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Aspartame is the name for an artificial, non-carbohydrate sweetener,
aspartyl-phenylalanine-1-methyl ester; i.e., the methyl ester of
the dipeptide of the amino acids aspartic acid and phenylalanine.
It is marketed under a number of trademark names, such as Equal,
and Canderel, and is an ingredient of approximately 6,000 consumer
foods and beverages sold worldwide. It is commonly used in diet
soft drinks, and is often provided as a table condiment. It is also
used in some brands of chewable vitamin supplements. However, aspartame
is not always suitable for baking, because it often breaks down
when heated and loses much of its sweetness. In the European Union,
it is also known under the E number (additive code) E951. Aspartame
is also one of the sugar substitutes used by diabetics.
Aspartame has been the subject of a vigorous public controversy
regarding its safety and the circumstances around its approval.
It is well-known that aspartame contains the naturally-occurring
amino acid phenylalanine, which is a health hazard to the few people
born with phenylketonuria, a genetic inability to process phenylalanine.
A few studies have also recommended further investigation into possible
connections between aspartame and diseases such as brain tumors,
brain lesions, and lymphoma. These findings, combined with notable
conflicts of interest in the approval process, have engendered vocal
activism regarding the possible risks of aspartame.
Chemistry
Aspartame is the methyl ester of the dipeptide of the natural
amino acids L-aspartic acid and L-phenylalanine. Under strongly-acidic
or -alkaline conditions, aspartame first generates methanol by hydrolysis.
Under more severe conditions, the peptide bonds are also hydrolyzed,
resulting in the free amino acids. This methanol point is disputed
by some doctors.
Properties and Use
Aspartames attractiveness as a sweetener comes from the
fact that it is approximately 180 times sweeter than sugar in typical
concentrations without the high energy value of sugar. While aspartame,
like other peptides, has a caloric value of 4 kilocalories (17 kilojoules)
per gram, the quantity of aspartame needed to produce a sweet taste
is so small that its caloric contribution is negligible, which makes
it a popular sweetener for those trying to avoid calories from sugar.
The taste of aspartame is not identical to that of sugar: aspartames
sweetness has a slower onset and longer duration than sugars,
and some consumers find it unappealing. Blends of aspartame with
acesulfame potassium are purported to have a more sugar-like taste,
and to be more potent than either sweetener used alone.
Like many other peptides, aspartame may hydrolyze (break down)
into its constituent amino acids under conditions of elevated temperature
(in the case of aspartame, 86 °C) or high pH. This makes aspartame
undesirable as a baking sweetener, and prone to degradation in high-pH
products requiring a long shelf life. Aspartames stability
under heating can be improved to some extent by encasing it in fats
or in maltodextrin. Aspartames stability when dissolved in
water depends markedly on pH. At room temperature, it is most stable
at pH 4.3, where its half-life is nearly 300 days. At pH 7, however,
its half-life is only a few days. Most soft-drinks have a pH between
3 and 5, where aspartame is reasonably stable. In products that
may require a longer shelf life, such as syrups for fountain beverages,
aspartame is sometimes blended with a more stable sweetener, such
as saccharin.
In products such as powdered beverages, aspartames amino
group can undergo a Maillard reaction with the aldehyde groups present
in certain aroma compounds. The ensuing loss of both flavor and
sweetness can be prevented by protecting the aldehyde as an acetal.
Discovery and Approval
Aspartame was discovered in 1965 by James M. Schlatter, a chemist
working for G.D. Searle & Company. Schlatter had synthesized
aspartame in the course of producing an anti-ulcer drug candidate.
He discovered its sweet taste serendipitously when he licked his
finger, which had accidentally become contaminated with aspartame.
Safety testing indicated aspartame may cause brain tumors in rats;
as a result, the U.S. Food and Drug Administration (FDA) did not
approve its use as a food additive in the United States for many
years. In 1980, the FDA convened a Public Board of Inquiry (PBOI)
consisting of independent advisors charged with examining the purported
relationship between aspartame and brain cancer. The PBOI concluded
that aspartame does not cause brain damage, but it recommended against
approving aspartame at that time, citing unanswered questions about
cancer in laboratory rats. In 1981, U.S. President Ronald Reagan
appointed as FDA commissioner Arthur Hull Hayes. Citing data from
a single Japanese study that had not been available to the members
of the PBOI, Hayes approved aspartame for use in dry goods. In 1983
FDA further approved aspartame for use in carbonated beverages,
and for use in other beverages, baked goods, and confections in
1993. It happened that from 1977 to 1985 Donald Rumsfeld served
as Chief Executive Officer, President, and then Chairman of G.D.
Searle. In 1996, the FDA removed all restrictions from aspartame
allowing it to be used in all foods.
