Aspartame
A Review of the Food Additive
By
Amy
W Phillips
Submitted
Fall Semester 2014
To
the Faculty of
Virginia
Polytechnic Institute and State University
in
partial fulfillment of the requirements for the degree of
MASTER
OF SCIENCE
in
Agricultural
and Life Science
Biosafety,
Biosecurity, and Public Health
____________________________
__________________________
Dr. Sally Paulson Dr. Michael Denbow
____________________________
Dr. Donald Mullins
Table
of Contents:
Introduction……………………………………………………………….....................3
History of Artificial
Sweeteners in the United States…………………………………..4
Discovery of
Aspartame………………………………………………………………...5
FDA Approval of
Aspartame…………………………………………….……………..5
Politics Behind the
Approval……………………………………………………………9
Research After the
Initial Approval…………………………………………………….12
Aspartame in the Market
Place………………………………………………………....15
Aspartame and its
Metabolites………………………………………………………….16
Phenylketonuria…………………………………………………………………………18
Critics of
Aspartame…………………………………………………………………….19
Conclusions……………………………………………………………………………...21
Literature
Cited………………………………………………………………………….25
Introduction
Aspartame
is one of the most researched, and possibly the most controversial, food
additives in U.S. history. Accidentally
discovered almost five decades ago, aspartame is a dipeptide ester of two amino
acids, phenylalanine and aspartic acid (Caseley and Dixon, 2001). Aspartame
currently holds Food and Drug Administration (FDA) approval as a low calorie artificial,
non-nutritive, sweetener, which can be calorie free or just as caloric as
nutritive sweeteners. Nutritive
sweeteners provide the body with energy in the form of carbohydrates. Sugar, fructose, agave, high fructose corn
syrup, and honey are all examples of nutritive sweeteners. In most cases, the non-nutritive sweetener is
so much sweeter than the nutritive sweetener that a very small amount of
non-nutritive sweetener is needed to reach the desired taste. The small amount of non-nutritive sweetener
would contribute a negligible amount of calories to the diet; such is the case
with aspartame (Caseley and Dixon, 2001).
These sweeteners allow consumers to enjoy foods while assisting in
weight control, management of diabetes, controlling dental cavities, and
increasing the palatability of foods and pharmaceuticals (Kemp, 2006).
Aspartame
is an odorless, white crystalline powder with a clean, sweet taste that is
about 200 times as sweet as sucrose (Harper and Olney, 1980). It can be found in over 5,000 products
worldwide including soft drinks, tabletop sweeteners, yogurt, ice cream, candy,
breakfast cereal, jams, vitamins, over the counter drugs, and prescription
drugs (Aspartame History, 2014). Because
low calorie sweeteners have sweetening power over 100 times that of nutritive
sweeteners, much less sweetener is needed for the desired flavor. Many products contain artificial sweeteners,
or a blend of natural and artificial sweeteners, to keep costs low, even if
caloric count is not an issue (Lindseth, et al., 2014). During aspartame’s peak sales in the mid
2000’s, nearly 66 percent of adults and 40 percent of children in the U.S.
regularly consumed the additive (Thomas, 2005).
The
first low calorie artificial sweeteners were discovered by accident, but the
newest have been specifically designed.
Currently, there are five low calorie artificial sweeteners approved by
the FDA: acesulfame potassium, aspartame, saccharin, sucralose, and
neotame. Rebaudioside A, a highly
purified product from the Stevia plant, is also FDA approved as a low calorie
sweetener (What’s the Deal with Stevia, 2014).
As one of the most widely used sweeteners in the world, aspartame is primarily
responsible for the sharp growth in the sugar free market over the last several
decades (Aspartame Benefits, 2014). Currently,
it is approved for use in over 100 countries.
Aspartame began the FDA approval process in 1973. This process, and the subsequent approval,
was fraught with medical and political controversy. Since its initial approval, aspartame has
been in the spotlight as a cause of many public health concerns, ranging from
cancer to neurological symptoms, and more recently, weight gain (Butchko and
Stargel, 2001).
This
paper will examine aspartame’s controversial history, from its discovery
through the FDA approval and its continuing debate. I will focus on the studies done before and
after the FDA approval to determine its safety, the concerns over the
metabolites of aspartame, the political controversy, and its critics. Finally, I will present an opinion of aspartame’s
safety and if it should remain on the FDA’s approved food additive list.
History
of Artificial Sweeteners in the United States
Sweeteners are food additives that are used to replace
sugar, both sucrose and fructose, in many products. They can be artificially synthesized or naturally
synthesized. Artificial sweeteners are
called intense sweeteners. Most of the
FDA approved sugar substitutes are artificial sweeteners. These sweeteners can be used individually or
blended with other sweeteners. Blends
are common because the flavors of different sweeteners can be synergistic
(O’Mullane et al., 2014).
The
earliest sweeteners were all discovered by accident. In 1879, the first artificial sweetener,
saccharin, was discovered. Sixty years
later, in the 1930’s, cyclamate was discovered.
It was later banned due to carcinogenic properties. Nearly a century after saccharin’s discovery,
aspartame was discovered in 1965. Acesulfame
potassium followed in 1967. All four of
these early sweeteners were discovered in the same manner. The sweetener was spilled and contaminated
the fingers or cigarette of the founder, and subsequently was put into the
founder’s mouth. The sweet taste of the
product was noticed and investigated. Neotame,
a derivative of aspartame, and sucralose were both discovered while doing specific
research to find new artificial sweeteners (Kemp, 2006).
Sitting next to the white sugar packet on the table at
most restaurants are its three competitors in pink, blue, and yellow packets. The pink packet is saccharine, sold under the
name Sweet ‘n Low. The blue packet is
Equal, a blend containing aspartame. The
yellow packet is sucralose, sold as Splenda.
Saccharine, aspartame, and sucralose are the most common of table top
sweeteners.
Discovery
of Aspartame
In
1965, chemist James Schlatter was working on a new anti-ulcer drug compound for
the pharmaceutical manufacturer G.D. Searle & Company. He needed an intermediate to generate a
tetrapeptide of the hormone gastrin to test the drug. The intermediate he used was N-L-a-aspartyl-L-phenylalanine-1-methyl ester
(C14H18N2O5), a dipeptide of two
amino acids, aspartic acid and the methyl ester of phenylalanine. While synthesizing the tetrapeptide, the
intermediate accidentally spilled on Schlatter’s hand. Because he knew it was not toxic, he did not
wash it off. He later licked his finger
to help turn a page in a notebook and his finger tasted sweet. Schlatter traced the sweet taste on his
finger back to the intermediate. Searle
examined approximately 200 analogues of that intermediate, but ultimately
decided to apply for FDA approval of the original one discovered by Schlatter,
now known as aspartame (Aspartame History, 2014; Nill, 2000; Caseley and Dixon,
2001). Aspartame has a clean, sweet
taste and exhibits no aftertaste like saccharine. In a blend, aspartame can mask bitterness of
other sweeteners. It is very stable in
dry conditions, except in high heats, and can act as a flavor extender and
enhancer. It can withstand high heat for
short periods of time during UHT processing, pasteurization and aseptic
processing. During extended periods of
high heat, however, aspartame can hydrolyze, lose sweetness, and convert to an
undesirable product. Although aspartame is as caloric as sugar, its calorie
contributions are negligible at the concentrations used, and it produces a
limited glycemic response. (Kemp, 2006; O’Mullane et al., 2014)
FDA
Approval of Aspartame
In
the spring of 1967, a year and a half after its discovery, G.D. Searle began
safety testing on aspartame, anticipating applying for FDA approval. Because half of aspartame is comprised of
phenylalanine, Searle approached respected phenylalanine toxicity expert Dr.
Harry Waisman. Dr. Waisman conducted a
study on the toxicity of aspartame in primates and the results were grim. Aspartame was mixed with milk and fed to
seven monkeys. One of the monkeys died
and five others had grand mal epileptic seizures (Thomas, 2005). They consumed aspartame in levels
approximately 300 times the anticipated intake level in humans (Harper and
Olney, 1980). Four years later, Dr. John
Olney, a professor of neuropathology and psychiatry at the Washington
University School of Medicine in St. Louis, approached Searle to inform them
that one of his studies showed that aspartic acid, a metabolite of aspartame,
caused lesions in the hypothalamus of newborn rodents (Harper and Olney,
1980). The majority of the studies submitted
to the FDA showed no adverse effects on humans. (Harper and Olney, 1980). All of the feeding studies conducted on
aspartame gave results comparable to feeding studies done on just
phenylalanine, using the same quantities (Harper and Olney, 1980). Excess accumulation of phenylalanine in the
body can stunt growth and cause mental retardation. Only the studies done with levels of
phenylalanine high enough to stunt growth showed any adverse effects on the
subjects (Harper and Olney, 1980).
