
House Concurrent Resolution #132 for Health Department panel
to decide aspartame ban by early 2010,
Hawaii Rep. Josh Green MD, Health Committee Chair:
Murray 2008.03.12
http://rmforall.blogspot.com/2008_03_01_archive.htm
Wednesday, March 12, 2008
____________________________________________________
Note: many recent aspartame bans.....
http://groups.yahoo.com/group/aspartameNM/message/1426
ASDA (unit of Wal-Mart Stores WMT.N) and Marks & Spencer
will join Tesco and also Sainsbury to ban and limit aspartame,
MSG, artificial flavors dyes preservatives additives, trans fats, salt
"nasties" to protect kids from ADHD: leading UK media:
Murray 2007.05.15
http://groups.yahoo.com/group/aspartameNMmessage/1451
Artificial sweeteners (aspartame, sucralose) and coloring agents
will be banned from use in newly-born and baby foods,
the European Parliament decided: Latvia ban in schools 2006:
Murray 2007.07.12
http://groups.yahoo.com/group/aspartameNM/message/1341
Connecticut bans artificial sweeteners in schools, Nancy Barnes,
New Milford Times: Murray 2006.05.25
http://groups.yahoo.com/group/aspartameNM/message/1369
Bristol, Connecticut, schools join state program to limit artificial
sweeteners, sugar, fats for 8800 students, Johnny J Burnham,
The Bristol Press: Murray 2006.09.22
bias, omissions, incuriosity = opportunity, aspartame safety
evaluation, Magnuson BA, Burdock GA, Williams GM, 7 more,
2007 Sept, Ajinomoto funded 98 pages html [ $ 32 pdf ]:
Murray 2007.09.15
http://rmforall.blogspot.com/2007_09_01_archive.htm
Saturday, September 15, 2007
http://groups.yahoo.com/group/aspartameNM/message/1491
industry scientists praise aspartame safety and benefits in Paris on
2006.05.30, Herve Nordmann, Andrew G. Renwick,
Carlo La Vecchia, Tommy Visscher, Jaap Seidell, France Bellisle,
Adam Drewnowski, Margaret Ashwell, Anne de la Hunty,
Sigrid A. Gibson, Alan R. Boobis: Murray 2007.11.18
http://groups.yahoo.com/group/aspartameNM/message/1070
critique of aspartame review, French Food Safety Agency AFSSA
2002.05.07 aspartamgb.pdf (18 pages, in English), Martin Hirsch:
Murray 2004.04.13
http://groups.yahoo.com/group/aspartameNM/message/957
safety of aspartame Part 1/2 12.4.2: EC HCPD-G SCF:
Murray 2003.01.12 EU Scientific Committee on Food, a whitewash
http://groups.yahoo.com/group/aspartameNM/message/1045
http://www.holisticmed.com/aspartame/scf2002-response.htm
Mark Gold exhaustively critiques European Commission Scientific
Committee on Food re aspartame ( 2002.12.04 ):
59 pages, 230 references
http://www.eatright.org/Nutritive(1).pdf
J Am Diet Assoc. 2004 Feb; 104(2): 255-75.
Position of the American Dietetic Association: use of nutritive and
nonnutritive sweeteners. American Dietetic Association.
http://groups.yahoo.com/group/aspartameNM/message/1068
critique of aspartame review
by American Dietetic Association Feb 2004,
Valerie B. Duffy & Madeleine J. Sigman-Grant: Murray 2004.05.14
http://www.dorway.com/upipart1.txt
http://groups.yahoo.com/group/aspartameNM/message/262
aspartame expose 96K Oct 1987 Part 1/3: Gregory Gordon,
UPI reporter: Murray 2000.07.10
http://www.dorway.com/enclosur.html
http://groups.yahoo.com/group/aspartameNM/message/53
aspartame history Part 1/4 1964-1976: Gold: Murray 1999.11.06
http://groups.yahoo.com/group/aspartameNM/message/927
Donald Rumsfeld, 1977 head of Searle Corp.,
got aspartame FDA approval: Turner: Murray 2002.12.23
http://groups.yahoo.com/group/aspartameNM/message/1483
Donald Rumsfeld CEO 1977-85 G.D. Searle & Co., got new
President Reagan to prohibit FDA opposition to aspartame
1981.01.25, history by lawyer James S. Turner:
Murray 2007.10.29
http://groups.yahoo.com/group/aspartameNM/message/928
revolving door, Monsanto, FDA, EPA: NGIN: Murray 2002.12.23
http://groups.yahoo.com/group/aspartameNM/message/858
Samuels: Strong: Roberts: Gold: flaws in double-blind studies re
aspartame and MSG toxicity: Murray 2002.08.01
"Survey of aspartame studies: correlation of outcome and funding
sources," 1998, unpublished: http://www.dorway.com/peerrev.html
Walton found 166 separate published studies in the peer reviewed
medical literature, which had relevance for questions of human
safety.
The 74 studies funded by industry all (100 %) attested to
aspartame's safety, whereas of the 92 non-industry funded studies,
84 (91 %) identified a problem.
Six of the seven non-industry funded studies
that were favorable to aspartame safety were from the FDA,
which has a public record that shows a strong pro-industry bias.
Ralph G. Walton, MD, Prof. of Clinical Psychology, Northeastern
Ohio Universities, College of Medicine, Dept. of Psychiatry,
Youngstown, OH 44501,
Chairman, The Center for Behavioral Medicine,
Northside Medical Center, 500 Gypsy Lane, P.O. Box 240
Youngstown, OH 44501 330-740-3621 rwalt...@aol.com
http://www.neoucom.edu/DEPTS/Psychiatry/walton.htm
http://groups.yahoo.com/group/aspartameNM/message/1395
Aspartame Controversy, in Wikipedia democratic
encyclopedia, 72 references (including AspartameNM # 864
and 1173 by Murray, brief fair summary of much more research:
Murray 2007.01.01
methanol impurity in alcohol drinks [ and aspartame ] is turned
into neurotoxic formic acid, prevented by folic acid, re Fetal Alcohol
Syndrome, BM Kapur, DC Lehotay, PL Carlen at U. Toronto,
Alc Clin Exp Res 2007 Dec. plain text: detailed biochemistry,
CL Nie et al. 2007.07.18: Rich Murray 2008.02.24
http://rmforall.blogspot.com/2008_02_01_archive.htm
Sunday, February 24, 2008
http://groups.yahoo.com/group/aspartameNM/message/1524
http://groups.yahoo.com/group/aspartameNM/message/1513
metabolic syndrome is tied to diet soda, PL Lutsey, LM Steffen,
J Stevens, Circulation 2008.01.22: role of formaldehyde and
formic acid from methanol in wines, liquors, or aspartame?:
Murray 2008.02.21
"But the one-third who ate the most fried food increased their risk
by 25 percent, compared with the one-third who ate the least, and
surprisingly, the risk of developing metabolic syndrome was 34
percent higher among those who drank one can of diet soda a day
compared with those who drank none.