In 1985, G.D. Searle was purchased by Monsanto. In this acquisition,
Searles aspartame business became a separate Monsanto subsidiary,
the NutraSweet Company. Monsanto subsequently sold the Nutrasweet
company to J.W. Childs Equity Partners II L.P. on May 25, 2000.[2]
The U.S. patent on aspartame expired in 1992, and the aspartame
market is now hotly contested between the NutraSweet Company and
other manufacturers such as Ajinomoto, Merisant and the Holland
Sweetener Company - the latter of which is exiting the business
in the fourth quarter of 2006 due to a 'persistently unprofitable
business position' because 'global aspartame markets are facing
structural oversupply, which has caused worldwide strong price erosion
over the last 5 years.
Health Risks Controversy
While it is well-known that aspartame contains phenylalanine
and is unsafe for those born with phenylketonuria, research has
also indicated more recently that aspartame can be implicated in
other public health issues and holds serious health risks.
In 1995, FDA Epidemiology Branch Chief, Thomas Wilcox reported
that aspartame complaints represented 75% of all reports of adverse
reactions to substances in the food supply from 1981 to 1995. Concerns
about aspartame frequently revolve around symptoms and health conditions
that are allegedly caused by the sweetener. The 92 health effects
reported to the FDA by patients and doctors are: abdominal pain,
anxiety attacks, arthritis, asthma, asthmatic reactions, bloating/edema,
blood sugar control problems (hypoglycemia or hyperglycemia), brain
cancer (Pre-approval studies in animals), breathing difficulties,
burning eyes or throat, burning urination, inability to think clearly,
chest pains, chronic cough, chronic fatigue, confusion, death, depression,
diarrhea, dizziness, excessive thirst or hunger, fatigue, feeling
unreal, flushing of face, hair loss (baldness) or thinning
of hair, headaches/migraines, hearing loss, heart palpitations,
hives (Urticaria), hypertension (high blood pressure), impotency
and sexual problems, inability to concentrate, infection susceptibility,
insomnia, irritability, itching, joint pains, laryngitis, like
thinking in a fog, marked personality changes, memory loss,
menstrual problems or changes, muscle spasms, nausea or vomiting,
numbness or tingling of extremities, other allergic-like reactions,
panic attacks, phobias, poor memory, rapid heartbeat, rashes, seizures
and convulsions, slurring of speech, swallowing pain, tachycardia,
tremors, tinnitus, vertigo, vision loss, and weight gain.
Questions have been raised about brain cancer, lymphoma, and genotoxic
effects such as DNA-protein crosslinks, but these questions are
primarily not based on reported case histories.
The sources for reported symptoms and health conditions that have
raised questions include:
- Reports and analysis of case histories in scientific journals
& at medical conferences
- Symptoms reported to the FDA and other governmental agencies
- Symptoms reported to non-governmental organizations, researchers,
and physicians
- Reports of symptoms and health conditions in the media
- Self-reported cases on the Internet.
- There is debate in the scientific and medical community as to
whether these symptoms are or are not caused by short-term or
long-term exposure to aspartame.
- Some human and animal studies have found adverse effects and
some have found no adverse effects.
It is not only the results of the research that have been questioned,
but the design of the research that led to specific outcomes. For
example, in human research of aspartame, the aspartame is usually
provided in slow-dissolving capsules. But the biochemical changes
from ingesting aspartame in slow-dissolving capsules are many times
smaller than those from ingesting aspartame dissolved in liquids
(such as carbonated beverages).
Some human studies provide more than the daily allowance of aspartame,
but in an encapsulated form. Based on the above-cited research,
the equivalent amount of real-world aspartame in these
human studies would be less. Other questions that have been raised
about aspartame research involving the length of the studies, the
number of test subjects, conflict of interest issues, and improper
testing procedures.
There are four chemical components of aspartame that have been
debated as to whether they are causing or can cause adverse health
effects:
Methanol
Approximately 10% of aspartame (by mass) is broken down into methanol
in the small intestine. Most of the methanol is absorbed and quickly
converted into formaldehyde. Some scientists believe that the methanol
cannot be a problem because: (a) there is not enough methanol absorbed
to cause toxicity, (b) methanol and formaldehyde are already a by-product
of human metabolism, and (c) there is more methanol in some alcoholic
beverages and fruit juices than is derived from aspartame ingestion.
Other scientists believe (a) fruit juices and alcoholic beverages
always contain protective chemicals such as ethanol that block conversion
of methanol into formaldehyde, but aspartame contains no protective
factors, (b) the levels of methanol and particularly formaldehyde
have been proven to cause chronic toxicity in humans, and (c) the
low levels of methanol and formaldehyde in human metabolism are
tightly-controlled such that significant increases from aspartame
ingestion are not safe.
In 1998, a team of scientists in Spain conducted an experiment
on rodents to indirectly measure the levels of formaldehyde adducts
in the organs after ingestion of aspartame. They did this by radiolabeling
the methanol portion of aspartame. The scientists concluded that
formaldehyde bound to protein and DNA accumulated in the brain,
liver, kidneys and other tissues after ingestion of either 20 mg/kg
or 200 mg/kg of aspartame.
However, it has been argued by Tephly that these scientists were
not directly measuring formaldehyde, but simply measuring levels
of some by-product of the methanol from aspartame. Tephly believes
that the by-product was not formaldehyde. The researchers have stated
that the data in the experiment have proven it was formaldehyde.