In
March of 1973, eight years after its initial discovery, Searle applied for FDA
approval of aspartame as a food additive (Aspartame, 1985). They submitted over 100 studies supporting
the safety of aspartame. These studies
showed no adverse effects on the cardiovascular, gastrointestinal, endocrine,
reproductive, or central nervous systems in animals given aspartame in levels
of 1mg/kg of body weight. In a study
done on rats given a dose of 4mg/kg of body weight, mild behavior changes were
observed (Harper and Olney, 1980). Despite
the fact that FDA scientists found deficiencies in Searle’s supporting studies,
the FDA commissioner approved aspartame for use in dry foods on July 26,
1974. Shortly after the approval, Dr.
Olney and attorney James Turner filed an objection to the approval of
aspartame, stating aspartic acid can cause brain lesions and neuroendocrine
disorders in animals and therefore can pose a risk to human infants and
children (Aspartame, 1985). Dr. Olney
was mainly concerned with the interaction of aspartic acid and other excitotoxins
in body, such as MSG (Harper and Olney, 1980).
Olney’s study included glutamic acid and aspartic acid administered in a
very large, single dose of 1g/kg of body weight. Studies have been conducted on other animals
and humans, with dosages up to 400 times that of the anticipated use, and
similar results have not occurred (Harper and Olney, 1980). Olney disagreed with the suggested acceptable
daily intake (ADI) because it was based on a 60kg adult, but still approved for
use in children’s foods (Harper and Olney, 1980). Turner began tackling the FDA’s policies,
especially the food additive approval process (Bailey, 1980). He contended that phenylalanine can cause
mental retardation (Aspartame, 1985). Between
the time Searle applied for the patent in 1973 and the FDA approval in 1981,
the majority of aspartame research focused on its metabolites. Studies on both animals and humans revolved
around how the body metabolized aspartame, increased phenylalanine levels in
the brain, and those levels returning back to normal (Table 1). Most studies were conducted on humans,
primates, mice, and rats. It was later
discovered that mice and rats are more sensitive to aspartame, and the high
levels of its metabolites, than primates and humans (Reynolds et al., 1976).
In
1975, an FDA scientist spotted an irregularity in a test conducted by Searle on
a new drug. This caused the FDA to look
into previous studies conducted by Searle.
They questioned the validity of 15 tests on seven of Searle’s products, 12
of those on aspartame (Aspartame, 1985).
One of the tests in question was a feeding study on diketopiperazine
(DKP). DKP was fed to rats and they subsequently
developed uterine polyps (Aspartame, 1985).
The FDA commissioner, Alexander Schmidt, appointed a special task force
to examine the safety concerns surrounding aspartame (Klotter, 2011). Searle agreed to the inquiry and pulled
aspartame from the shelves in December of 1975 (Aspartame, 1985). The task force found that Searle
misrepresented and manipulated the data and product testing. A few months later, a second task force, lead
by Jerome Bressler, was formed to look closer at the irregularities found
during the initial task force’s inspection.
They also addressed the safety concerns and questions raised by Dr.
Olney. One year later, their in-depth
report on three of Searle’s aspartame studies was released. This report, known as the Bressler Report,
found serious errors and inconsistencies in the studies (Klotter, 2011). In one study, deceased animals were not
immediately necropsied, making it impossible to identify the actual cause of
death. In another study, animals that
developed tumors had the tumors removed and were placed back in the study
(Klotter, 2011). After the Bressler report
was released, a third task force was formed to review that report. Ultimately, the approval of aspartame was put
to a board of public inquiry in 1980.
The Bureau of Foods, a unit of the FDA, recommended the approval of
aspartame.
Clinical
evidence conducted by Searle, the Bureau of Foods, and independent researchers
who were funded by both Searle and the federal government, was presented to the
board (Smyth, 1983). Despite Dr. Olney’s
claims that aspartame was unsafe, he admitted to the board that he had not
conducted any additional studies on aspartic acid, or aspartame, since he
submitted his claim in 1974 (Bailey, 1980).
The board’s main concern focused on aspartame alone, or in combination
with glutamate, contributing to brain damage and the possibility that it could
induce brain tumors in rats. They also
addressed issues about its stability in liquid and the possibility that
aspartame, in combination with dietary carbohydrates, may have a synergistic
effect on brain chemicals (Council on Scientific Affairs, 1985). Searle submitted data from the chronic
feeding studies they had conducted on mice and rats. All parties agreed that the results from the
study on mice were negative. However,
there were questions about the rat study.
The board was charged with evaluating whether or not aspartame induced
brain tumors in rats. The results of the
studies were questionable and the board concluded that in high doses, such as
those administered in the study, aspartame may, indeed, contribute to the development
of brain tumors (Smyth, 1983). The board
also concluded that it is possible for aspartame to decompose into DKP. As aspartame decomposes, it loses the methyl
of the methyl ester, leaving the dipeptide L-aspartyl-L-phenylalanine. This loses water and cycles into
diketopiperazine. Aspartame loses its
sweetness in this decomposition (Harper and Olney, 1980). This occurs quicker in a neutral or alkaline
solution (Harper and Olney, 1980). Their
opinion was that this decomposition might lead to a marginally acceptable
product, however it would not be an unsafe product (Council on Scientific
Affairs, 1985). Finally, the board
reviewed studies relating to neurotransmitter activity. They concluded that aspartame increased
plasma and brain phenylalanine levels, but that alone and in combination with
dietary carbohydrates, it did not alter neurotransmitter activity or behavior
(Council on Scientific Affairs, 1985). They
ultimately recommended that approval be withdrawn until more tests could be
done on brain tumors. The FDA took
exception to this conclusion and stated the data did not show a dose-response
relationship (Smythe, 1983).
In
October of 1981, the FDA approved aspartame for use in breakfast cereals,
chewing gum, instant coffee and tea, gelatins, puddings, dry bases for
beverages, and dairy product toppings.
One year later, Searle filed a petition with the FDA to allow aspartame
to be included in soft drinks, children’s vitamins, and other liquids. By July of 1983, aspartame was approved to be
used in soft drinks (Brackett, 2008; Thomas, 2005; Klotter, 2011). At the time of approval, it was known that
aspartame would break down in liquids at a rate directly correlated to storage
temperature and pH. Later, studies would
show this breakdown could be avoided, but was not dangerous if it occurred
(Klotter, 2011). During this time, the
aspartame based table top sweetener sold in Europe, under the name Canderel,
was released in the U.S. as Equal. In
1996, the FDA removed all restrictions on aspartame use, allowing it to be part
of any food or beverage (Thomas, 2005).
Aspartame
was initially approved for use in many European countries in the late 1970’s,
in Canada in 1981, and the UK in 1982. Since
1995, its use in Europe has been governed by a European Council Directive
called Sweeteners in Food Regulations 1995, which permits its use in many
products across all EU member states (Caseley and Dixon, 2001). The World Health Organization and food
regulatory authorities in Canada and Europe have set the suggested ADI of
aspartame as 40mg/kg of body weight. The
FDA has set the ADI in the United States as 50mg/kg of body weight/day. These
authorities uphold the safety of the use of aspartame within these ADIs, and up
to 200 times the estimated levels of consumption, for all individuals except those
with phenylketonuria (PKU) (Harper and Olney, 1980).
Average
sugar consumption is between 100-150g/day.
The equivalent in aspartame is 0.5-0.8g.
However, aspartame is not substituted for sugar in everything, so the
average daily consumption would be less.
Intake should not exceed 0.5g/day, although it is taken into
consideration that some people will exceed it that recommendation. The 0.5g of aspartame will provide 280mg of
phenylalanine, 226mg of aspartic acid, and 54mg of methanol. A 6 oz glass of milk or a 3 oz serving of
beef would provide more phenylalanine and aspartic acid than the recommended
daily intake of aspartame (Harper and Olney, 1980).
Politics
Behind the Approval
While
the FDA was investigating Searle, there were political changes happening in
aspartame’s favor. In January of 1977, after
the initial inquiry, the FDA’s chief counsel requested that the US Attorney’s
office begin grand jury proceedings against Searle for failing to make required
reports to the FDA, concealing material facts, and making false statements
(Klotter, 2011). During the proceedings,
the law firm representing Searle began to recruit Samuel Skinner, the US
Attorney in charge of the investigation.
