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The artificial sweetener aspartame has been the subject of public controversy regarding its safety since 1974. Some scientific studies, combined with allegations of conflicts of interest in the approval process—which were refuted by an official US governmental inquiry—have been the focus of vocal activism and conspiracy theories regarding the possible risks of aspartame.

The conspiracy theories, claims of aspartame dangers, and the source of those claims have been the subject of critical examination. In 1987, the US Government Accountability Office concluded that the food additive approval process had been followed for aspartame. Based on government research reviews and recommendations from advisory bodies such as the European Commission’s Scientific Committee on Food and the Joint FAO/WHO Expert Committee on Food Additives, aspartame has been found to be safe for human consumption by more than ninety countries world-wide. In 1999 Jon Henkel reported that the U.S. Food and Drug Administration scientists believe that the safety of aspartame is "clear cut" and "one of the most thoroughly tested and studied food additives the agency has ever approved." As of 2008, however, concerns still exist among some scientists over aspartame's role in certain mental disorders, compromised learning, and emotional functioning, although other scientists are not concerned. According to a 2007 safety evaluation, the weight of existing evidence indicates that aspartame is safe at current levels of consumption as a non-nutritive sweetener.

Origins of the aspartame controversy

The controversy about aspartame safety finds its origin in some individual scientific studies, as well as in false rumors spread over the internet.

Approval in the United States

Controversy surrounding the approval process led Senator Howard M. Metzenbaum to request a report by the Government Accountability Office (GAO) of aspartame's approval. The GAO concluded that protocol was followed, although it did not analyze aspartame's safety. The GAO provided a timeline of the events. Aspartame was originally approved for use in dry foods in 1974 by then Commissioner Alexander Schmidt after review by the FDA's Center for Food Safety and Applied Nutrition, but G.D. Searle, its creator, was not allowed to market it until 1981 because of questions surrounding the reliability of its data. Searle initially submitted 168 studies on aspartame, including 7 animal studies which were considered crucial by the FDA and one controversial study on whether aspartame caused seizures in monkeys. Soon after aspartame was approved, three objections were filed, including one by the scientist John Olney and another by James Turner, a public-interest lawyer who partnered with Olney. A Public Board of Inquiry was planned, but delayed because the FDA noticed problems with Searle's laboratory practices and inaccuracies in its data on two other drugs. The FDA Commissioner appointed an FDA task force to investigate 3 of Searle's studies while the Universities Associated for Research and Education in Pathology (UAREP) examined 12 others. Errors were found, but CFSAN concluded that they were not significant. In 1980 the Public Board of Inquiry (PBOI) of three university scientists (one from each list provided by CFSAN, Searle, and Olney) heard John Olney's objections, and responded by revoking aspartame's approval because of concerns over the reliability of two of the three crucial studies related to brain cancer. In 1981 FDA Commissioner Arthur Hull Hayes set up another panel, which did not reach consensus on aspartame's safety, but in 1981 the Commissioner overturned the PBOI's decision and approved aspartame. Hayes justified his approval through the results of a Japanese brain tumor study, the results of which, the PBOI chairman later said, would have resulted in an "unqualified approval" from the PBOI panel. Several objections followed, but all were denied. In November 1983, Hayes left the FDA and joined Searle's public-relations firm Burson-Marsteller as senior medical advisor, a decision which would fuel conspiracy theories.

Scientific Studies

According to a poll in 1987, most scientists doubted aspartame's safety Later on, some scientists have recommended further investigation into any possible connection between aspartame and diseases such as brain tumors, brain lesions, mental disorders, and lymphoma. In one study, rats given the recommended daily maximum dose of aspartame had altered oncogene and suppressor gene expression. These studies, combined with allegations of conflicts of interest in the approval process—which were refuted by an official US governmental enquiry—have been the focus of vocal activism and conspiracy theories regarding the possible risks of aspartame.

Several large scientific assessments of available research by expert panels have refuted the claims of negative health effects attributed to aspartame. Food safety authorities worldwide have set acceptable daily intake (ADI; the amount of substance that can be consumed daily over a lifetime without appreciable health risk to a person on the basis of all the known facts at the time of the evaluation) values for aspartame at 40 mg/kg of body weight based on a 1980 Joint FAO/WHO Expert Committee on Food Additives recommendation. JECFA re-confirmed its evaluation in a later addendum to its monograph) and the same value was approved in a December 2002 evaluation of all aspartame research by the European Commission’s Scientific Committee on Food. The FDA has set its ADI for aspartame at 50 mg/kg.

