Aspartame controversy

The artificial sweetener aspartame has been the subject of public controversy regarding its safety and the circumstances around its approval. Many studies have recommended further investigation into the possible connection between aspartame and diseases such as brain tumors, brain lesions, and lymphoma. These findings, combined with alleged conflicts of interest in the approval process, have engendered vocal activism regarding the possible risks of aspartame. In 1987 the US Government Accountability Office concluded that the food additive approval process had been followed for aspartame.

Reported effects

In 1995, FDA Epidemiology Branch Chief Thomas Wilcox reported that aspartame complaints represented 75% of all reports of adverse reactions to substances in the food supply from 1981 to 1995. Author Barbara Mullarkey reproduced a U.S. Department of Health and Human Services Memorandum that includes in their list 92 aspartame symptoms and health conditions reported by physicians and consumers.

Questions have been asked by some scientists about brain cancer, lymphoma, and genotoxic effects such as DNA-protein crosslinks, but these questions are not based on reported case histories.

The sources for reported symptoms and health conditions that have raised questions include:

1. Reports and analysis of case histories in scientific journals and at medical conferences
2. Symptoms reported to the FDA and other governmental agencies
3. Symptoms reported to non-governmental organizations, researchers, and physicians
4. Reports of symptoms and health conditions in the media
5. Self-reported cases on the Internet.

There is debate in the scientific and medical community as to whether these symptoms are caused by exposure to aspartame. Some human and animal studies have found adverse effects and some have found no adverse effects. It is not only the results of the research that have been questioned, but the design of the research that led to specific outcomes. For example, in human research on aspartame, the aspartame is usually provided in slow-dissolving capsules. But the concentration of aspartate in the blood from ingesting aspartame using slow-dissolving capsules is much lower than that from ingesting liquid aspartame (such as in carbonated beverages).

Some human studies provide more than the daily allowance of aspartame, but in an encapsulated form. Based on the above-cited research, the equivalent amount of “real-world” aspartame in these human studies would be less. Other questions that have been raised about aspartame research involve the length of the studies, the number of test subjects, conflict of interest issues, and improper testing procedures .

The US Air Force issued an alert in 1992, warning air force pilots about drinking diet drinks containing aspartame before flying.

The debate over possible adverse health effects has focused mainly on four metabolites of aspartame:

Methanol and formaldehyde

Approximately 10% of aspartame (by mass) is broken down into methanol in the small intestine. Most of the methanol is absorbed and quickly converted into formaldehyde and then to formic acid. Some scientists believe that the metabolism of aspartame does not damage the body because: (a) the quantity of methanol produced is too small to disrupt normal physiological processes; (b) methanol and formaldehyde are natural by-products of human metabolism and are safely processed by various enzymes; (c) there is more methanol in some natural fruit juices and alcoholic beverages than is derived from aspartame ingestion. and (d) even large doses of pure methanol have been shown in non-human primate studies to lead to ample accumulation of formic acid (as formate), while no formaldehyde was detected. Formate is toxic because it inhibits mitochondrial cytochrome c oxidase, causing the symptoms of hypoxia at cellular level, and also causing metabolic acidosis among a variety of other metabolic disturbances. One of the common symptoms seen in methanol poisoning is permanent blindness by destruction of the optic nerve.

Other experts and scientists believe that (a) fruit juices and alcoholic beverages contain protective chemicals such as ethanol that block conversion of methanol into formaldehyde, while beverages with aspartame contain no "protective factors"; (b) exposure to very low levels of methanol and formaldehyde have been proven to cause chronic toxicity in humans;(c) the low levels of methanol and formaldehyde in natural human metabolism are tightly-controlled and small increases above these levels can contribute to chronic poisoning.; and (d) independent research has shown formaldehyde accumulation from aspartame ingestion.

In 1998, a team of scientists in Spain conducted an experiment on rodents to indirectly measure the levels of formaldehyde adducts in the organs after ingestion of aspartame. They did this by radiolabeling the methanol portion of aspartame. The scientists concluded that formaldehyde bound to protein and DNA accumulated in the brain, liver, kidneys and other tissues after ingestion of either 20 mg/kg or 200 mg/kg of aspartame. However, representatives of the manufacturer of aspartame have argued that these scientists were not directly measuring formaldehyde, but simply measuring levels of some by-product of the methanol from aspartame. The researchers have stated that the data in the experiment prove it was formaldehyde.