Skinner removed himself from the case and it was moved to William Conlon. Skinner was later hired by Searle’s law firm
and Conlon took over Skinner’s job.
Needing help to turn the company around amidst their problems with
aspartame, Searle hired Donald Rumsfeld as CEO in 1977. Six months after Rumsfeld took his position
as CEO, the FDA published a report exonerating Searle from any wrongdoing. During this time, Conlon stalled the grand
jury prosecution so long, that the statute of limitations on the aspartame
charges ran out. Approximately one year
later, Conlon joined Skinner at Searle’s law firm. The FDA’s 1980 public board of inquiry ended
with three scientists on the board unanimously voting against aspartame’s
approval until there were more investigations into the brain tumors found in
animals. During this time, aspartame was
approved throughout much of Europe (Thomas, 2005; Gennet, 2011; Gorman, 1999). In 1981, shortly after the public board of
inquiry voted against aspartame’s approval, Ronald Regan was sworn in as
president of the United States. Donald
Rumsfeld, CEO of Searle, served on his transition team. This team nominated Dr. Arthur Hull Hayes as
the new FDA commissioner. The day after
Regan was inaugurated, Searle reapplied to the FDA for approval of
aspartame. The new FDA commissioner, Dr.
Hayes, appointed a five person panel to review the public board of inquiry’s
findings. Three of the five members of
the panel continued to advise against the approval of aspartame. Dr Hayes added a sixth member to the panel
and the vote was deadlocked. Ultimately,
in July of 1981, Dr Hayes sided against his panel and the public board of
inquiry. He broke the tie himself by
approving aspartame for use in dry goods (Thomas, 2005; Nill, 2000; Smythe,
1983).
During
the summer of 1983, shortly before the first carbonated beverage containing
aspartame was released in the U.S., James Turner filed another petition against
the approval of aspartame. Turner’s
petition was denied in the winter of 1984.
The FDA stated that they reviewed the studies on aspartame and it was
deemed safe. Just a month after Turner’s
petition was denied, the first cases of the adverse affects of aspartame were
submitted to the FDA. Amidst the
unresolved scientific issues and customer complaints, Senator Howard Metzenbaum
asked the US General Accounting Office (GAO) to review the FDA’s process for
approving aspartame. The US GAO
investigated, and ruled the FDA had followed the correct process. However, the GAO only reviewed the approval
process. They did not evaluate the
scientific testing that had been submitted for the approval (Klotter,
2011). The FDA asked the Center for
Disease Control (CDC) to begin investigations.
Although the CDC found that sensitive individuals continually had the
same symptoms each time they ingested aspartame, they still deemed it
safe. On the same day the CDC gave their
conclusion, Pepsi announced they would begin to use aspartame for all of their
diet drinks. During the same period, Dr
Hayes resigned as FDA commissioner due to controversy. He later went to work for the public
relations firm used by Searle and Monsanto (Thomas, 2005; Nill, 2000; Smythe,
1983).
Searle’s
attorney during the approval process, Robert Shapiro, gave aspartame its trademarked
name, NutraSweet. In October of 1985, Monsanto acquired
Searle. NutraSweet became a separate
subsidiary of Monsanto and Robert Shapiro became CEO of NutraSweet. In the
following years, as aspartame was approved to be used in more products, more
petitions were filed regarding its safety (Thomas, 2005; Klotter 2011). More cases of adverse reactions were reported
to the FDA, including over 3,000 neurological cases. At this point, at least 10 federal officials
involved in the approval of aspartame were working in the private sector in
jobs linked to aspartame (Thomas, 2005).
The controversy over aspartame’s approval was really heating up in
November of 1987. A Senate hearing, lead
by Senator Metzenbaum, was held regarding the safety and labeling of
aspartame. Resulting from the hearing,
an amendment was proposed to label products containing aspartame with the
quantity of aspartame in the product (Thomas, 2005; Nill, 2000; Smythe,
1983). This would allow sensitive
consumers the ability to track how much they consumed. Ultimately the amendment failed (Klotter,
2011). During the hearing, numerous
scientists and medical professionals testified on the toxicity of
aspartame. The head of the 1977 Universities
Associated for Research and Education in Pathology (UAREP) committee that
looked into 12 of Searle’s tests of aspartame, testified that her committee was
told they should not be concerned with the overall validity of the studies and
not to comment on it. They were
restricted to reviewing only the data Searle provided. There were few discrepancies in this material
and the UAREP committee decided that Searle’s studies were reliable (Klotter,
2011; Aspartame, 1985).
From
1992 to 1996, aspartame continued to be approved for use in more products. In 1995, the FDA announced it would no longer
collect information on adverse reactions to aspartame or monitor any new
research. In May of 2000, Monsanto sold
NutraSweet to JW Childs Associates, a private equity firm comprised of several
former Monsanto employees (Gilman, 2004).
Research
After The Initial Approval
Much of the
research conducted after aspartame’s initial approval has disproven the
original findings of Olney and Waisman.
Most of the studies conducted have been feeding studies. Since aspartame is used as a food additive,
only those studies will yield appropriate results. Many feeding studies on
primates have been conducted since Dr. Waisman’s grim study in the 1970’s. In the majority of these other studies,
primates have shown no health issues from consuming aspartame. Studies have shown that mice and rats are
sensitive to aspartame and its metabolites.
Health issues mice and rats have exhibited in studies have not been
shown to occur in primates and humans. Dr.
Olney’s study was conducted on mice, a species now known to be sensitive to aspartame
and its metabolites (Marinovich et al., 2013; Reynolds et al., 1976).
Many of the earliest studies focused on aspartame’s
metabolites, especially phenylalanine.
Metabolizing aspartame causes high levels of phenylalanine and tyrosine
in the brain. Studies have shown that in
non-sensitive individuals, the phenylalanine levels returned to normal over
time. The majority of studies did not
show any correlation between aspartame consumption and brain damage, seizures,
brain tumors, other cancers, or behavior changes in primates or humans. Similar studies in rats did find that fetal
exposure to aspartame can be carcinogenic, metabolism of methanol can cause a
formaldehyde build up in their bodies, and aspartame mixed with dietary
carbohydrates can significantly alter brain chemical levels. Studies on humans
did not show the buildup of formaldehyde in the body or alteration of brain chemicals. Aspartame does not have an effect on plasma
glucose or insulin level (Shigeta et al., 1985). Using aspartame as a blend, especially with
sucrose, does not change the way aspartame is metabolized (Stegink et al.,
1990). Several studies concluded that
aspartame is metabolized the same in children as it is in adults, and there is
no risk to a fetus from maternal consumption (Filer et al., 1983). Research has also shown that long term
consumption is safe. Some studies have
found that aspartame could be to blame for minor side effects, like headaches,
in those that have a predisposed sensitivity to it (Lajtha et al., 1994; Lim et
al., 2004; Kemp, 2006; Marinovich et al., 2013; Reynolds et al., 1976).
After
its 1983 approval for use in carbonated beverages, the number of consumer
complaints regarding aspartame escalated.