"This is interesting," said Lyn M. Steffen, an associate professor of
epidemiology at the University of Minnesota and a co-author of the
paper, which was posted online in the journal Circulation on Jan. 22.
"Why is it happening? Is it some kind of chemical in the diet soda,
or something about the behavior of diet soda drinkers?""
"The diet soda association was not hypothesized
and deserves further study."
http://groups.yahoo.com/group/aspartameNM/message/1143
methanol (formaldehyde, formic acid) disposition:
Bouchard M et al, full plain text, 2001:
substantial sources are degradation
of fruit pectins, liquors, aspartame, smoke:
Murray 2005.04.02
http://groups.yahoo.com/group/aspartameNM/message/1511
vinyl acetate, ethyl alcohol, or aspartame in womb increases later
cancers in adults with lifetime exposure in many studies, M Soffritti
et al, Ramazzini Foundation, Basic Clin. Pharm. Toxicol. 2008 Feb.:
Rich Murray 2008.02.07
http://groups.yahoo.com/group/aspartameNM/message/1016
President Bush & formaldehyde (aspartame) toxicity:
Ramazzini Foundation carcinogenicity results Dec 2002:
Soffritti: Murray 2003.08.03 rmforall
p. 88 "The sweetening agent aspartame hydrolyzes in the
gastrointestinal tract to become free methyl alcohol,
which is metabolized in the liver
to formaldehyde, formic acid, and CO2. (11)"
Medinsky MA & Dorman DC. 1994;
Assessing risks of low-level methanol exposure.
CIIT Act. 14: 1-7.
http://groups.yahoo.com/group/aspartameNM/message/1453
Souring on fake sugar (aspartame), Jennifer Couzin,
Science 2007.07.06: 4 page letter to FDA from 12 eminent
USA toxicologists re two Ramazzini Foundation cancer studies
2007.06.25: Murray 2007.07.18
Avoiding formaldehyde allergic reactions in children, aspartame,
vitamins,
shampoo, conditioners, hair gel, baby wipes, Sharon E Jacob, MD, Tace
Steele, U. Miami, Pediatric Annals 2007 Jan.: eyelid contact
dermatitis, AM
Hill, DV Belsito, 2003 Nov.: Murray 2008.03.27
http://rmforall.blogspot.com/2008_03_01_archive.htm
Thursday, March 27, 2008
http://groups.yahoo.com/group/aspartameNM/message/1532
"It is generally recommended that exposure to products containing
formaldehyde, FRP's, and aspartame (NutraSweet) be avoided
in children."
"Through metabolism, aspartame is converted metabolically
in the liver to methanol,
which is in turn metabolized to formaldehyde. 8"
www.pediatricannalsonline.com/showPdf.asp?rID=21306
Avoiding formaldehyde allergic reactions in children
Pediatric Annals. 2007 Jan.; 36(1): 55-6. PMID: 17269284
Sharon E. Jacob, MD, Director, Contact Dermatitis Clinic,
Dept. of Dermatology and Cutaneous Surgery, U. of Miami,
1295 NW 14th St., Miami, FL 33125, fax 305-243-6191
formaldehyde from many sources, including aspartame, is major cause of
Allergic Contact Dermatitis, SE Jacob, T Steele, G Rodriguez, Skin and
Aging
2005 Dec.: Murray 2008.03.27
http://rmforall.blogspot.com/2008_03_01_archive.htm
Thursday, March 27, 2008
http://groups.yahoo.com/group/aspartameNM/message/1533
"For example, diet soda and yogurt containing aspartame
(Nutrasweet), release formaldehyde in their natural biological
degradation.
One of aspartame's metabolites, aspartic acid methyl ester,
is converted to methanol in the body, which is oxidized to
formaldehyde in all organs, including the liver and eyes. 22
Patients with a contact dermatitis to formaldehyde have been seen
to improve once aspartame is avoided. 22
Notably, the case that Hill and Belsito reported had a 6-month
history of eyelid dermatitis that subsided after 1 week of avoiding
diet soda. 22"
"We present a case of a medical student who presented with
erythematous eczematoid plaques on her trunk and legs and
fine vesiculation of her scalp, 3 weeks after starting anatomy class.
Of note, she routinely washed her face and arms after leaving the
anatomy lab, but remained in her scrubs for the rest of the day.
Formaldehyde and Quaternium-15 positive reactions
in the same patient."
"Our patient underscores the importance of appropriate patch
testing and education.
Once we identified the allergy to formaldehyde and quaternium-15,
we provided patient education materials regarding the common and
not-so-common locations of these chemicals and cross-reactors.
We also gave the patient information on avoidance
and safe alternatives (see Table 5).
Fortunately, with technical advances, this student completed the
anatomy section via electronic learning tools.
By avoiding formaldehyde, including anatomy lab, FRP
in her shampoo and cosmetics,
and aspartame in her diet, this patient dramatically improved.
As with all contact dermatitides, the mainstay of treatment for
allergic contact dermatitis is avoidance."
http://www.skinandaging.com/article/5158
Allergen Focus:
Focus on T.R.U.E. Test Allergens #21, 13 and 18:
Formaldehyde and Formaldehyde-Releasing Preservatives
Skin & Aging, ISSN 1096-0120; 13(12) 2005 Dec.: 22-27.
Sharon E. Jacob, M.D.,
Tace Steele, B.A.,
and Georgette Rodriguez, M.D., M.P.H.