Phenylalanine

One of the moieties of the aspartame molecule is phenylalanine, which is unsafe for those born with phenylketonuria, a rare genetic condition. Phenylalanine is one of the nine essential amino acids and is commonly found in foods. Approximately 50% of aspartame (by mass) is broken down into phenylalanine, which is considered safe for everyone except sufferers of phenylketonuria. Because aspartame is metabolized and absorbed very quickly (unlike phenylalanine-containing proteins in foods), it is known that aspartame could spike blood plasma levels of phenylalanine. The debate centers on whether a significant spike in blood plasma phenylalanine occurs at typical aspartame ingestion levels, whether a sudden influx of phenylalanine into the bloodstream adversely affects uptake of other amino acids into the brain and the production of neurotransmitters (since phenylalanine competes with other Large Neutral Amino Acids (LNAAs) for entry into the brain at the blood brain barrier), and whether a significant rise in phenylalanine levels would be concentrated in the brain of fetuses and be potentially neurotoxic.

Based on anecdotes from aspartame users, measuring levels of neurotransmitters in the brains of animals and measuring the potential of aspartame to cause seizures in animals, some scientists think that aspartame may affect neurotransmitter production. They think that even a moderate spike in blood plasma phenylalanine levels from typical ingestion may have adverse consequences in long-term use. They are especially concerned that the phenylalanine can be concentrated in fetal brains to a potentially neurotoxic level. However, other scientists think that a rise in blood plasma phenylalanine is negligible in typical use of aspartame and their studies show no significant effects on neurotransmitter levels in the brain or changes in seizure thresholds. In addition, they say that proven adverse effects of phenylalanine on fetuses has only been seen when blood phenylalanine levels stay at high levels as opposed to occasionally being spiked to high levels.

An alternative sweetener, neotame, has been developed apparently to solve the phenylalanine problem said to be associated with aspartame.

Aspartic acid

Food contains aspartic acid as an amino acid bound to proteins. Approximately 40% of aspartame (by mass) is broken down into aspartic acid. Because aspartame is metabolized and absorbed very quickly (unlike aspartic acid-containing proteins in foods), it is known that aspartame can spike blood plasma levels of aspartate to very high levels. Large spikes in blood plasma aspartate levels have not been seen when ingesting natural foods.

Aspartic acid belongs to a class of chemicals that in high concentrations act as an excitotoxin, inflicting damage on brain and nerve cells. Aspartate does not normally cross the blood-brain barrier in most parts of the brain without active uptake by transporters. High levels of excitotoxins have been shown in hundreds of animal studies to cause damage to areas of the brain unprotected by the blood-brain barrier and a variety of chronic diseases arising out of this neurotoxicity. The debate among scientists has been raging since the early 1970s, when Dr. John Olney found that high levels of aspartic acid caused damage to the brains of infant mice. Dr. Olney and consumer attorney James Turner filed a protest with the FDA to block the approval of aspartame. The debate is complex and has focused on several areas: (a) whether the increase in plasma aspartate levels from typical ingestion levels of aspartame is enough to cause neurotoxicity in one dose or over time, (b) whether humans are susceptible to the neurotoxicity from aspartic acid seen in some animal experiments, (c) whether aspartic acid increases the toxicity of formaldehyde, (d) whether neurotoxicity from excitotoxins should consider the combined effect of aspartic acid and other excitotoxins such as glutamic acid from monosodium glutamate. The neuroscientists at a 1990 meeting of the Society for Neuroscience had a split of opinion on the issues related to neurotoxic effects from excitotoxic amino acids found in some additives such as aspartame.

Some scientists think that humans and other primates are not as susceptible to excitotoxins as rodents and therefore there is little concern with aspartic acid from aspartame. While they agree that the combined effects of all food-based excitotoxins should be considered, they believe that their measurements of the blood plasma levels of aspartic acid after ingestion of aspartame and monosodium glutamate demonstrate that there is not a cause for concern. Other scientists think that primates are susceptible to excitotoxic damage and that humans concentrate excitotoxins in the blood more than other animals. Based on these findings, they think that humans are approximately 5-6 times more susceptible to the effects of excitotoxins than are rodents. While they agree that typical use of aspartame does not spike aspartic acid to extremely high levels in adults, they are particularly concerned with potential effects in infants and young children, the potential long-term neurodegenerative effects of small-to-moderate spikes on plasma excitotoxin levels, and the potential dangers of combining formaldehyde exposure from aspartame with excitotoxins given that chronic methanol exposure increases excitoxin levels in susceptible areas of the brain and that excitotoxins may potentiate formaldehyde damage.