In 1984, the FDA asked the CDC to evaluate the consumer complaints. The purpose of the CDC’s investigation was to
give an analysis of the
Table 1. Timeline of aspartame research
Year
|
Research Conducted
|
Results/Findings
|
1973
|
Feeding
study – aspartame in monkeys
|
Phenylalanine metabolism not modified
|
1976
|
Feeding
study - aspartame and sucrose in healthy adults
|
Phenylalanine and tyrosine levels normal, no physical changes or
product side effects
|
1976
|
Feeding
study - MSG and aspartame in monkeys and mice
|
Monkeys can handle excess amino acids better than mice
|
1977
|
Feeding
study – aspartame in healthy adults
|
Phenylalanine levels return back to normal
|
1981
|
Aspartame
and DKP and brain tumors in rats
|
Neither aspartame nor DKP caused brain tumors in rats.
|
1983
|
Feeding
study - aspartame in infants
|
Infants metabolize the amino acids of aspartame the same as
adults.
|
1984
|
Feeding
study - aspartame and glucose in rats
|
High aspartame doses can generate major neurochemical changes in
rats, especially when consumed with carbohydrates.
|
1985
|
Safety issues of aspartame - toxicity of metabolites, effects on
brain neurochemicals
|
Ingestion safe for healthy humans, PKU patients must be careful
|
1985
|
Feeding
study – aspartame in diabetic humans and diabetic rats
|
Aspartame has no influence on plasma glucose or insulin values
in diabetic rats and humans with non insulin-dependent diabetes.
|
1986
|
Feeding study - aspartame and a high carbohydrate diet in rats
|
Suppression of carbohydrate-induced increases in brain
tryptophan concentration and serotonin synthesis occur with high doses of
aspartame in rats.
|
1986
|
Feeding
study – aspartame in PKU patients
|
Investigations indicated that 10 mg/kg doses of aspartame are
safe for those with phenylketonuria, not on a restricted diet.
|
1986
|
Feeding
study - behavior changes in children when fed aspartame and sucrose
|
Data provided little evidence for any effect of sucrose on
behavior, and none at all for aspartame.
|
1988
|
Feeding
study - aspartame in pregnant women
|
Aspartame poses no hazard to the fetus or the mother unless she has
PKU.
|
1988
|
Feeding
study – aspartame and headaches
|
The incidence rate of headache after aspartame (35%) was not
significantly different from that after placebo (45%).
|
1989
|
Feeding
study - aspartame and headaches
|
Aspartame may be an important dietary trigger of headache in
some people.
|
1989
|
Long
term consumption of aspartame
|
Long-term consumption of aspartame (10 liters of beverage/day)
safe.
|
1989
|
Neurotoxicity
and seizures
|
Consumption of aspartame does not induce brain damage, nor does
it provoke seizures.
|
1990
|
Effects
of aspartame in combination with sucrose
|
The simultaneous ingestion of sucrose with aspartame had only
minor effects on aspartame's metabolic disposition.
|
1993
|
Aspartame
and allergic reactions
|
Aspartame no more likely than placebo to cause urticaria and/or
angioedema reactions.
|
1994
|
Feeding
test - aspartame in children with ADD
|
No significant difference between aspartame and placebo for
seven tests of behavior and cognition
|
1994
|
Feeding
test – aspartame and sucrose in young children
|
Intake of sucrose or aspartame exceeding typical dietary levels has
no adverse effects on children's behavior or cognitive function.
|
1997
|
Brain
tumors in children
|
Aspartame not likely cause of brain tumors in children. No evidence of risk to the child from
maternal consumption.
|
1998
|
Feeding
test – build up of formaldehyde in rats after ingesting aspartame
|
Aspartame possible hazard because of formation of formaldehyde
adducts.
|
1998
|
Neurological
effects
|
Large daily doses of aspartame had no effect on
neuropsychological, neurophysiological or behavioral functioning in healthy
young adults.
|
2002
|
Risks of methanol, formate, and formaldehyde at abuse doses in
rats
|
Aspartame at abuse doses is harmless to humans.
|
2006
|
Consumption of beverages with aspartame and risk of brain cancer
|
Aspartame does not increase hematopoietic or brain cancer risk.
|
2007
|
Prenatal aspartame exposure in rats
|
The study demonstrates that when life-span exposure to aspartame
begins during fetal life, its carcinogenic effects are increased.
|
symptoms being
reported, and to determine if there was enough consistency in the symptoms to
warrant more clinical studies. The CDC
interviewed 517 complainants and noted that though there were a great variety
of complaints, all were mild in nature.
Of the people interviewed, 96 percent were white, 76 percent were
female, and 79 percent were between the ages of 21 and 60 years old. Of the symptoms reported, 67 percent were neurological
or behavioral symptoms, 24 percent were gastrointestinal symptoms, and 15
percent were dermatologic symptoms. (Center for Disease Control, 1984). Subsequent analysis revealed that
approximately one quarter of the initial complaints were actually able to be linked
to aspartame consumption (Shaban and Albert, 1988). Patients with phenylketonuria (PKU) and
Parkinson’s disease were more likely to show adverse affects to aspartame
(Shaban and Albert, 1988). The CDC
concluded that certain individuals may have sensitivity to aspartame, but in
those with no sensitivity, there is no evidence of serious, widespread health
concerns from consuming aspartame (Center for Disease Control, 1984; Smythe,
1983).
The
focus of the research after initial approval varied as aspartame became an
ingredient in more products. From 1982
through 1985, most research focused on the use of aspartame in new foods, its
use in diabetics, preventing dental cavities, the difference between children
and adults metabolizing aspartame, and neurological and brain changes. From 1986 through 1990, most research focused
on the use of aspartame in dairy, its effect on food intake, and helping with weight
loss. From 1991 through the present, a
majority of the research has focused on consumption in children, its effects on
food intake, brain tumors, neurological effects, its affect on ADD, and
formaldehyde build up in the body.
Recently, aspartame has been in the news with stories that it might
contribute to weight gain (Table 1).
Aspartame
is metabolized rapidly and never makes its way into the blood stream, therefore
only those studies that focus on ingestion of aspartame are sound when
evaluating its safety. The studies the
FDA used as a basis for their approval involved ingestion of aspartame. Some private studies were conducted that
included injection of aspartame directly into the blood stream, brain, or other
organs. Findings from these studies
would not be consistent with what would naturally occur from ingestion. It is not possible for aspartame to be passed
on to a fetus or an infant, through lactation, because it never enters the
blood stream (Magnuson, 2010).
Recently,
studies have been done on aspartame, and all other artificial sweeteners, to
determine how they affect metabolism.
Over the last two decades, research has found that diet soda drinkers
have worse health overall than regular soda drinkers. They believe that consumption of artificial
sweeteners has tricked the body into thinking it is consuming real sugar, when
it is not. The body responds in the same
way as it would to sugar and it throws metabolism off. When real sugar is consumed, the body does
not know how it should be processed because it has been tricked so many times
(Wilson, 2014).
Most
recently, the European Food Safety Authority (EFSA) conducted a reevaluation of
the safety of aspartame. The
reevaluation was completed in 2013. They
confirmed the safety of aspartame for the ADI of 40mg/kg. Specifically, they addressed concerns about leukemia
and solid tumors (EFSA ANS Panel, 2001; EFSA ANS Panel, 2013).
Aspartame
in the Market Place
Aspartame
was first patented by Searle in 1970. During
the decades following its approval, aspartame took over much of saccharin’s
place in the market share. When consumed
in high quantities, saccharine can be bitter and produce a metallic aftertaste. Aspartame offers a more pleasant flavor. While it held the patent, NutraSweet branded
itself as an ingredient in other foods (Warner, 2004; Warner, 2006; Klotter,
2011; Thomas, 2005). Aspartame used as a
table top sweetener is sold under the name Equal. During their monopoly, NutraSweet did
something novel in the ingredient industry; they branded an ingredient and made
it a household name. Consumers demanded
their sugar free products contain NutraSweet.
This put NutraSweet in a good position with food and beverage
manufacturers. It was unheard of for an
ingredient supplier to be controlling the distribution and labeling. If
aspartame was used, NutraSweet required their iconic red and white swirl logo
be included on the packaging. This was
the first time in history that a major company, like Coca Cola or Pepsi, was
forced to promote another product’s branding on their own packaging (Jabbonsky,
1992).
In
1987, when NutraSweet’s patent expired in Europe, Canada, and Japan, they
severely undercut all their competition in order to drive them out of the
market before the US patent expired in 1992 (Shapiro, 1989). At the time, 60 percent of NutraSweet’s total
sales were in the US (Shapiro, 1989). When
the first patents expired, there were several companies waiting to enter the
market. NutraSweet immediately signed an
agreement with Coca Cola and Pepsi, wherein the soft drink giants stated NutraSweet
was their preferred aspartame supplier. NutraSweet’s
years of ingredient branding had solidified their position in the marketplace. Consumers were used to NutraSweet and the
huge soft drink companies were afraid to be the first one to make a move to a
different sweetener. If either Coke or
Pepsi made a move, the other company would create a marketing campaign assuring
customers that their brand was sticking with NutraSweet while the other company
was moving on to an unknown sweetener.
Diet soft drinks were so profitable at the time, that neither Coke nor
Pepsi wanted to change their diet formula and risk losing market share. At the time, Coca Cola was the world’s
largest consumer of aspartame (Shaprio, 1989).
Holland Sweetener Company and Ajinomoto entered the market when the
European, Canadian, and Japanese patents expired.