30 female pet store rats drinking lifelong 13.5 mg aspartame,
1/3 packet of Equal, had 33% with obvious tumors -- also bulging,
sick, and missing eyes, paralysis, obesity, skin sores -- agrees with
Ramazzini Foundation results, Victoria Inness-Brown:
Murray 2008.02.15
http://rmforall.blogspot.com/2008_02_01_archive.htm
Friday, February 15, 2008
http://groups.yahoo.com/group/aspartameNM/message/1521
http://groups.yahoo.com/group/aspartameNM/message/1490
details on 6 epidemiological studies since 2004 on diet soda (mainly
aspartame) correlations, as well as 14 other mainstream studies
on aspartame toxicity since summer 2005: Murray 2007.11.27
http://groups.yahoo.com/group/aspartameNM/message/1340
aspartame groups and books:
updated research review of 2004.07.16: Murray 2006.05.11
old tiger roars -- Woodrow C Monte, PhD -- aspartame causes
many breast cancers, as ADH enzyme in breasts makes methanol
from diet soda into carcinogenic formaldehyde -- same in dark
wines and liquors, Fitness Life 2008 Jan.: Murray 2008.02.11
http://rmforall.blogspot.com/2008_02_01_archive.htm
Monday, February 11, 2008
http://groups.yahoo.com/group/aspartameNM/message/1517
"Alcohol dehydrogenase ADH is required for the conversion of
methanol to formaldehyde (112).
ADH is not a common enzyme in the human body -- not many cells
in the human body contain this enzyme.
The human breast is one of the few organs in the body with a high
concentration of ADH (190b), and it is found there exclusively in the
mammary epithelial cells, the very cells known to transform into
adenocarcinoma (190c) (breast cancer).
The most recent breast cancer scientific literature implicates ADH
as perhaps having a pivotal role in the formation of breast cancer,
indicating a greater incidence of the disease in those
with higher levels of ADH activity in their breasts (190a)."
role of formaldehyde, made by body from methanol from foods
and aspartame, in steep increases in fetal alcohol syndrome, autism,
multiple sclerosis, lupus, teen suicide, breast cancer, Nutrition
Prof. Woodrow C. Monte, retired, Arizona State U., two reviews,
190 references supplied, Fitness Life, New Zealand
2007 Nov, Dec: Murray 2007.12.26
http://rmforall.blogspot.com/2007_12_01_archive.htm
Wednesday, December 26 2007
http://groups.yahoo.com/group/aspartameNM/message/1498
Since no adequate data has ever been published on the
exact disposition of toxic metabolites in specific tissues in humans
of the 11 % methanol component of aspartame,
the many studies on morning-after hangover from the methanol
impurity in alcohol drinks are the main available resource to date.
http://groups.yahoo.com/group/aspartameNM/message/1469
highly toxic formaldehyde, the cause of alcohol hangovers, is
made by the body from 100 mg doses of methanol from
dark wines and liquors, dimethyl dicarbonate, and aspartame:
Murray 2007.08.31
http://groups.yahoo.com/group/aspartameNM/message/1052
DMDC: Dimethyl dicarbonate 200mg/L in drinks adds
methanol 98 mg/L ( becomes formaldehyde in body ):
EU Scientific Committee on Foods 2001.07.12:
Murray 2004.01.22
http://europa.eu.int/comm/food/fs/sc/scf/out96_en.pdf
"...DMDC was evaluated by the SCF in 1990 and considered
acceptable for the cold sterilization of soft drinks and fruit juices
at levels of addition up to 250 mg/L (1)
...DMDC decomposes primarily to CO2 and methanol ...
[ Note: Sterilization of bacteria and fungi is a toxic process,
probably due to the inevitable conversion in the body of methanol
into highly toxic formaldehyde and then formic acid. ]
The use of 200 mg DMDC per liter would add 98 mg/L
of methanol to wine which
already contains an average of about 140 mg/L from natural sources.
http://groups.yahoo.com/group/aspartameNM/message/1286
methanol products (formaldehyde and formic acid) are main cause
of alcohol hangover symptoms [same as from similar amounts of
methanol, the 11% part of aspartame]: YS Woo et al, 2005 Dec:
Murray 2006.01.20
Addict Biol. 2005 Dec;10(4): 351-5.
Concentration changes of methanol in blood samples during
an experimentally induced alcohol hangover state.
Woo YS, Yoon SJ, Lee HK, Lee CU, Chae JH, Lee CT, Kim DJ.
Chuncheon National Hospital, Department of Psychiatry,
The Catholic University of Korea, Seoul, Korea.
http://www.cuk.ac.kr/eng/ sy...@catholic.ac.kr
Songsin Campus: 02-740-9714 Songsim Campus: 02-2164-4116
Songeui Campus: 02-2164-4114
http://www.cuk.ac.kr/eng/sub055.htm eight hospitals
[ Han-Kyu Lee ]
A hangover is characterized by the unpleasant physical and mental
symptoms that occur between 8 and 16 hours after drinking alcohol.
After inducing experimental hangover in normal individuals,
we measured the methanol concentration prior to
and after alcohol consumption
and we assessed the association between the hangover condition
and the blood methanol level.
A total of 18 normal adult males participated in this study.
They did not have any previous histories of psychiatric
or medical disorders.
The blood ethanol concentration prior to the alcohol intake
(2.26+/-2.08) was not significantly different from that
13 hours after the alcohol consumption (3.12+/-2.38).
However, the difference of methanol concentration
between the day of experiment (prior to the alcohol intake)
and the next day (13 hours after the alcohol intake)
was significant (2.62+/-1.33/l vs. 3.88+/-2.10/l, respectively).
A significant positive correlation was observed
between the changes of blood methanol concentration
and hangover subjective scale score increment when covarying
for the changes of blood ethanol level (r=0.498, p<0.05).
This result suggests the possible correlation of methanol
as well as its toxic metabolite to hangover. PMID: 16318957
[ The toxic metabolite of methanol is formaldehyde, which in turn
partially becomes formic acid -- both potent cumulative toxins
that are the actual cause of the toxicity of methanol.]
This study by Jones AW (1987) found next-morning hangover
from red wine with 100 to 150 mg methanol
(9.5 % w/v ethanol, 100 mg/l methanol, 0.01 %).
Fully 11% of aspartame is methanol --
1,120 mg aspartame in 2 L diet soda,
almost six 12-oz cans, gives 123 mg methanol (wood alcohol).
Pharmacol Toxicol. 1987 Mar; 60(3): 217-20.
Elimination half-life of methanol during hangover.
Jones AW. wayne...@RMV.se
Department of Forensic Toxicology,
University Hospital, SE-581 85 Linkoping, Sweden.
This paper reports the elimination half-life of methanol in human
volunteers.
Experiments were made during the morning after the subjects had
consumed 1000-1500 ml red wine
(9.5 % w/v ethanol, 100 mg/l methanol)
the previous evening. [ 100 to 150 mg methanol ]
The washout of methanol from the body
coincided with the onset of hangover.