Aspartylphenylalanine diketopiperazine

This type of diketopiperazine (DKP) is created in products as aspartame breaks down over time. For example, researchers found that 6 months after aspartame was put into carbonated beverages, 25% of the aspartame had been converted to DKP. Concern among some scientists has been expressed that this form of DKP would undergo a nitrosation process in the stomach producing a type of chemical that could cause brain tumors. Other scientists think that the nitrosation of aspartame or the DKP in the stomach would not produce a chemical that would cause brain tumors. In addition, only a minuscule amount of the nitrosated chemical would be produced. There are very few human studies on the effects of this form of DKP. However, a (one-day) exposure study showed that the DKP was tolerated without adverse effects.

Recently published research

Mario Negri research institute

A 2007 study, published in Annals of Oncology of the European Society for Medical Oncology, reviewed Italian studies of instances of cancer from 1991 and 2004 and concluded a "lack of association between saccharin, aspartame and other sweeteners and the risk of several common neoplasms".

Ramazzini Foundation

Since the FDA approved aspartame for consumption in 1981, some researchers have suggested that a rise in brain tumor rates in the United States may be at least partially related to the increasing availability and consumption of aspartame. The results of a large seven-year study into the long-term effects of eating aspartame in rats by the European Ramazzini Foundation for cancer research in Bologna, Italy were released in July 2005. In the study of 1,800 rats, the research concluded that aspartame administered at varying levels in feed causes a statistically significant increase of lymphomas-leukemias and malignant tumors of the kidneys in female rats and malignant tumors of peripheral nerves in male rats. The study showed that there was no statistically significant link between aspartame and brain tumors.

The Ramazzini study, published in Environmental Health Perspectives, raised concerns about the levels of aspartame exposure. While a review by the American Food & Drug Administration's (FDA) of the Razzamini study was still pending, the European Food Safety Authority (EFSA) issued a press release about the report fairly promptly.

The EFSA's press release about the Ramazzini study, published on 5 May 2006, concluded that the increased incidence of lymphomas/leukaemias reported in treated rats was unrelated to aspartame, the kidney tumors found at high doses of aspartame were not relevant to humans, and that based on all available scientific evidence to date, there was no reason to revise the previously established Acceptable Daily Intake levels for aspartame. FDA later submitted its findings based on the evidence, and replied:

"Based on the available data (…) we have identified significant shortcomings in the design, conduct, reporting, and interpretation of this study. FDA finds that the reliability and interpretation of the study outcome is compromised by these shortcomings and uncontrolled variables, such as the presence of infection in the test animals."

The European Ramazzini Foundation responded to the EFSA press release, standing by their results and stating that they considered the 16% increase in incidence of lymphoma and leukemia between the aspartame group and control group signified that these cancers were caused by aspartame ingestion. As the EFSA felt it had already addressed this in their 5 May 2006 press release, no further press release was made. Betty Martini (founder of Mission Possible World Health International), in an open letter to the European Union Food Safety Authority states the EFSA's published conclusion regarding the Ramazzini study's raw data "is bizarre", and also draws attention to conflicts of interest regarding members of the EFSA's panel:

The Guardian on 15 May 2006 quoted EFSA Executive Director, Dr Herman Koeter:

"Dr Koeter said, he wanted to clear up misunderstandings about "conflicts of interest" among his advisory panel overseeing the review. MEPs complained last month that the scientist who chairs the advisory panel, Dr Susan Barlow, works for the International Life Sciences Institute, a body funded by sweetener manufacturers and major aspartame users such as Coca Cola, PepsiCo and Nestle, and Monsanto.

The European commission was also told by MEPs of other "conflicts of interest". One scientist involved in the review had declared a research grant from Ajinomoto, the leading Japanese manufacturer of aspartame, they said. Other panel members listed links with food processors such as Nestlé in their declarations of interest.