A 12 ounce can of diet soda contains 180 mg of aspartame, and one liter of aspartame-sweetened soda contains 600 mg aspartame. U.S. diet beverage consumers average approximately 200 mg of daily aspartame consumption. For a 75 kilograms (165 lb) adult, it takes approximately 21 cans of diet soda to consume the 3,750 mg of aspartame that would surpass the the FDA's 50 mg/kg ADI of aspartame. Surveys of aspartame intake, particualrly via diet soda, indicate that even high consumers of aspartame are typically "well below" the 40 mg/kg ADI. The European Commission’s Scientific Committee on Food concluded in 2002 that, while some minor effects on health may occur at very high doses, no effects are expected at normal levels of consumption.

In 1987, the US Government Accountability Office concluded that the food additive approval process had been followed for aspartame. Based on government research reviews and recommendations from advisory bodies such as those listed above, aspartame has been found to be safe for human consumption by more than ninety countries world-wide.

Internet rumors and activism

The FDA approval of aspartame and claims of deleterious medical effects attributed to aspartame have been the subject of a conspiracy theory, widely distributed on the internet and via email.

Internet sites are commonly the source of claims against the safety of aspartame. Some websites contain claims, attributed to "Nancy Markle", that include allegations that aspartame is responsible for multiple sclerosis, systemic lupus, and methanol toxicity, causing "blindness, spasms, shooting pains, seizures, headaches, depression, anxiety, memory loss, birth defects" and death.

In late 1995, misleading and inaccurate information about aspartame started spreading on the Internet. This rash of Internet misinformation was based on an email signed "Nancy Markle", allegedly based on Markle's talks at the "World Environmental Conference". According to the Media Awareness Network, Markle does not appear to exist, and investigators suspect that the real author of the email was anti-aspartame activist Betty Martini, who posted a host of similar messages to Usenet newsgroups in late 1995 and early 1996. She believes that there is a conspiracy between the FDA and the producers of aspartame. This conspiracy theory has been discussed on several major internet conspiracy theory and urban legend websites. Although most of her allegations contradict the bulk of medical evidence, this email started spreading over the world as a chain email since mid-December 1998, leaving traces on many websites, such as those citing an association between aspartame and systemic lupus. It has become an urban legend that continues to scare consumers.

An Editor's Note from the Multiple Sclerosis Foundation describes the nature of the "hoax":

"The report claiming aspartame causes MS, often referred to as the Nancy Merkle hoax, is believed to have been circulating since 1995. The message is attributed to "Nancy Merkle," yet no one has come forward claiming to be the author. No credentials, research or sources are cited. This hoax first came to the attention of the Multiple Sclerosis Foundation in 1998, when those circulating it added the false claim that the MSF was suing the U.S. Food and Drug Administration to halt the sale and use of aspartame. The MSF neither condemns nor endorses aspartame, and has never filed suit against the FDA."

Reported effects

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Some human and animal studies have found adverse effects associated with very high dosages of aspartame, or in certain susceptible groups. Some scientific studies showed adverse effects with doses less than the ADI. Some studies 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.

The debate over possible adverse health effects has focused mainly on four metabolites of aspartame: methanol, phenylalanine, aspartic acid, and aspartylphenylalanine diketopiperazine.

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 research has indicated formaldehyde accumulation from aspartame ingestion. However, 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.

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, these scientists were not directly measuring formaldehyde, but simply measuring levels of some by-product of the methanol from aspartame.

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. Scientists have reported 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 (aspartate), an amino acid in the structure of 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.

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 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. John Olney found in 1970 that high levels of aspartic acid caused damage to the brains of infant mice. Olney and consumer attorney James Turner filed a protest with the FDA to block the approval of aspartame.

Humans and other primates are not as susceptible to excitotoxins as rodents and therefore comparisons to human safety are problematic. The measurements of the blood plasma levels of aspartic acid after ingestion of aspartame and monosodium glutamate do not indicate to human subject researchers a cause for concern. One group was 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

Aspartylphenylalanine diketopiperazine, a 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. However, the nitrosation of aspartame or the DKP in the stomach likely does not produce chemicals that cause brain tumors. In addition, only a minuscule amount of the nitrosated chemical can 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

In 1996, John Oleny suggested that a rise in brain tumor rates in the United States could be partially related to the increasing availability and consumption of aspartame.

In 2006, the results of a large seven-year study into the long-term effects of eating aspartame in rats by the European Ramazzini Foundation Institute were published. The study of 1,800 rats found that aspartame administered at varying levels in feed led to 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 found no statistically significant link between aspartame and brain tumors. Shortly thereafter, the European Food Safety Authority (EFSA) issued a press release about the Ramazzini study on 5 May 2006. The EFSA stated 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.

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 to criticism, the Ramazzini Foundation conducted a new study entitled "Lifespan Exposure to Low Doses of Aspartame Beginning During Prenatal Life Increases Cancer Effects in Rats", confirming the carcinogenic effects of aspartame from previous studies. The Foundation stated: "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) disparaged the significance of the new study with a in a press release:

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. ... 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.