Holland
Sweetener Company, Ajinomoto, and NutraSweet competed for several years in the
aspartame market. Sucralose, a newcomer to the artificial sweetener industry,
gained FDA approval in 1998. Unlike
aspartame, sucralose does not lose its sweetness when heated and has twice the
shelf life. Sucralose gained popularity
and aspartame started to lose market share. In the mid 2000’s, global aspartame markets
faced over supply, lowering the price and making it a less profitable business
(Gilman, 2004; Ryan, 1991). Although it
has been used for decades in other countries, stevia is the newest sweetener on
the market in the US. In 2008, the FDA
recognized Rebaudioside A, a processed form of stevia, as GRAS (generally
recognized as safe) for use as a food additive.
However, the whole stevia leaf and other extracts are still only
available as dietary supplements (Food Additives Permitted for Direct Addition
to Food for Human Consumption, 2012; O’Mullane et al., 2014; Wahba, 2014). Sucralose and stevia are aspartame’s main
competitors in both the table top market and as ingredients. Recently, stevia entered the cola market with
a product called Zevia (Whaba, 2014). Due
to consumer concerns about the safety of aspartame, colas with stevia have the
ability to become very popular. A new
product, along with consumer concern over aspartame, could be detrimental to
the current diet cola market.
Aspartame
and Its Metabolites
Once
aspartame enters the body, it is immediately absorbed by the intestine and
metabolized to methanol (10%), aspartic acid (40%), and phenylalanine (50%)
(Humphries et al., 2008; Simintzi et al., 2007) (Figure 1). It is broken down so quickly that, even in
very high doses, no aspartame can be found in the blood. The human body is well equipped to use small
amounts of methanol and these amino acids.
Alcohol
dehydrogenase in the liver quickly converts methanol into formate, which can be
excreted or give rise to formaldehyde. Formaldehyde
is immediately used or completely oxidized into formic acid. Formic acid has a very long half life and if
it builds up in the body, it can cause methanol poisoning. However, in most cases the formic acid is converted
into water and carbon dioxide for excretion.
Methanol is naturally occurring in most fruits and vegetables and the
levels metabolized from aspartame do not exceed what would be found in a normal
diet (Caseley and Dixon, 2001).
Aspartic
acid and phenylalanine are two common amino acids found in a typical diet of
protein rich foods, such as meat, milk, and fruit (Magnuson, 2010). The amount of these amino acids metabolized
from the ADI of aspartame account for only two to three percent of the total dietary
intake in adults (O’Mullane et al., 2014).
Aspartic acid is a nutritionally dispensable amino acid, meaning if it
is not present in the diet, the body can synthesize it from glucose, ammonia,
or other amino acids. It acts as an
excitatory neurotransmitter in the central nervous system. Phenylalanine is a
nutritionally essential, or indispensible, amino acid. The body is not able to synthesize it. It is essential for bodily function and must
be provided by a food source.
Phenylalanine is involved in neurotransmitter regulation (Humphries et
al., 2008; Lindseth et al., 2014, Harper and Olney, 1980).
Aspartame
is susceptible to conversion to diketopiperazine (DKP) when stored in high
temperatures and neutral pH conditions (O’Mullane et al., 2014). While DKP has not been studied as extensively
as aspartame, it is generally recognized as safe. Care should be taken not to use aspartame in
foods or beverages that might act as catalysts for this racemization, such as
neutral or alkaline liquids, or be heated or cooled because the conversion to
DKP will change the sweetener’s taste and create a less than ideal product
(Boehm and Bada, 1984).
Aspartame
is made of two commonly occurring amino acids, therefore having them in the
body is not a health issue. Scientists
are most concerned about high levels of those amino acids in the body without
other naturally occurring amino acids that are normally found in protein rich
foods. Dr. Richard Wurtman, a professor of
neuroendocrine regulation at MIT, expressed concerns about the combination of
aspartame and carbohydrates. In natural
protein rich food, phenylalanine would be found along with other amino
acids. These amino acids would compete
for transport into the brain’s capillaries.
When aspartame is consumed along with carbohydrates, phenylalanine and
aspartic acid are the only amino acids being sent to the brain
capillaries. This can result in
neurotransmitter disturbances, as both alter neurotransmitter regulation. However, Dr. Wurtman was not able to provide
empirical evidence that this happens (Aspartame, 1985). Some early studies have shown that increased
levels of phenylalanine and aspartic acid are responsible for decreased
production of dopamine and serotonin. These
studies suggest that aspartame’s metabolites could be responsible for neurobehavioral
changes (Lindseth et al., 2014; Klotter, 2011).
Many studies on high levels of phenylalanine in the brains have been
done since aspartame’s approval and no neurological issues have occurred in
humans. In healthy people, the high levels
of phenylalanine return to normal themselves within four hours (Stegink et al.,
1977). The combination of aspartame and
dietary carbohydrates has been shown to be safe in humans. The carbohydrates do not cause the body to
metabolize aspartame differently or change the way the amino acids react in the
brain. Studies have not been able to
correlate high levels of phenylalanine with behavioral changes or neurochemical
changes in the human brain (Lajtha et al., 1994; Humphries et al., 2008; Lindseth
et al., 2014).
Phenylketonuria
Phenylalanine
is broken down to tyrosine once it is metabolized in a healthy body. If phenylalanine is not broken down to
tyrosine, high levels of phenylalanine can accumulate in the brain. This accumulation can cause serious
neurological effects including mental retardation, brain damage, and seizures
(Klotter, 2011). Consumption of
phenylalanine can be a hazard to individuals born with phenylketonuria (PKU). PKU is a rare, inherited condition which
prevents phenylalanine from being metabolized, leading to potentially harmful
levels of accumulation. Approximately
one in 10,000 babies is born with this defect (Harper and Olney, 1980; Caseley
and Dixon, 2001). PKU is a serious
metabolic disorder and newborns are screened during a routine blood test. Those diagnosed with PKU must follow a strict
diet that limits consumption of phenylalanine (Caseley and Dixon, 2001). For this reason, products containing
aspartame in
Figure 1: Aspartame, its metabolites, and decomposition
products (Renwick, 1985).
the US, Canada, and the
UK must have labeling stating the product contains phenylalanine (Gilman,
2004). While aspartame itself cannot
enter the blood stream and pass to a fetus, high maternal levels of phenylalanine
can harm an unborn baby. Pregnant women
with PKU must follow a strict phenylalanine controlled diet. Since aspartame’s approval, several studies
have been conducted on consumption of aspartame in PKU patients. In general, most studies have found that PKU
patients that are not on a phenylalanine-restricted diet can consume moderate
amounts of aspartame, such as 10mg/kg of weight, safely (Caballero et al.,
1986).
Critics
of Aspartame
Hundreds
of studies have been conducted on aspartame since its initial approval in
1981. Some were the basis for the petitions
filed to the FDA to ban aspartame as a food additive. Many of those studies had findings that
linked aspartame to conditions such as brain tumors, leukemia, other cancers,
neurological conditions, heart conditions, brain damage, headaches, seizures, and
more. These findings have prompted many individuals
and groups to call for an FDA ban on aspartame.
Some of these individuals and groups are very radical. They take studies out of context, and choose
to promote only the information they can use as scare tactics. They have created websites and literature
meant to frighten consumers. Websites,
like sweetpoison.com run by Janet Starr Hull, list over 90 medical conditions
thought to be caused by aspartame and ask people to submit their aspartame
related health issues. Mercola.com
declared aspartame to be the most dangerous substance added to foods today. It has even prompted a snopes.com article
debunking myths found all over the internet, including the Nancy Markle email
hoax (described below). The American
Cancer Society states that “claims have been made that aspartame is related to
health effects ranging from mild problems such as headache, dizziness,
digestive symptoms, and changes in mood, to more serious health issues such as
Alzheimer disease, birth defects, diabetes, Gulf War syndrome, attention
deficit disorders, Parkinson disease, lupus, multiple sclerosis, and seizures.
However, studies done to date have not found any consistent evidence of harm.”
(Aspartame, 2014). The earliest studies
claimed that aspartame use increased incidents of brain tumors and blood
cancers. However, it was found that the
increase of brain tumors actually started in 1970, before aspartame was
approved, and evened out over the years as aspartame intake increased
(Magnuson, 2010).
Aspartame
manufacturer Ajinomoto manages the website aspartame.net. It counters the claims made by the radical
groups and promotes the safety of aspartame.
The Calorie Control Council manages the website aspartame.org. The Calorie Control Council is owned by The
Kellen Company, a firm that offers professional services to other
companies. It is not clear if The Kellen
Company is managing this website for another aspartame manufacturer, but
aspartame.org is very similar to aspartame.net.