But to say that these scientists therefore have a conflict of interest was a misunderstanding, Dr Koeter explained to the Rome conference. 'The expertise required (to judge any new study on whether aspartame causes cancer) almost inevitably means having a previous involvement.' Eliminate the scientists who had worked in the area before or who had worked for industry and there would be no scientists left, he said. The panel had been 'fully impartial'."

In response Betty Martini produced "an open letter to EU safety authority about aspartame":

"He insults our intelligence. Are we to believe there are no scientists in Europe capable of conducting this study except those paid by the aspartame industry? The one thing Dr Koeter didn't get from the advisory panel was impartiality."

In response to criticism, the Ramazzini Foundation conducted a new study confirming the carcinogenic effects of aspartame from previous studies. The results of the study have been published in the academic journal Environmental Health Perspectives.

Second ERF study on the artificial sweetener aspartame by Dr Morando Soffritti of European Ramazzini Foundation Institute, entitled "Lifespan Exposure to Low Doses of Aspartame Beginning During Prenatal Life Increases Cancer Effects in Rats" has been accepted for publication in Environmental Health Perspectives on June 14th 2007.

"The results of this carcinogenicity bioassay not only confirm, but also reinforce the first experimental demonstration of APM’s multipotential carcinogenicity at a dose level close to the acceptable daily intake (ADI) for humans. Furthermore, the study demonstrates that when lifespan exposure to APM begins during fetal life, its carcinogenic effects are increased.

In August 2007, the New Zealand Food Safety Authority (NZFSA) published a press release commenting upon the Italian study:

"... These studies were conducted in a way that could not possibly have provided any information about the toxicity of aspartame – or in fact anything else in the rats’ diet. The animals used were allowed to live until they died naturally, meaning that all the study did was show the results of ageing, which as we all know is a natural process that leads, inevitably, to death.

In fact, the only conclusion that can be drawn from the results is that aspartame appears to be safe because the studies showed that those rats fed it (even at very high doses) lived as long (if not longer) as untreated rats, despite consuming up to more than 100 times the ADI every day of their lives. If aspartame was as horrendously toxic as is being claimed, it would be logical to expect the rats dosed with it to have shortened life-spans. The conclusions drawn by the researchers were clearly not backed up by their own data."

National Cancer Institute

A study published in April 2006 sponsored by the National Cancer Institute involved 340,045 men and 226,945 women, ages 50 to 69, found no statistically significant link between aspartame consumption and leukemias, lymphomas or brain tumors. The study used surveys filled out in 1995 and 1996 detailing food and beverage consumption. The researchers calculated how much aspartame they consumed, especially from sodas or from adding the sweetener to coffee or tea. The researchers report, "Our findings from this epidemiologic study suggest that consumption of aspartame-containing beverages does not raise the risk of hematopoietic or brain malignancies."

Critics of this study point out that while the study looked at humans, it did not look at lifelong aspartame consumption as did the Ramazzini study on rats. The Ramazzini study simulated lifelong consumption from childhood through old age (simulating 60 to 90 years of use). However the new National Cancer Institute study simply looked at subjects who consumed diet drinks during a twelve-month period from 1995 to 1996, without determining aspartame intake prior to the start of the study. Neurosurgeon Dr Russell Blaylock, commenting on the NCI study, remarked that "The greatest risk of leukemia and lymphoma would be in a younger population (young children and adolescents) and they would need to be exposed regularly from early in life." Given that aspartame has only been publicly available for about a quarter of a century (in France from 1979, the USA since 1982, and the UK since 1983), not one of the people examined in the NCI study could have ingested any aspartame product during their formative growth years, until they were at least into their mid-twenties.

The Ramazzini study had the disadvantage of being an animal study but looked at lifelong consumption of aspartame. The National Cancer Institute study was a human study, but only looked at a limited range of older subjects with relatively short-term consumption of diet drinks. Finally, the questionnaire did not ask users to estimate aspartame consumption, only diet drink consumption.