Phenylalanine
Phenylalanine is an amino acid commonly found in foods. Approximately
50% of aspartame (by mass) is broken down into phenylalanine. Because
aspartame is metabolized and absorbed very quickly (unlike phenylalanine-containing
proteins in foods), it is known that aspartame could spike blood
plasma levels of phenylalanine. The debate centers on whether a
significant spike in blood plasma phenylalanine occurs at typical
aspartame ingestion levels, whether a sudden influx of phenylalanine
into the bloodstream adversely affects uptake of other amino acids
into the brain and the production of neurotransmitters (since phenylalanine
competes with other Large Neutral Amino Acids (LNAAs) for entry
into the brain at the blood brain barrier), and whether a significant
rise in phenylalanine levels would be concentrated in the brain
of fetuses and be potentially neurotoxic.
Based on case histories from aspartame users, measuring levels
of neurotransmitters in the brains of animals and measuring the
potential of aspartame to cause seizures in animals, some scientists
believe that aspartame may affect neurotransmitter production. They
believe that even a moderate spike in blood plasma phenylalanine
levels from typical ingestion may have adverse consequences in long-term
use. They are especially concerned that the phenylalanine can be
concentrated in fetal brains to a potentially neurotoxic level.
Other scientists believe that rise in blood plasma phenylalanine
is negligible in typical use of aspartame and their studies show
no significant effects on neurotransmitter levels in the brain or
changes in seizure thresholds. In addition, they say that proven
adverse effects of phenylalanine on fetuses has only been seen when
blood phenylalanine levels stay at high levels as opposed to occasionally
being spiked to high levels.
Aspartic acid
Aspartic acid is an amino acid commonly found in foods. Approximately
40% of aspartame (by mass) is broken down into aspartic acid. Because
aspartame is metabolized and absorbed very quickly (unlike aspartic
acid-containing proteins in foods), it is known that aspartame could
spike blood plasma levels of aspartate. Aspartic acid is in a class
of chemicals known as excitotoxins. Abnormally high levels of excitotoxins
have been shown in hundreds of animals studies to cause damage to
areas of the brain unprotected by the blood-brain barrier and a
variety of chronic diseases arising out of this neurotoxicity. The
debate amongst scientists has been raging since the early 1970s,
when Dr. John Olney found that high levels of aspartic acid caused
damage to the brains of infant mice. Dr. Olney and consumer attorney,
James Turner filed a protest with the FDA to block the approval
of aspartame. The debate is complex and has focused on several areas:
(a) whether the increase in plasma aspartate levels from typical
ingestion levels of aspartame is enough to cause neurotoxicity in
one dose or over time, (b) whether humans are susceptible to the
neurotoxicity from aspartic acid seen in some animal experiments,
(c) whether aspartic acid increases the toxicity of formaldehyde,
(d) whether neurotoxicity from excitotoxins should consider the
combined effect of aspartic acid and other excitotoxins such as
glutamic acid from monosodium glutamate. The neuroscientists at
a 1990 meeting of the Society for Neuroscience had a split of opinion
on the issues related to neurotoxic effects from excitotoxic amino
acids found in some additives such as aspartame.
Some scientists believe that humans and other primates are not
as susceptible to excitotoxins as rodents and therefore there is
little concern with aspartic acid from aspartame. While they agree
that the combined effects of all food-based excitotoxins should
be considered, their measurements of the blood plasma levels of
aspartic acid after ingestion of aspartame and monosodium glutamate
demonstrate that there is not a cause for concern. Other scientists
feel that primates are susceptible to excitotoxic damage and that
humans concentrate excitotoxins in the blood more than other animals.
Based on these findings, they feel that humans are approximately
5-6 times more susceptible to the effects of excitotoxins than are
rodents. While they agree that typical use of aspartame does not
spike aspartic acid to extremely high levels in adults, they are
particularly concerned with potential effects in infants and young
children, the potential long-term neurodegenerative effects of small-to-moderate
spikes on plasma excitotoxin levels, and the potential dangers of
combining formaldehyde exposure from aspartame with excitotoxins
given that chronic methanol exposure increases excitoxin levels
in susceptible areas of the brain and that excitotoxins may potentiate
formaldehyde damage.
Aspartylphenylalanine diketopiperazine
This type of diketopiperazine (DKP) is created in products as aspartame
breaks down over time. For example, researchers found that 6 months
after aspartame was put into carbonated beverages, 25% of the aspartame
had been converted to DKP. Concern amongst some scientists has been
expressed that this form of DKP would undergo a nitrosation process
in the stomach producing a type of chemical that could cause brain
tumors. Other scientists feel that the nitrosation of aspartame
or the DKP in the stomach would not produce a chemical that would
cause brain tumors. In addition, only a minuscule amount of the
nitrosated chemical would be produced. There are very few human
studies on the effects of this form of DKP. However, a (one-day)
exposure study showed that the DKP was tolerated without adverse
effects.
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