It emphasizes the safety of aspartame.
There is a lot of information available today, and as a consumer it is
difficult to know which to believe.
Aspartame
has several critics dedicated to banning the product. Betty Martini, the founder of Mission
Possible World Health International, is one of these critics. She speaks out against aspartame at venues
all over the world. She is an advocate
for sick individuals that believe aspartame led to their illnesses. Mission Possible World Health International
runs a very extensive website about aspartame. (mpwhi.com) Some of the information is factual, but the
majority is Martini’s opinion and evidence from early studies that have shown
ill-effects of aspartame. Many of the
studies conducted early on in aspartame’s existence have since been refuted. She often takes studies out of context or
projects results found in rodents to human beings.
The
website dorway.com has the same mission as Mission Possible World Health
International but has a much different approach. This website, originally founded and run by
the late Dave Rietz, has a very professional look, similar to many government
websites. They publish many of the same
articles and anti-aspartame information as mpwhi.com, but to the consumer, it
looks more legitimate. Dave Rietz,
similar to Betty Martini, was dedicated to banning aspartame.
An
elaborate email hoax in the late 1990’s tried to use scare tactics to gain
consumer support in banning aspartame.
An email chain-letter from a “Dr. Nancy Markle” was circulated. No one has been able to confirm who Dr. Nancy
Markle is and no one has ever come forward to claim responsibility for the
letter. The contents of the letter are
very similar to an article written by Betty Martini around the same time. The email was circulated at such a high
volume, it prompted a snopes.com review, labeling it a hoax. Many other websites, such as
aspartmekills.com, sweetpoison.com, and mercola.com publish information
questioning the safety of aspartame and calling for an FDA ban of the food
additive. Martini, Rietz’s successors,
and many others are still actively involved in filing petitions with the FDA
over aspartame. In October 2014, the FDA
rejected the most recent call to ban aspartame, saying there is still no
evidence that aspartame can cause cancer.
The evidence submitted is easily refuted, taken out of context, already
been disproven, or from non reliable studies (Overley, 2014). For those with background knowledge of the
extensive research conducted on aspartame, this information can be easily
dismissed. Much of the information
available to the average consumer comes from either aspartame producers or its
critics. Both sources are biased in
their own way and do not provide consumers with the factual information they need
to make an educated choice.
Conclusions
According
to Diane Stadler, research assistant professor and bionutritionist at Oregon
Health and Science University, "the historical background on aspartame is
really astounding. It establishes
criteria that research on new food additives needs to live up to" (Gilman,
2004). Aspartame is one of the most
studied food additives on the market.
The FDA has continuously stood behind their opinion that aspartame is
safe and stopped accepting claims of possible aspartame-induced health issues
in 1995. Beginning in 2001, the European
Food Safety Authority (EFSA) has continuously reviewed the safety of aspartame. More recently, in 2013, the EFSA published a
full risk assessment in which they conclude that aspartame and its metabolites
are safe for the general population (EFSA ANS Panel, 2001; EFSA ANS Panel,
2013). Aspartame has been consistently
studied since its discovery. The FDA and
EFSA have an overwhelming amount of scientific research to back their decision. Given all the research that has been done,
and all the reviews that both the FDA and EFSA have conducted on aspartame, it
is obvious that there is significant science behind their decisions.
Not
all aspartame studies are comparable.
The methods of aspartame studies vary and may include ingestion of
aspartame, as well as injection directly into the brain or other organs. Many of the non-feeding studies do show that
aspartame has a carcinogenic, or other harmful, effect on its subjects. While it is troublesome that aspartame can
have a harmful effect on the subject, a study that involves aspartame entering
the body in a way other than ingestion is not relevant. Aspartame is approved as a food additive, so
only feeding studies are applicable. It
is meant to be metabolized during digestion.
The digestive system in our bodies is built to handle the amino acid
breakdown and does so efficiently.
Studies that focus on aspartame entering the body in any way other than
ingestion should be overlooked when considering its safety. While there have been a few studies during
aspartame’s existence that show possible risks with ingestion, there are
multiple other studies that have been conducted to refute those finding. The metabolites of aspartame are found in
natural foods we eat on a regular basis and our bodies are capable of taking
care of these chemical reactions.
Many
of the studies conducted on aspartame use rodents as subjects. Rodents are often used because they are
cheaper subjects, easier to care for, and have shorter life spans than primates
or humans. The findings in rodent studies
often have different outcomes than those using primates or humans. It has been found that rodents are more
sensitive to the metabolites of aspartame and it is considered to be
carcinogenic in them. Studies on
primates and human have not had the same results. Because of this sensitivity, the studies
conducted on rodents should not be used as criteria for approving aspartame for
human use.
The
majority of the research conducted on aspartame concludes that aspartame is
safe as a food additive for humans.
There are some studies that suggest aspartame is carcinogenic, or can
cause other health issues, however those are either incomplete, easily refuted,
or have already been disproven. The FDA
should uphold their approval of aspartame as a food additive. The extensive research has shown that
aspartame is safe for healthy humans.
Those with PKU should be careful not to ingest aspartame if they are on
a phenylalanine restricted diet.
Legislation, like that which Metzenbaum proposed, requiring companies to
label products with the amount of phenylalanine or aspartame they contain would
help prevent illnesses in sensitive individuals.
Considering
the research conducted over the last 50 years, aspartame appears to be a
problem only for those individuals who are sensitive to it. Even without a PKU diagnosis, a person might
still be slightly sensitive to abrupt, high levels of phenylalanine, or another
of aspartame’s metabolites. It is
possible that the headaches, or gastrointestinal problems, that many blame on
aspartame could just be a sign of sensitivity to one, or all, of its
metabolites. More research into possible
sensitivities would benefit both the people consuming aspartame and the
companies using it as an ingredient.
While aspartame is safe enough to remain on the market, companies losing
market share due to its controversy would be wise to move on to another
sweetener. With so much misinformation
available and so many individuals working to have it banned, aspartame will
continue to be a controversial food additive causing companies to lose
customers.
While
the claims against aspartame made on websites like Mission Possible World
Health International’s and dorway.com are wild and unfounded, they can provide
good subjects for new areas of research.
There are several accounts made by these websites suggesting that
aspartame has caused autism (Martini, 2012).
While claims like this one cannot possibly be true as not all children
who have consumed aspartame have autism, it can be a basis for new areas of
research. It is possible that
individuals with slight sensitivities to phenylalanine, or other metabolites of
aspartame, could experience side effects that have not been accounted for in
studies on healthy individuals. These
sensitivities could be so slight that the medical tests currently available
could not detect them. Environmental
factors, in combination with these sensitivities, can also be the cause of some
side effects. It is possible that
aspartame or its metabolites can be an allergen in some. Additional research should focus on
investigating if there are individuals who have a slight sensitivity to
aspartame, especially in children and pregnant women. While aspartame is safe for healthy
individuals, additional research could clear up misconceptions about the
additive and possibly shed some light on new conditions that are still being
investigated. Research into aspartame
use and newly increasing conditions such as autism, ADD, ADHA, and weight gain,
should be conducted.
Despite
the controversy surrounding aspartame, it is one of the most researched food
additives in history and has significantly more information available to prove
its safety than most food additives on the market today. Many governments have deemed the product safe
for human consumption and continually monitor its safety. Aspartame’s history should be used as an
example and can set a standard for food additive FDA approval. All food additives need to be studied to the
extent that aspartame has been to assure their safety. Research should continue on all artificial
sweeteners, including aspartame, to be sure of their safety in combination with
new additives and environmental factors.
Literature Cited
Aspartame, October 4, 1985; Congressional Record Daily Edition (131 Cong Rec S 12612); 99th
Congress; Records of the U.S. Senate, Record Group 131(128) p S12612; National Archives, Washington, DC.
Aspartame. (2014, May 28). Retrieved from
http://www.cancer.org/cancer/cancercauses/othercarcinogens/athome/aspartame.
Aspartame Benefits. (n.d.). Retrieved November 21, 2014, from
http://www.aspartame.org/about/benefits/#.VG69QmeBGP8.
Aspartame History. (n.d.). Retrieved November 21, 2014, from http://www.aspartame.net/about-
aspartame/aspartame_approved.asp.
Bailey, M. (1980, February 4). Aspartame Wins a Nod. Barron’s National Business and
Financial Weekly, p 26.