This appears to life-span data from the 2006 paper, as Soffritti et al. did not directly compare life expectancies of control and treated rats in the 2007 paper.

A June 2008 letter reviewing the 2007 Soffritti paper stated the researchers ought to have improved upon the methodologic and conceptual weaknesses that had been present in the 2006 paper. Magnuson and Willams state that:

1. The aspartame dosages were not given properly: "The doses are 'estimates' based on assuming constant food consumption of 20 g/day and constant body weights of 400 g for each rat from in utero (fetal day 12) to death."
2. The rats entered the study prenatally, but the researchers did not provide necessary information on the parents, the pregnancies, the condition of the pups at birth, food consumption by mother rats while pregnant and nursing -- all important to figuring out if the control and treatment groups are properly matched.
3. The lymphoma/leukemia incidences in the high-dose group were in or near historical control ranges.
4. Many of the studied rats were infected with a chronic form of pneumonia that causes an increase in lymphoma. "Therefore, we believe it is highly likely that the present findings are due to infection and not aspartame consumption."
5. The high-dose breast cancer rates were similar to historical controls.
6. No data were provided on in utero exposure.

Soffritti responded to Magnuson's letter with the following statements:

1. Magnuson and Williams’s letter is substantially a repetition of the arguments set forth in a recent article (Magnuson et al. 2007), which was a "safety evaluation" sponsored entirely by Ajinomoto, the manufacturer of aspartame.
2. The incidence of lymphomas/leukemias observed in both sexes treated with 2,000 ppm aspartame is nearly double the concurrent control (Soffritti et al. 2007). The suggestion that concurrent control data should be ignored is contrary to the widely accepted standard of good laboratory science.
3. We observed the diffusion of neoplastic tissue not only in the lung but also concurrently in various organs (liver, spleen, mediastinal and other lymph nodes).
4. The idea that we must provide a "biologically plausible explanation" for human or rodent carcinogens is a time-honored approach to postpone or prevent the application of regulatory measures to minimize carcinogenic risks.

The 2006 study was conducted with 1,900 rats, as opposed to the 280 to 688 rodents used in Searle's studies, and the rats lived for up to three years instead of being sacrificed after two. Dr. Soffritti said:

Cancer is a disease of the third part of life. You have 75 percent of cancer diagnoses for people who are 55 years old or older. So if you truncate the experiments at 110 weeks and the rats are supposed to survive until 150 to 160 weeks, it means you avoid the development of cancer at the time when cancer would be starting to arise.

A study from 2008 concluded that a two-year exposure for identifying chemical carcinogens is too short and that the 3-year period, as was used by Ramazzini, should become a standard for future research.

In June 2007, 12 U.S. environmental health experts wrote a letter to the FDA to urge them to immediately commence a careful review of the Ramazzini study. The letter stated it raised new serious questions about the safety of the artificial sweetener aspartame.

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."

In a response, Dr. Soffritti wrote:

Without specific information on each individual’s consumption rate and duration it is difficult to assess the power of the survey, in spite of the large number of participants. The second related issue is whether aspartame is an early-or late-stage carcinogen. If it is an early-stage initiator of cancer, then reporting the lack of effects in older individuals who have not consumed aspartame since early childhood would be expected to show little or no increased cancer (Hoel 1985).

Political attempts to ban aspartame

In Hawaii, state politicians wanted to ban aspartame in 2008, even though there is a federal approval of the product, following a similar attempt by state legislators in New Mexico in 2007. In the Philippines, the small political party Alliance for Rural Concerns introduced House Bill 4747 in 2008 with the aim of having aspartame banned from the food supply. In 2007, the Indonesian government considered banning Aspartame.

Controversy in the UK and voluntary withdrawal by food retailers

Due to public concerns over artificial sweeteners, in 1997 the UK government introduced new regulations on sweeteners. These regulations say that manufacturers must state clearly next to the name of the product the phrase "with sweeteners". In 2007, the UK supermarket chains Sainsbury's, M&S and ASDA announced that they would remove aspartame from their own label products

Postulated conflict of interest prior to 1996

In 1996, Ralph G. Walton, then Professor of Clinical Psychiatry, Northeastern Ohio Universities College of Medicine, made a private survey of 166 studies of aspartame in peer reviewed medical literature prior to 1996. 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 (private and personal) 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.

See also

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

References

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External links

• 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.
• Sugar Substitutes (U.S. FDA web page)
• Centers for Disease Control: Evaluation of Consumer Complaints Related to Aspartame Use
• International Programme on Chemical Safety: Aspartame toxicology evaluation and further evaluation

• Misplaced Pages neutral point of view disputes from November 2008
• Articles with minor POV problems from December 2008
• Medical controversies
• Food safety