The concentrations of ethanol and methanol in blood were
determined indirectly by analysis of end-expired alveolar air.
In the morning when blood-ethanol dropped
below the Km of liver alcohol dehydrogenase (ADH)
of about 100 mg/l (2.2 mM),
the disappearance half-life of ethanol was 21, 22, 18 and 15 min.
in 4 test subjects respectively.
The corresponding elimination half-lives of methanol
were 213, 110, 133 and 142 min. in these same individuals.
The experimental design outlined in this paper can be used
to obtain useful data on elimination kinetics of methanol
in human volunteers without undue ethical limitations.
Circumstantial evidence is presented to link methanol
or its toxic metabolic products, formaldehyde and formic acid,
with the pathogenesis of hangover. PMID: 3588516
http://groups.yahoo.com/group/aspartameNM/message/1047
Avoiding Hangover Hell 2003.12.31 Mark Sherman, AP writer:
Robert Swift, MD [ formaldehyde from methanol in aspartame ]:
Murray 2004.01.16
http://groups.yahoo.com/group/aspartameNM/message/1048
hangovers from formaldehyde from methanol (aspartame?):
Schwarcz: Linsley: Murray 2004.01.18
Thrasher (2001): "The major difference is that the Japanese
demonstrated the incorporation of FA and its metabolites
into the placenta and fetus.
The quantity of radioactivity remaining in maternal and fetal tissues
at 48 hours was 26.9 % of the administered dose." [ Ref. 14-16 ]
Arch Environ Health 2001 Jul-Aug; 56(4): 300-11.
Embryo toxicity and teratogenicity of formaldehyde. [100 references]
Thrasher JD, Kilburn KH. toxic...@drthrasher.org
Sam-1 Trust, Alto, New Mexico, USA.
www.drthrasher.org/formaldehyde_embryo_toxicity.html full text
http://www.drthrasher.org/formaldehyde_1990.html full text
Jack Dwayne Thrasher, Alan Broughton, Roberta Madison.
Immune activation and autoantibodies in humans
with long-term inhalation exposure to formaldehyde.
Archives of Environmental Health. 1990; 45: 217-223.
"Immune activation, autoantibodies,
and anti-HCHO-HSA antibodies
are associated with long-term formaldehyde inhalation."
PMID: 2400243
formaldehyde in FEMA trailers and other sources (aspartame,
dark wines and liquors, tobacco smoke): Murray 2008.01.30
http://rmforall.blogspot.com/2008_01_01_archive.htm
Wednesday, January 30, 2008
http://groups.yahoo.com/group/aspartameNM/message/1508
The FEMA trailers give about the same amount of formaldehyde
daily as from a quart of dark wine or liquor, or two quarts
(6 12-oz cans) of aspartame diet soda, from their over 1 tenth gram
methanol impurity (one part in 10,000),
which the body quickly makes into formaldehyde -- enough
to be the major cause of "morning after" alcohol hangovers.
Methanol and formaldehyde also result from many fruits and
vegetables, tobacco and wood smoke, heater and vehicle exhaust,
household chemicals and cleaners, cosmetics, and new cars, drapes,
carpets, furniture, particleboard, mobile homes, buildings,
leather ...
so all these sources add up and interact
with many other toxic chemicals.
BN Ames and LS Gold, 1998, have presented detailed information
that there is no increase in recent decades for most cancers,
and that common carcinogens do not result in significant exposures
to the average human population.
However, individuals are not average -- each person has a unique
genetic makeup, resulting in a huge range of variation of
vulnerability
to specific chemicals, as is well evidenced in the case of methanol,
formaldehyde, and formic acid, especially with regard
to behavioral effects.
Each is subject to very wide ranges of exposure levels.
Many are in especially vulnerable groups, depending on diet, obesity,
sex, exercise, life stress, age from conception to very old, unusually
severe toxic exposures, injuries, and diseases.
It is clear that a variety of multiple chemical sensitivity syndromes
do
exist, often with remarkable hypersensitivity.
Methanol, formaldehyde, and formic acid toxicity are unusual, in that
humans are far more vulnerable than any other mammal, as much as
ten to sixty-fold, which complicates the utility of animal data.
The unusally long human life span also increases the role of long-term
chronic low-level exposure.
http://groups.yahoo.com/group/aspartameNM/message/1455
FEMA slow to safety test Katrina toxic trailers, Charles Babington,
Associated Press -- 1 ppm formaldehyde in air is about half the daily
dose from 3 cans aspartame diet soda and ten times the 1999 EPA
alarm level for drinking water: Murray 2007.07.23
http://groups.yahoo.com/group/aspartameNM/message/1277
50% UK baby food is now organic - aspartame or MSG
with food dyes harm nerve cells, CV Howard 3 year study
funded by Lizzy Vann, CEO, Organix Brands,
Children's Food Advisory Service: Murray 2006.01.13
http://groups.yahoo.com/group/aspartameNM/message/1271
combining aspartame and quinoline yellow, or MSG and
brilliant blue, harms nerve cells, eminent
C. Vyvyan Howard et al, 2005 education.guardian.co.uk,
Felicity Lawrence: Murray 2005.12.21
http://groups.yahoo.com/group/aspartameNM/message/1373
aspartame rat brain toxicity re cytochrome P450 enzymes,
especially CYP2E1, Vences-Mejia A, Espinosa-Aguirre JJ et al,
2006 Aug, Hum Exp Toxicol: relevant abstracts re formaldehyde
from methanol in alcohol drinks: Murray 2006.09.29
http://groups.yahoo.com/group/aspartameNM/message/1463
Direct and indirect cellular effects of aspartame on the brain,
Humphries P, Pretorius E, Naude H, U. Pretoria, South Africa,
Eur J Clin Nutr. 2007 Aug 8: Murray 2007.08.12
http://groups.yahoo.com/group/aspartameNMmessage/1452
phenylalanine and aspartic acid from low dose aspartame
in rabbits interfere with blood coagulation,
Pretorius E and Humphries P, U. of Pretoria,
Ultrastruct Pathol 2007 March: Murray 2007.07.14
http://groups.yahoo.com/group/aspartameNM/message/1459
third study by expert Greek team of neurotoxicity in infant rats by
aspartame (or its parts, methanol, phenylalanine, aspartic acid), KH
Schulpis et al, Food Chem Toxicol 2007.06.16: Murray 2007.08.05
http://groups.yahoo.com/group/aspartameNMmessage/1447
second study by expert Greek team of neurotoxicity in infant rats by
aspartame (or its parts, methanol, phenylalanine, aspartic acid), KH
Schulpis et al, Toxicology 2007.05.18: Murray 2007.07.04
http://groups.yahoo.com/group/aspartameNMmessage/1444
expert Greek group finds aspartame (or its parts, methanol,
phenylalanine, aspartic acid) harm infant rat brain enzyme activity,
KH Schulpis et al, Pharmacol. Res. 2007.05.13:
Murray 2007.06.23
http://groups.yahoo.com/group/aspartameNM/message/939
aspartame (aspartic acid, phenylalanine) binding to DNA:
Karikas July 1998: Murray 2003.01.05 rmforall
Karikas GA, Schulpis KH, Reclos GJ, Kokotos G
Measurement of molecular interaction of aspartame and
its metabolites with DNA. Clin Biochem 1998 Jul; 31(5): 405-7.