Boehm, M. F. & Bada, J. L. (1984). Racemization of aspartic acid and phenylalanine in the
sweetener aspartame at 100˚C. P. Natl. Acad. Sci. Usa., 81(16) 5263-5266.
http://dx.doi.org/10.1073/pnas.81.16.5263.
Brackett, R. (2008). Aspartame – A guide for consumers, policy makers, and the media.
Retrieved from http://www.gmaonline.org/downloads/research-and-
reports/SciPol_Aspartame_0722.pdf.
Butchko, H. H. & Stargel, W. W. (2001). Aspartame: Scientific Evaluation in the Postmarketing
Period. Regul. Toxicol. Pharm., 34, 221-233.
doi:http://dx.doi.org/10.1006/rtph.2001.1500.
Caballero, B., Mahon, B.
E., Rohr, F. J., Levy, H. L., & Wurtman, R. J. (1986). Plasma amino
acid levels after
single-dose aspartame consumption in phenylketonuria, mild
hyperphenylalaninemia,
and heterozygous state for phenylketonuria.
J. Pediatr., 109(4),
668-671. doi:http://dx.doi.org/ 10.1016/S0022-3476(86)80239-6.
Caseley, J. & Dixon, W. (2001). Aspartame: in perspective. Nutrition & Food Science, 31(1), 23-
27. doi:http://dx.doi.org/10.1108/00346650110361310.
Center for Disease Control. (1984, November 2). Evaluation of Consumer Complaints Related to
Aspartame Use. Morbidity and Mortality Weekly Report, 33(43), 605-607. Retrieved
from http://www.cdc.gov/mmwr/preview/mmwrhtml/00000426.htm.
Copestake, P. (1988). Aspartame – A bit of a headache? Food. Chem. Toxicol., 26(6), 571-574.
doi:http://dx.doi.org/10.1016/0278-6915(88)90011-7.
Council
on Scientific Affairs. (1985). Aspartame: Review of Safety Issues. J. Amer. Med. Assoc.,
254(3), 400-402.
doi:http://dx.doi.org/10.1001/jama.254.3.400.
EFSA
ANS Panel. (2001). Statement of the EFSA on the scientific evaluation of
two
studies related to the safety of artificial sweeteners. EFSA J., 9(2), 2089-2105.
Retrieved
from
http://www.aspartame.net/OnPagePDF/EFSA%20on%20sweeteners%2028%20Feb%20
1.pdf.
EFSA
ANS Panel. (2013). Statement on two reports published after the closing date of
the public
consultation
of the draft Scientific Option on the re-evaluation of aspartame (E 951) as a
food
additive. EFSA J., 11(12):3504, 1-10.
doi:http://dx.doi.org/10.2903/j.efsa.2013.3504.
Ferguson, H. B.,
Stoddart, C., & Simeon, J. G. (1986). Double-blind challenge studies of
behavioral and cognitive
effects of sucrose-aspartame ingestion in normal children.
Nutr. Res. Rev., 44,
144-150.
Fernstrom, J. D.,
Fernstrom, M. H., & Grubb, P. E. (1986).
Effects of aspartame ingestion on the
carbohydrate-induced
rise in tryptophan hydroxylation rate in rat brain. Am. J.
Clin.
Nutr., 44(2), 195-205.
Filer, L. J., Jr.,
Baker, G. L., & Stegink, L. D. (1983).
Effect of aspartame loading on plasma
and erythrocyte free
amino acid concentrations in one-year-old infants. J.
Nutr., 113(8),
1591-1599.
Fisher, R.S.
(1989). Aspartame, neurotoxicity, and
seizures: a review. J. Epilepsy, 2(2), 55-64.
Food
Additives Permitted for Direct Addition to Food for Human Consumption, 21
C.F.R. pt.
I(I),
172.804 (2012).
Frey,
G.H. (1976). Use of aspartame by
apparently healthy children and adolescents.
J. Toxicol.
Env. Health., 2(2),
401-415. doi:http://dx.doi.org/10.1080/15287397609529442.
Geha, R., Buckley, C. E., Greenberger, P., Patterson, R., Polmar, S., Saxon, A., Rohr, A., Yang,
W., & Drouin, M. (1993). Aspartame is no more likely than placebo to cause
urticaria/angioedema: Results of a multicenter, randomized, double-blind, placebo-
controlled, crossover study. J. Allergy. Clin. Immun., 92(4), 513-520.
doi:http://dx.doi.org/10.1016/0091-6749(93)90075-q.
Gennet,
R. (2011, January 6). Donald Rumsfeld and the Strange History of Aspartame.
[Weblog].
Retrieved from http://www.huffingtonpost.com/robbie-gennet/donald-
rumsfeld-and-the-s_b_805581.html.
Gilman,
V. (2004, June 21). Artificial Sweeteners. Chemical
& Engineering News, 82(25), 43.
Gorman,
C. (1999, February 8). A Web of Deceit. Time
Magazine. Retrieved from
http://content.time.com/time/magazine/article/0,9171,990167,00.html.
Gurney, J. G., Pogoda,
J. M., Holly, E. A., Hecht, S. S., & Preston-Martin, S. (1997). Aspartame
consumption in relation
to childhood brain tumor risk: results from a case-control study.
J. Natl. Cancer I., 89(14),
1072-1074. doi:http://dx.doi.org/10.1093/jnci/89.14.1072.
Harper,
A. E. & Olney, J. W. (Eds.). (1980). Proceedings from FDA Public Board of
Inquiry on
Aspartame:
Sweeteners: Issues and Uncertainties.
Washington, DC: National Academy
of
Sciences.
Humphries,
P., Pretorius, E., & Naude, H. (2008). Direct and indirect cellular effects
of
aspartame
on the brain. Eur. J. Clin. Nutr., 62(4),451-462.
http://dx.doi.org/10.1038/sj.ejcn.1602866.
Ishii,
H. (1981). Incidence of brain tumors in rats fed aspartame. Toxicol.
Lett., 7(6), 433-437.
Jabbonsky,
L. (1992). Aspartame by another name. Beverage
World, 111(1509), 6. Retrieved
from
http://search.proquest.com.ezproxy.lib.vt.edu:8080/docview/
213236593/fulltext?accountid=14826.
Kemp,
S. E. (2006). Low-calorie sweeteners. In Optimising
sweet taste in foods, (pp.175-251).
Cambridge, UK: Woodhead Publishing
in Food Science, Technology, and Nutrition.
Klotter,
J. (2011, June 1). Aspartame Myth. Townsend
Letter, 335, 85-87. Retrieved from
http://www.biomedsearch.com/article/Aspartame-myth/258828794.html.
Lajtha,
A., Reilly & M. A., Dunlop, D. S. (1994). Aspartame consumption: lack of
effects on
neural
function. J. Nutr. Biochem., 5, 266-283. doi:http://dx.doi.org/10.1016/0955-
2863(94)90032-9.
Leon, A. S., Hunninghake, D. B.,
Bell, C., Rassin, D. K., & Tephly, T. R. (1989). Safety of long-
term large doses of aspartame. Arch.
Intern. Med., 149(10), 2318-2324.
doi:http://dx.doi.org/
10.1001/archinte.149.10.2318.
Lim, U., Subar, A. F., Mouw, T., Hartge, P., Morton, L. M., Stolzenberg-Solomon, R.,
Campbell, D., Hollenbeck, A. R., & Schatzkin, A. (2006). Consumption of Aspartame-Containing Beverages and Incidence of Hematopoietic and Brain Malignancies. Cancer. Epidem. Biomar., 15, 1654-1659. doi:http://dx.doi.org/10.1158/1055-9965.epi-06-0203.
Lindseth,
G. N., Coolahan, S. E., Petros, T. V., & Lindseth, P. D. (2014).
Neurobehavioral
Effects of
Aspartame Consumption. Res. Nurs.
Health., 37, 185-193. doi:http://dx.doi.org/10.1002/nur.21595.
Lipton, R. B., Newman, L. C., Cohen,
J. S., & Solomon, S. (1989).
Aspartame as a dietary
trigger of headache. J.
Headache Pain, 29(2), 90-92.
doi:http://dx.doi.org/
10.1111/j.1526-4610.1989.hed2902090.x.
London,
R.S. (1988). Saccharin and aspartame. Are they safe to
consume during pregnancy? J.
Reprod. Med., 33(1), 17-21.
Magnuson,
B. (2010). Aspartame--facts and fiction. New.
Zeal. Med. J., 123(1311), 53.
