Friday, January 9, 2015

Southern Baptist Hymnal

It's been a while since I posted, so I figured it's high time I get back on here and start writing. Last night, I posted on Facebook about how I sing to Hank every night and I usually cycle through the songs on the Johnny Cash album The Legend of Johnny Cash. Well, I decided I should probably change it up a bit. Tonight I sang a medley of my favorite songs out of the Southern Baptist hymnal. It was awesome. At least for me. I'd like to think it was for him too. And, wouldn't you know it, he fell asleep to one of my favorites... Come Thou Fount of Every Blessing. I was completely overcome. I couldn't help but realize how incredibly lucky I am. 


My gorgeous wife. And my incredibly cool youngest son. And I had this for dinner tonight!


The part that hit me tonight, and has on several nights before, is that this is temporary. It's a kind of dark thought, but I think it's an okay one to have. The appreciation of all that one's been given and the stark realization that nothing on this Earth lasts forever. Just like my time away from Amy while I'm on deployment makes me cherish her and our time together even more when I'm home, remembering that this won't last makes me appreciate my time with Jack, Emma and Hank even more than I already do.

- Matt

Monday, December 1, 2014

Aspartame - all you ever wanted to know....and more than I care to think about anymore






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.


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