Dept. of Chemistry, University of Athens, Greece
http://www.chem.uoa.gr gkok...@atlas.uoa.gr
K.H. Schulpis inch...@otenet.gr ; G.J. Reclos rek...@otenet.gr
5 recent aspartame reports by S Tsakiris, KH Schulpis, I Simintzi,
with responses to critiques by AG Renwick and
by EB Abegaz, RG Bursey, 2005-2008 2008.03.05
Pharmacological Research 57 (2008) 89-90
Letter to the Editor
Answer to Letter sent to the Editor by
Drs. E. Abegaz and R. Bursey
(Ajinomoto Corporate Services LLC, Washington, USA)
related to Simintzi et al. report published in
Pharmacol Res 2007; 56: 155-9
Letter to the Editor / Pharmacological Research 57 (2008) 89-90
Stylianos Tsakiris a,? sts...@cc.uoa.gr;
Kleopatra H. Schulpis b inch...@otenet.gr;
a Department of Experimental Physiology, Medical School,
Athens University, P.O. Box 65257, GR-15401 Athens, Greece
b Inborn Errors of Metabolism Department, Institute of Child
Health, Research Center, Greece
? Corresponding author.
E-mail addresses:
S. Tsakiris sts...@cc.uoa.gr;
K.H. Schulpis inch...@otenet.gr;
Pharmacological Research 57 (2008) 87-88
Response to "The effect of aspartame on the acetylcholinesterase
activity in hippocampal homogenates of suckling rats"
by Simintzi et al.
Eyassu G. Abegaz ?
Robert G. Bursey
Ajinomoto Corporate Services LLC,
Scientific & Regulatory Affairs,
1120 Connecticut Ave., N.W., Suite 1010,
Washington, DC 20036, United States
? Corresponding author. Tel.: +1 202 457 0284;
fax: +1 202 457 0107.
E-mail addresses: abeg...@ajiusa.com; (E.G. Abegaz),
bur...@ajiusa.com; (R.G. Bursey)
Keywords:
Aspartame; Aspartate; Phenylalanine; Methanol; AChE activity
Tsakiris S, Schulpis KH.
Answer to letter sent by Professor A.G. Renwick
(University of Southampton, UK)
related to Simintzi et al. report published in Food and Chemical
Toxicology 2007; 45(12): 2397-401.
Food Chem Toxicol. 2008 Mar; 46(3): 1208-9.
Epub 2007 Oct 25. No abstract available. PMID: 18054419
doi:10.1016/j.fct.2007.10.016
Copyright © 2007 Elsevier Ltd All rights reserved.
Renwick AG.
The effect of aspartame metabolites on the suckling rat frontal cortex
acetylcholinesterase. An in vitro study. By I. Simintzi, K.H.
Schulpis,
P. Angelogianni, C. Liapi and S. Tsakiris.
Food Chem Toxicol. 2008 Mar; 46(3): 1206-7.
Epub 2007 Oct 26. No abstract available. PMID: 18061330
1: Simintzi I, Schulpis KH, Angelogianni P, Liapi C, Tsakiris S.
The effect of aspartame metabolites on the suckling rat frontal cortex
acetylcholinesterase. An in vitro study.
Food Chem Toxicol. 2007 Dec;45(12):2397-401.
Epub 2007 Jun 16. PMID: 17673349
2: Simintzi I, Schulpis KH, Angelogianni P, Liapi C, Tsakiris S.
L-Cysteine and glutathione restore the reduction of rat
hippocampal Na+, K+-ATPase activity
induced by aspartame metabolites.
Toxicology. 2007 Jul 31;237(1-3):177-83.
Epub 2007 May 18. PMID: 17602817
3: Simintzi I, Schulpis KH, Angelogianni P, Liapi C, Tsakiris S.
The effect of aspartame on acetylcholinesterase activity in
hippocampal homogenates of suckling rats.
Pharmacol Res. 2007 Aug;56(2):155-9.
Epub 2007 May 13. PMID: 17580119
4: Schulpis KH, Papassotiriou I, Parthimos T, Tsakiris T, Tsakiris S.
The effect of L-cysteine and glutathione
on inhibition of Na+, K+-ATPase activity by aspartame metabolites
in human erythrocyte membrane.
Eur J Clin Nutr. 2006 May;60(5):593-7. PMID: 16391576
5: Tsakiris S, Giannoulia-Karantana A, Simintzi I, Schulpis KH.
The effect of aspartame metabolites on human erythrocyte
membrane acetylcholinesterase activity.
Pharmacol Res. 2006 Jan;53(1):1-5.
Epub 2005 Aug 29. PMID: 16129618
C. Trocho (1998):
"In all, the rats retained, 6 hours after administration, about 5 %
of the label, half of it in the liver."
They used a very low level of aspartame ingestion, 10 mg/kg,
for rats, which have a much greater tolerance for aspartame
than humans.
So, the corresponding level for humans would be
about 1 or 2 mg/kg.
Many headache studies in humans used doses of
about 30 mg/kg daily.
http://groups.yahoo.com/group/aspartameNM/message/925
aspartame puts formaldehyde adducts into tissues, Part 1/2
full text, Trocho & Alemany 1998.06.26: Murray 2002.12.22
http://ww.presidiotex.com/barcelona/index.html full text
Formaldehyde derived from dietary aspartame
binds to tissue components in vivo.
Life Sci June 26 1998; 63(5): 337-49.