Marinovich,
M., Galli, C. L., Bosetti, C., Gallus, S., & La Vecchia, C. (2013). Aspartame,
low
calorie
sweeteners and disease: Regulatory safety and epidemiological issues. Food.
Chem. Toxicol.,
60,109-115.
doi:http://dx.doi.org/10.1016/j.fct.2013.07.040.
Martini,
B. & Hum, D. (2012, August 13).
Mothers Using Aspartame in Pregnancy & Autism
Epidemic:
The FDA Knew it Would Happen. Retrieved
from
http://rense.com/general95/mothers.html.
Nill,
A.G. (2000). The History of Aspartame. Retrieved
from Digital Access to Scholarship at
Harvard.
(http://dash.harvard.edu/bitstream/handle/1/8846759/Nill,_Ashley_-
_The_History_of_Aspartame.pdf?sequence=3).
Olney,
J.W. (1981). Excitatory neurotoxins as food
additives: an evaluation of risk.
Neurotoxicology, 2(1), 163-192.
O’Mullane,
M., Fields, B., & Stanley, G. (2014). Food Additives. Enc. Food.
Saf., 2, 477-484.
doi:http://dx.doi.org/10.1016/B978-0-12-378612-8.00231-6.
Oppermann,
J.A., Muldoon, E., & Ranney, R.E. (1973). Effects of aspartame on
phenylalanine
metabolism
in the monkey. J. Nutr., 103(10),
1460-1466.
Overley,
J. (2014, October 27). FDA Rejects Ban On Diet Soda Sweetener Aspartame. Law360.
Retrieved
from http://www.law360.com/articles/590576/fda-rejects-ban-on-diet-soda-
sweetener-aspartame.
Oyama, Y. (2002).
Cytotoxic effects of methanol, formaldehyde, and formate on dissociated
rat
thymocytes: a possibility of
aspartame toxicity. Cell Biol. Toxicol, 18(1), 43-
50.
doi:http://dx.doi.org/10.1023/A:1014419229301.
Renwick,
A. G. (1985). The fate of intense sweeteners in the body. Food. Chem., 16(3-4), 281-
Reynolds,
W. A., Butler, V., & Lemkey-Johnston, N. (1976). Hypothalamic morphology
following
ingestion of aspartame or MSG in the neonatal rodent and primate: a
preliminary
report. J. Toxicol. Env. Health., 2(2), 471-480.
doi:http://dx/doi.org/10.1080/15287397609529448.
Ryan,
N. (1991, July 15). End of patent to alter market for NutraSweet. Chicago Tribune.
Retrieved
from http://articles.chicagotribune.com/1991-07-
15/business/9103190881_1_alitame-aspartame-sweeteners.
Schiffman, S. S.,
Buckley, C. E., III, Sampson, H. A., Massey, E. W., Baraniuk, J. N., Follett,
J.
V., & Warwick, Z. S.
(1988). Aspartame and susceptibility to headache. New Engl. J.
Med., 317(19), 1181-1185.
doi:http://dx.doi.org/10.1056/NEJM198711053171903.
Shaban,
H. M. & Albert, M. L. (1988) Aspartame: an evaluation of adverse effects. Hosp.
Formul., 23(6), 543-546.
Shapiro,
E. (1989, November 19). NutraSweet’s Bitter Fight. The New York Times.
Retrieved
from
http://www.nytimes.com/1989/11/19/business/nutrasweet-s-bitter-
fight.html?pagewanted=all.
Shaywitz, B. A.,
Sullivan, C. M., Anderson, G. M., Gillespie, S. M., Sullivan, B., & Shaywitz,
S.
E. (1994). Aspartame, behavior, and cognitive function
in children with attention deficit
disorder. J.
Pediatr., 93(1), 70-75.
Shigeta, H., Yoshida,
T., Nakai, M., Mori, H., Kano, Y., Nishioka, H., Kajiyama, S., Kitagawa,
Y., Kanatsuna, T.,
Kondo, M., & Otsuki, K. (1985).
Effects of aspartame on diabetic rats
and diabetic patients. J.
Nutr. Sci. Vitaminol., 31(5), 533-540.
doi:http://dx.doi.org/10.3177/jnsv.31.533.
Simintzi,
I., Schulpis, K. H., Angelogianni, P., Liapi, C., & Tsakiris, S. (2007).
The effect of
aspartame
metabolites on the suckling rat frontal cortex acetyl cholinesterase. An in vitro
study.
Food. Chem. Toxicol., 45(12),
2397-2401.
doi:http://dx.doi.org/10.1016/j.fct.2007.06.016.
Soffritti, M., Belpoggi,
F., Tibaldi, E., Esposti, D. D., & Lauriola, M. (2007). Life-span
exposure to low doses of
aspartame beginning during prenatal life increases cancer
effects in rats. Environ.
Health Persp., 115(9), 1293-1297.
doi:http://dx.doi.org/10.1289/ehp.10271.
Smyth,
T. R. (1983). The FDA’s Public Board of Inquiry and the Aspartame Decision. Indiana
Law Journal, 58(4), 3, 627-649. Retrieved from
http://www.repository.law.indiana.edu/ilj/vol58/iss4/3?utm_source=www.repository.law.
indiana.edu%2Filj%2Fvol58%2Fiss4%2F3&utm_medium=PDF&utm_campaign=PDFC
overPages.
Spiers, P. A.,
Sabounjian, L., Reiner, A., Myers, D. K., Wurtman, J., & Schomer, D. L.
(1998).
Aspartame:
neuropsychologic and neurophysiologic evaluation of acute and chronic
effects. Am. J. Clin. Nutr., 68(3), 531-537.
Stegink, L. D., Brummel,
M. C., Persoon, T. J., Filer, L. J., Jr., Bell, E. F., & Ziegler, E. E.
(1990). Effect of sucrose on the metabolic
disposition of aspartame. Am. J. Clin. Nutr.,
52(2), 335-341.
Stegink,
L.D., Filer, L.J., Jr., & Baker, G.L. (1977). Effect of aspartame and
aspartate loading
upon
plasma and erythrocyte free amino acid levels in normal adult volunteers. J.
Nutr.,
107(10),
1837-1845.
Thomas,
P. (2005, September). Aspartame. The
Ecologist, 35(7), 36-46.
Trocho, C., Pardo, R.,
Rafecas, I., Virgili, J., Remesar, X., Fernández-López, J. A., & Alemany,
M. (1998). Formaldehyde derived from dietary aspartame
binds to tissue components in
vivo. Life Sci., 63(5), 337-349. doi:http://dx.doi.org/ 10.1016/S0024-3205(98)00282-3.
Wahba,
P. (2014, June 27). Pepsi and Coke’s new
cola war challenger? Zevia. Retrieved from
http://fortune.com/2014/06/27/zevia-pepsi-coke/.
Warner,
M. (2006, February 12). The Lowdown on Sweet. The New York Times.
Retrieved from
http://www.nytimes.com/2006/02/12/business/yourmoney/12sweet.html?pagewanted=all
&_r=2&.
Warner,
M. (2004, December 22). A Something Among the Sweet Nothings. The New York
Times. Retrieved from
http://www.nytimes.com/2004/12/22/business/22splenda.html?_r=1&.
What’s
the Deal with Stevia. (n.d.). Retrieved November 21, 2014, from www.diabetes.org/food-
and-fitness/food/what-can-i-eat/understanding-carbohydrates/artificial-sweeteners/.
Wilson,
J. (2014, September 25). Soda makers want
to cut calories: But is diet really better.
Retrieved
from http://www.cnn.com/2014/09/24/health/soda-makers-cut-
calories/index.html.
Wolraich, M. L., Lindgren, S. D., Stumbo, P. J., Stegink, L.
D., Appelbaum, M. I., & Kiritsy, M.
C. (1994). Effects of diets high in sucrose or aspartame
on the behavior and cognitive
performance of children. New
Engl. J. Med., 330(5), 301-307.
doi:http://dx/doi.org/ 10.1056/NEJM199402033300501.
Yellowlees,
H. (1983, September 24). Aspartame. Brit.
Med. J., 287(6396), 912-913.
doi:http://dx.doi.org/10.1136/bmj.287.6396.912-d.
Yokogoshi,
H., Roberts, C.H., Caballero, B., & Wurtman, R.J. (1984). Effects of
aspartame and
glucose
administration on brain plasma levels of large neutral amino acids and brain 5-
hydroxyindoles. Am. J.
Clin. Nutr., 40(1), 1-7.