FDA approval process

Some critics of Aspartame use have expressed concerns about its approval. Specifically, they note that the head of the FDA, Jere E. Goyan, was removed from his post on the first day of Ronald Reagan's presidency (1981). Goyan had refused to approve the use of aspartame due to studies documenting increase of cancers in rats. Reagan appointed Arthur Hull Hayes, MD as FDA Commissioner in April 1981. In the same year Hayes approved aspartame as a food additive against an FDA Public Board of Inquiry (PBOI) recommendation. It is notable however that Hayes had available results from a new Japanese study which the PBOI chairman later claimed would have reversed his recommendation. In November 1983 Hayes quit and joined Searle's public-relations firm Burson-Marsteller as senior medical advisor.

Conflict of interest

In Survey of Aspartame studies: correlation of outcome and funding sources, Ralph G. Walton, Professor of Clinical Psychiatry, Northeastern Ohio Universities College of Medicine (NEOUCOM) , surveyed 166 studies of aspartame in peer reviewed medical literature. According to Walton's review, 74 studies had Nutrasweet industry related funding and 92 were independently funded. 100% of the industry funded research attested to aspartame's safety, whereas 92% (85 of 92) of the independently funded research identified a problem.

In a rebuttal to Walton's review, the 'Aspartame Information Service' (a service provided by Ajinomoto, a producer of aspartame and supplier to well known food and drink makers) states that of the 85 studies:

• 10 studies actually involve aspartate and not aspartame and are irrelevant to aspartame safety.
• 18 of the studies do not draw any negative conclusions about aspartame.
• 5 are reviews, not peer-reviewed studies.
• 2 are reports, not peer-reviewed studies.
• 5 are anecdotes, based on observations of patients.
• 11 are conference proceedings, not peer-reviewed studies.
• 19 are letters to medical journals.
• 3 are different reports of the same study.
• 2 are exact duplicates of other documents appearing in the list.
• 3 are different reports of the same allegations.

This totals 78 of 85 studies, leaving 7 independently funded studies that found a problem with aspartame, that the Aspartame Information Service did not find issue with.

Further reading

• Dr Joseph Mercola and Dr Kendra Pearsall, Sweet Deception: Why Splenda, NutraSweet, and the FDA May Be Hazardous to Your Health, (Nelson Books, November 2006). ISBN 0-78522-179-4 and ISBN-13 978-0785221791
• H.J. Roberts, MD, Aspartame Disease: An Ignored Epidemic, (Sunshine Sentinel Press, May 2001). ISBN 1-88424-317-7 and ISBN-13 978-1884243172.
• H.J. Roberts, MD, Breast Implants Or Aspartame (Nutrasweet) Disease? : The Suppressed Opinion About Perceived Medicolegal Travesty, (Sunshine Sentinel Press, July 1999). ISBN 1-88424-310-X and ISBN-13 978-1884243103.
• Miladie L. Dillard, Food Sweeteners - Aspartame and Its Adverse Reactions, Strange Symptoms, Illness Behavior and Controversy: Index of New Information With Authors and Subjects, (Abbe Pub Assn of Washington DC, Reprint edition, March 1997). ISBN 1-55914-850-0 and ISBN-13 978-1559148504.
• Russell L. Blaylock, MD, Excitotoxins: The Taste That Kills, (Health Press, December 1996). ISBN 0-92917-325-2 and ISBN-13 978-0929173252.
• Christian Tschanz (Editor), Harriett H. Butchko (Editor), W. Wayne Stargel (Editor), Frank N. Kotsonis (Editor), The Clinical Evaluation of a Food Additive: Assessment of Aspartame, (CRC, June 1996). ISBN 0-84934-973-7 and ISBN-13 978-0849349737.

Films

• Sweet Misery: A Poisoned World at IMDb (2004)
• Sweet Misery: A Poisoned World at Rotten Tomatoes (2004)

See also

• Canderel
• Equal (sweetener)
• Excitotoxicity
• G. D. Searle & Company
• NutraSweet
• Sugar substitute

External links

Pro-aspartame

• Deconstructing Web Pages - An exercise deconstructing a web page to determine its credibility as a source of information, using the aspartame controversy as the example.
• Aspartame Archives
• Sugar Substitutes (U.S. FDA web page)

Anti-aspartame

• Aspartame—DORway to Discovery - A repository for articles published by scientists, physicians, non-governmental organizations, media and laypersons related to aspartame.
• Aspartame Toxicity Information Center
• Aspartame—Truth About Stuff