Departament de Bioquimica i Biologia Molecular,
Facultat de Biologia, Universitat de Barcelona, Spain.
http://www.bq.ub.es/cindex.html Línies de Recerca: Toxicitat de
l'aspartame http://www.bq.ub.es/grupno/grup-no.html
Sra. Carme Trocho, Sra. Rosario Pardo, Dra. Immaculada Rafecas,
Sr. Jordi Virgili, Dr. Xavier Remesar, Dr. Jose Antonio
Fernandez-Lopez, Dr. Marià Alemany [male]
Fac. Biologia Tel.: (93)4021521, FAX: (93)4021559
Sra. Carme Trocho "Trok-ho" Fac. Biologia Tel.: (93)4021544,
FAX: (93)4021559 ale...@porthos.bio.ub.es;
bi...@sun.bq.ub.es
Abstract:
Adult male rats were given an oral dose of 10 mg/kg aspartame,
14C-labeled in the methanol carbon.
At timed intervals of up to 6 hours, the radioactivity in plasma
and several organs was investigated.
Most of the radioactivity found (>98 % in plasma, >75 % in liver)
was bound to protein.
Label present in liver, plasma and kidney was in the range
of 1-2 % of total radioactivity administered per g or mL,
changing little with time.
Other organs (brown and white adipose tissues, muscle, brain,
cornea and retina) contained levels of label
in the range of 1/12th to 1/10th of that of liver.
In all, the rats retained, 6 hours after administration,
about 5 % of the label, half of it in the liver.
The specific radioactivity of tissue protein, RNA and DNA
was quite uniform.
The protein label was concentrated in amino acids,
different from methionine, and largely coincident
with the result of protein exposure to labeled formaldehyde.
DNA radioactivity was essentially in a single different adduct base,
different from the normal bases present in DNA.
The nature of the tissue label accumulated was, thus,
a direct consequence of formaldehyde binding to tissue structures.
The administration of labeled aspartame to a group of cirrhotic rats
resulted in comparable label retention by tissue components,
which suggests that liver function (or its defect) has little effect
on formaldehyde formation from aspartame
and binding to biological components.
The chronic treatment of a series of rats with 200 mg/kg of
non-labeled aspartame during 10 days results in the accumulation
of even more label when given the radioactive bolus,
suggesting that the amount of formaldehyde adducts
coming from aspartame in tissue proteins and nucleic acids
may be cumulative.
It is concluded that aspartame consumption may constitute
a hazard because of its contribution
to the formation of formaldehyde adducts. PMID: 9714421
[ Extracts ]
"The high label presence in plasma and liver is in agreement with the
carriage of the label from the intestine to the liver via the portal
vein.
The high label levels in kidney and, to a minor extent, in brown
adipose tissue and brain are probably a consequence
of their high blood flows (45).
Even in white adipose tissue, the levels of radioactivity found 6
hours
after oral administration were 1/25th those of liver.
Cornea and retina, both tissues known to metabolize actively
methanol (21,28) showed low levels of retained label.
In any case, the binding of methanol-derived carbon to tissue
proteins was widespread, affecting all systems,
fully reaching even sensitive targets such as the brain and retina....
The amount of label recovered in tissue components was quite high
in all the groups, but especially in the NA rats.
In them, the liver alone retained, for a long time, more than 2 % of
the methanol carbon given in a single oral dose of aspartame,
and the rest of the body stored an additional 2 % or more.
These are indeed extremely high levels for adducts of formaldehyde,
a substance responsible of chronic deleterious effects (33),
that has also been considered carcinogenic (34,47).
The repeated occurrence of claims that aspartame
produces headache and other neurological and psychological
secondary effects --
more often than not challenged by careful analysis --
(5, 9, 10, 15, 48)
may eventually find at least a partial explanation in the permanence
of the formaldehyde label,
since formaldehyde intoxication can induce similar effects (49).
The cumulative effects derived from the incorporation of label in the
chronic administration model suggests that regular intake of
aspartame may result in the progressive accumulation
of formaldehyde adducts.
It may be further speculated that the formation of adducts can help to
explain the chronic effects aspartame consumption may induce on
sensitive tissues such as brain (6, 9, 19, 50).
In any case, the possible negative effects that the accumulation of
formaldehyde adducts can induce is, obviously, long-term.
The alteration of protein integrity and function may needs some time
to induce substantial effects.
The damage to nucleic acids, mainly to DNA,
may eventually induce cell death and/or mutations.
The results presented suggest that the conversion of aspartame
methanol into formaldehyde adducts in significant amounts in vivo
should to be taken into account because of the widespread utilization
of this sweetener.
Further epidemiological and long-term studies are needed to
determine the extent of the hazard that aspartame consumption
poses for humans."
Many scientific studies and case histories report: * headaches
* many body and joint pains (or burning, tingling, tremors, twitching,
spasms, cramps, stiffness, numbness, difficulty swallowing)
* fever, fatigue, swollen glands * "mind fog", "feel unreal",
poor memory, confusion, anxiety, irritability, depression, mania,
insomnia, dizziness, slurred speech, sexual problems,
poor vision, hearing (deafness, tinnitus), or taste
* red face, itching, rashes, allergic dermatitis, hair loss,
burning eyes or throat, dry eyes or mouth, mouth sores,
burning tongue * obesity, bloating, edema, anorexia,
poor appetite or excessive hunger or thirst
* breathing problems, shortness of breath
* nausea, diarrhea or constipation * coldness * sweating
* racing heart, low or high blood pressure, erratic blood sugar levels
* hypothryroidism or hyperthyroidism * seizures * birth defects
* brain cancers * addiction * aggrivates diabetes, autism, allergies,
lupus, ADHD, fibromyalgia, chronic fatigue syndrome,
multiple chemical sensitivity, multiple sclerosis, pseudotumor cerebri
and interstitial cystitis (bladder pain).
http://groups.yahoo.com/group/aspartameNM/message/870
Aspartame: Methanol and the Public Interest 1984: Monte:
Murray 2002.09.23 rmforall
Dr. Woodrow C. Monte
Aspartame: methanol, and the public health.
Journal of Applied Nutrition 1984; 36 (1): 42-54.
(62 references) Professsor of Food Science [retired 1992]
Arizona State University, Tempe, Arizona 85287
woody...@xtra.co.nz; woody...@canyoncountry.net;
The methanol from 2 L of diet soda, 5.6 12-oz cans, 20 mg/can, is
112 mg, 10% of the aspartame.
The EPA limit for water is 7.8 mg daily for methanol
(wood alcohol), a deadly cumulative poison.
Many users drink 1-2 L daily.
The reported symptoms are entirely consistent with chronic methanol
toxicity. (Fresh orange juice has 34 mg/L, but, like all juices, has
16
times more ethanol, which strongly protects against methanol.)
"The greater toxicity of methanol to man is deeply rooted in the
limited biochemical pathways available to humans for detoxification.
The loss of uricase (EC 1.7.3.3.),
formyl-tetrahydrofolate synthetase (EC 6.3.4.3.) (42)
and other enzymes (18) during evolution sets man apart from all
laboratory animals including the monkey (42).
There is no generally accepted animal model
for methanol toxicity (42, 59).
Humans suffer "toxic syndrome" (54) at a minimum lethal dose
of <1 gm/kg, much less than that of monkeys, 3-6 g/kg (42, 59).
The minimum lethal dose of methanol in the
rat, rabbit, and dog is 9.5, 7.0 , and 8.0 g/kg, respectively (43);
ethyl alcohol is more toxic than methanol to these test animals (43)."
Recent research [see links at end of post] supports his focus on the
methanol to formaldehyde toxic process:
"The United States Environmental Protection Agency in their
Multimedia Environmental Goals for Environmental Assessment
recommends a minimum acute toxicity concentration
of methanol in drinking water at 3.9 parts per million,
with a recommended limit of consumption below 7.8 mg/day (8).
This report clearly indicates that methanol:
"...is considered a cumulative poison due to the low rate of excretion
once it is absorbed. In the body, methanol is oxidized to
formaldehyde and formic acid; both of these metabolites
are toxic." (8)...
Recently the toxic role of formaldehyde (in methanol toxicity)
has been questioned (34).
No skeptic can overlook the fact that, metabolically, formaldehyde
must be formed as an intermediate to formic acid production (54).
Formaldehyde has a high reactivity,
which may be why it has not been found in humans or other primates
during methanol poisoning (59)....
If formaldehyde is produced from methanol and does have a
reasonable half life within certain cells in the poisoned organism
he chronic toxicological ramifications could be grave.
Formaldehyde is a known carcinogen (57) producing squanous-cell
carcinomas by inhalation exposure in experimental animals (22).
The available epidemiological studies do not provide adequate data
for assessing the carcinogenicity of formaldehyde in man
(22, 24, 57).
However, reaction of formaldehyde with deoxyribonucleic acid
(DNA) has resulted in irreversible denaturation that could interfere
with DNA replication and result in mutation (37)..."
It is certain that high levels of aspartame use,
above 2 liters daily for months and years,
must lead to chronic formaldehyde-formic acid toxicity.
Fully 11 % of aspartame is methanol -- 1,120 mg aspartame
in 2 L diet soda, almost six 12-oz cans, gives 123 mg methanol
(wood alcohol). The methanol is immediately released
into the body after drinking .
Within hours, the liver turns much of the methanol into formaldehyde,
and then much of that into formic acid, both of which in time
are partially eliminated as carbon dioxide and water.
However, about 30 % of the methanol remains in the body
as cumulative durable toxic metabolites of formaldehyde
and formic acid -- 37 mg daily,
a gram every month, accumulating in and affecting every tissue.
If only 10 % of the methanol is retained daily as formaldehyde,
that would give 12 mg daily formaldehyde accumulation -- about
60 times more than the 0.2 mg from 10 % retention
of the 2 mg EPA daily limit for formaldehyde in drinking water.
Bear in mind that the EPA limit for formaldehyde in drinking water is
1 ppm, or 2 mg daily for a typical daily consumption of 2 L of water.
http://groups.yahoo.com/group/aspartameNM/message/835
ATSDR: EPA limit 1 ppm formaldehyde in drinking water July 1999:
Murray 2002.05.30
This long-term low-level chronic toxic exposure leads to typical
patterns of increasingly severe complex symptoms,
starting with headache, fatigue, joint pain, irritability, memory
loss,
rashes, and leading to vision and eye problems, and even seizures.
In many cases there is addiction. Probably there are immune system
disorders, with a hypersensitivity to these toxins and other
chemicals.
J. Nutrition 1973 Oct; 103(10): 1454-1459.
Metabolism of aspartame in monkeys.
Oppermann JA, Muldoon E, Ranney RE.
Dept. of Biochemistry, Searle Laboratories,
Division of G.D. Searle and Co. Box 5110, Chicago, IL 60680
They found that about 70 % of the radioactive methanol in aspartame
put into the stomachs of 3 to 7 kg monkeys
was eliminated within 8 hours, with little additional elimination,
as carbon dioxide in exhaled air and as water in the urine.
They did not mention that this meant that about 30 % of the methanol
must transform into formaldehyde and then into formic acid,
both of which must remain as toxic products in all parts of the body.
They did not report any studies on the distribution of radioactivity
in body tissues, except that blood plasma proteins after 4 days
held 4 % of the initial methanol.
This study did not monitor long-term use of aspartame.
The low oral dose of aspartame and for methanol
was 0.068 mmol/kg, about 1 part per million [ppm]
of the acute toxicity level of 2,000 mg/kg, 67,000
mmol/kg, used by McMartin (1979).
Two L daily use of diet soda provides 123 mg methanol,
2 mg/kg for a 60 kg person, a dose of 67 mmole/kg,
a thousand times more than the dose in this study.
By eight hours excretion of the dose in air and urine had leveled off
at
67.1 +-2.1 % as CO2 in the exhaled air
and 1.57+-0.32 % in the urine, so 68.7 % was excreted,
and 31.3 % was retained.
This data is the average of 4 monkeys.
"...the 14C in the feces was negligible."
"That fraction not so excreted (about 31%) was converted to body
constituents through the one-carbon metabolic pool."
"All radioactivity measurements were counted to +-1 % accuracy..."
This indicates that the results could not be claimed to have a
precision of a tenth of a percent. OK, so this is a nit-pick -- but I
believe espousing spurious accuracy is a sign of scientific
insecurity.
The abstract ends, "It was concluded that aspartame was digested to
its three constituents that were then absorbed
as natural constituents of the diet.
Thus, the concept is very subtly insinuated that methanol, as a
constituent of aspartame, is absorbed as a natural constituent
of the diet.
Nowhere in this report are mentioned the dread words,
"formaldehyde" and "formic acid".
Of course, methanol and formaldehyde toxicity studies are highly
relevant to the issue of aspartame toxicity.
[ Aspartame has to be turned into its toxic products,
formaldehyde and formic acid, in the body, before it is toxic,
so some pro-aspartame reseach studies test aspartame outside the
body, and then proclaim that they have proved that it is not toxic. ]
http://www.dorway.com/tldaddic.html 5-page review
Roberts HJ Aspartame (NutraSweet) addiction.
Townsend Letter 2000 Jan; HJRob...@aol.com
http://www.sunsentpress.com/ sunsen...@aol.com
Sunshine Sentinel Press P.O.Box 17799
West Palm Beach, FL 33416
800-814-9800 561-588-7628 561-547-8008 fax
http://groups.yahoo.com/group/aspartameNM/message/669
1038-page medical text "Aspartame Disease: An Ignored Epidemic"
published May 30 2001 $ 60.00 postpaid data from 1200 cases
available at http://www.amazon.com
over 600 references from standard medical research
http://groups.yahoo.com/group/aspartameNM/message/790
Moseley: review Roberts
"Aspartame Disease: An Ignored Epidemic":
Murray 2002.02.07 rmforall
Roberts, Hyman J., 1924- ,
Useful insights for diagnosis, treatment and public heath: an updated
anthology of original research, 2002, 798 pages,
aspartame disease, pages 627-685, 778-780
http://groups.yahoo.com/group/aspartameNM/message/859
Roberts: the life work of a brilliant clinician: aspartame toxicity:
Murray 2002.08.02 rmforall
Russell L. Blaylock, MD 601-982-1175 Madison, Mississippi
"Excitotoxins: The Taste that Kills", 1977, 298 p., 493 references.
"Health and Nutrition Secrets that can save your life", 2002, 459 p.,
558 + 30 references, $ 30 http://www.russellblaylockmd.com/
http://groups.yahoo.com/group/aspartameNM/message/1090
aspartame, MSG, excitotoxins, NMDA glutamate receptors,
multiple sclerosis: Blaylock: Murray 2004.06.09
http://groups.yahoo.com/group/aspartameNM/message/97
Lancet website aspartame letter 1999.07.29:
Excitotoxins 1999 Part 1/3 Blaylock: Murray 2000.01.14
The Medical Sentinel Journal 1999 Fall; (95 references)
http://www.dorway.com/blayenn.html
http://groups.yahoo.com/group/aspartameNM/message/935
Comet assay finds DNA damage from sucralose, cyclamate,
saccharin in mice: Sasaki YF & Tsuda S Aug 2002:
Murray 2003.01.01
[ Also borderline evidence, in this pilot study of 39 food additives,
using test groups of 4 mice, for DNA damage from for stomach,
colon, liver, bladder, and lung 3 hr after oral dose of 2000 mg/kg
aspartame -- a very high dose. Methanol is the only component of
aspartame that can lead to DNA damage. ]
http://groups.yahoo.com/group/aspartameNM/message/961
genotoxins, Comet assay in mice: Ace-K, stevia fine;
aspartame poor; sucralose, cyclamate, saccharin bad:
Y.F. Sasaki Aug 2002: Murray 2003.01.27
[A detailed look at the data] ]
MSG and Aspartame -- A Personal Story, TV health reporter
Dick Allgire (vegetarian) healed of migraines and panic attacks:
Murray 2008.02.12
http://rmforall.blogspot.com/2008_02_01_archive.htm
Tuesday, February 12, 2008
http://groups.yahoo.com/group/aspartameNM/message/1520
http://groups.yahoo.com/group/aspartame/messages
group with 1,080 members, 22,439 posts in a public archive
E. Bryant Holman bry...@presidiotex.com
Carol Guilford CarolG...@sbcglobal.net
http://www.presidiotex.com/aspartame/
aspa...@presidiotex.com
http://www.presidiotex.com/aspartame/Links/links.html
http://www.HolisticMed.com/aspartame mg...@holisticmed.com
Aspartame Toxicity Information Center Mark D. Gold
12 East Side Drive #2-18 Concord, NH 03301 603-225-2100
http://www.holisticmed.com/aspartame/abuse/methanol.html
"Scientific Abuse in Aspartame Research"
http://health.groups.yahoo.com/group/GFCFKids/ excellent group
Gluten Free Casein Free Kids
This list is unmoderated and unrestricted.
The principle aim of this list is to provide a discussion forum for
parents of children on the autism spectrum who are avoiding gluten
and casein and other substances in their children's diets.
9,108 members, 234,968 posts in public archive since Dec. 1998
http://health.groups.yahoo.com/group/GFCFKids/links
A very detailed, highly credible account of the dubious approval
process for aspartame in July, 1981 is part of the just released
two-hour documentary "Sweet Misery, A Poisoned World:
An Industry Case Study of a Food Supply In Crisis"
by Cori Brackett: co...@soundandfuryproductions.com
http://www.soundandfuryproductions.com/ 520-624-9710
2301 East Broadway, Suite 111 Tucson, AZ 85719
Mary Nash Stoddard
Toxicology Sourcebook: "Deadly Deception Story of Aspartame"
Aspartame Consumer Safety Network and Pilot Hotline
[since 1987]
P.O. Box 2001 Frisco, Texas 75034 U.S. [ North of Dallas ]
Phone/FAX: 214.387.4001
mary...@airmail.net http://www.aspartamesafety.com
http://www.aspartamesafety.com/en_espanol.htm
http://www.sweetpoison.com/ http://www.issplendasafe.com/
http://www.sweetpoison.com/food-additives-to-avoid.html
Dr. Janet Starr Hull, PhD, CN jsh...@sweetpoison.com
Splenda®: Is It Safe Or Not?
http://www.truthinlabeling.org/ Truth in Labeling Campaign [MSG]
Adrienne Samuels, PhD The toxicity/safety of processed
free glutamic acid (MSG): a study in suppression of information.
Accountability in Research 1999; 6: 259-310. 52-page review
P.O. Box 2532 Darien, Illinois 60561
858-481-9333 adan...@aol.com
http://www.fedupwithfoodadditives.info/ an excellent group
These web pages provide:
independent information about the effects of food on behaviour,
health and learning ability in both children and adults.
support for families using a low-chemical elimination diet free of
additives, low in salicylates, amines and flavour enhancers
(FAILSAFE) for health, behaviour and learning problems.
Food Intolerance Network, Sue Dengate sden...@ozemail.com.au;
http://www.fedupwithfoodadditives.info/biodata.htm
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