Aspartame controversy

The artificial sweetener aspartame has been the subject of several controversies since its initial approval by the U.S. Food and Drug Administration (FDA) in 1974. The FDA approval of aspartame was highly contested, with critics alleging that the quality of the initial research supporting its safety was inadequate and flawed and that conflicts of interest marred the approval of aspartame. In 1987, the U.S. Government Accountability Office concluded that the food additive approval process had been followed properly for aspartame. In spite of this, rumors, unsupported by medical evidence, propagate that numerous health conditions (such as multiple sclerosis, systemic lupus, methanol toxicity, blindness, spasms, shooting pains, seizures, headaches, depression, anxiety, memory loss, birth defects and death) are caused by the consumption of aspartame in normal doses. Publicity of this controversy has been spread through an elaborate health scare and "Internet smear campaign" involving the hoax "Nancy Markle" e-mails which widely circulated a conspiracy theory.

The potential health risks have been examined and dismissed by numerous scientific research projects. With the exception of the risk to those with phenylketonuria, aspartame is considered to be a safe food additive by governments, worldwide, and major health and food safety organizations. with FDA officials describing aspartame as "one of the most thoroughly tested and studied food additives the agency has ever approved" and its safety as "clear cut". The weight of existing scientific evidence indicates that aspartame is safe as a non-nutritive sweetener.

History of approval and controversies over safety

The controversy over aspartame safety originated in perceived irregularities in the aspartame approval process during the 1970s and early 1980s, including allegations of a revolving door relationship between regulators and industry and claims that aspartame producer G.D. Searle had withheld and falsified safety data. In 1996, the controversy reached a wider audience with a 60 Minutes report that discussed criticisms of the FDA approval process and concerns that aspartame could cause brain tumors in humans. The 60 Minutes special stated that "aspartame's approval was one of the most contested in FDA history."

Around the same time, one of many Usenet posts authored by Betty Martini was possibly slightly altered (but still largely identical with originals) and then widely circulated under the pen name "Nancy Markle", creating the basis for a misleading and unverifiable hoax chain letter that was spread through the Internet. Numerous websites have spread the email's claims, which were not backed by scientific evidence, about safety issues purportedly linked to aspartame, including Gulf War Syndrome and lupus.

USFDA approval

Aspartame was originally approved for use in dry foods in 1974 by then FDA Commissioner Alexander Schmidt after review by the FDA's Center for Food Safety and Applied Nutrition. Searle had submitted 168 studies on aspartame, including seven animal studies that were considered crucial by the FDA. Soon afterwards, John Olney, a professor of psychiatry and prominent critic of MSG, along with James Turner, a public-interest lawyer and author of an anti-food-additive book, filed a petition for a public hearing, citing safety concerns. Other criticisms (presented in the 1996 60 Minutes special) of the Searle studies included assertions of unreported medical treatments that may have affected the study outcomes and discrepancies in the reported data. Schmidt agreed, pending an investigation into alleged improprieties in safety studies for aspartame and several drugs. In December 1975, the FDA placed a stay on the aspartame approval, preventing Searle from marketing aspartame. The Searle studies were criticized by the FDA commissioner as "... at best ... sloppy and suffering from "... a pattern of conduct which compromises the scientific integrity of the studies."

U.S. Attorney Samuel Skinner was requested to "open a grand jury investigation into whether two of Searle's aspartame studies had been falsified or were incomplete". Skinner withdrew from the case when he was considering a job offer from the law firm Sidley & Austin, Searle's Chicago-based law firm, a job he later took. The investigation was delayed and eventually the statute of limitations on the charges against Searle expired and a grand jury was never convened.

In 1977 and 1978, an FDA task force and a panel of academic pathologists reviewed 15 aspartame studies by Searle, and concluded that, although minor inconsistencies were found, they would not have affected the studies' conclusions. In 1980, a Public Board of Inquiry (PBOI) heard testimony from Olney and disagreed with his claims that aspartame could cause brain damage, including in the developing fetus. The board decided that further study was needed on a postulated connection between aspartame and brain tumors, and revoked approval of aspartame.

In 1981, FDA Commissioner Arthur Hull Hayes sought advice on the issue from a panel of FDA scientists and a lawyer. The panel identified errors underlying the PBOI conclusion that aspartame might cause brain tumors, and presented arguments both for and against approval. Hayes approved the use of aspartame in dry foods. Hayes further justified his approval with 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, a little more than a year after approving aspartame Hayes left the FDA and joined public-relations firm Burson-Marsteller, Searle's public relations agency at the time, as a senior medical adviser.

The actions of Samuel Skinner, in taking a job with a law firm retained by Searle during an investigation into Searle, and Arthur Hull Hayes, in taking a job with Searle's public relations agency following aspartame's approval, fueled conspiracy theories.

Because of the approval controversy, Senator Howard M. Metzenbaum requested an investigation by the U.S. Government Accountability Office (GAO) of aspartame's approval. In 1987, the GAO reported that protocol had been followed and provided a time-line of events in the approval process. The GAO review included a survey of scientists who had conducted safety reviews; of the 67 scientists who responded to a questionnaire, 12 had major concerns about aspartame's safety, 26 were somewhat concerned but generally confident in aspartame safety, and 29 were very confident in aspartame safety.

Food additive safety evaluations by many countries have led to approval of aspartame, citing the general lack of adverse effects following consumption in reasonable quantities. 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 worldwide.

Alleged conflict of interest prior to 1996

In 1976, the FDA notified then-U.S. attorney for Chicago, Sam Skinner, of the ongoing investigation of Searle, and in January 1977, formally requested that a grand jury be convened. In February, 1977, Searle's law firm, Sidley & Austin offered Skinner a job and Skinner recused himself from the case. Mr. Skinner's successor was in place several months later, and the statute of limitations for the alleged offenses expired in October 1977. Despite complaints and urging from DOJ in Washington, neither the interim U.S. attorney for Chicago, William Conlon, nor Skinner's successor, Thomas Sullivan, convened a grand jury. In December, 1977, Sullivan ordered the case dropped for lack of evidence. A year and a half later, Conlon also was hired by Sidley & Austin. Concern about conflict of interest in this case inflamed the controversy, and Senator Metzenbaum investigated in 1981 Senate Hearings. In 1989, the U.S. Senate approved the nomination of Sam Skinner to be Secretary of Transportation, noting that both Sullivan and Senator Metzenbaum had concluded that Skinner had not acted improperly.

Ralph G. Walton, a psychologist at Northeastern Ohio Universities College of Medicine, stated in a self-published 1996 analysis of aspartame research that industry-funded studies found no safety concerns while 84 of 92 independent studies did identify safety concerns. This analysis by Walton was submitted to the television show 60 Minutes and has been extensively discussed on the Internet. An analysis of Walton's claims showed that Walton left out at least 50 peer-reviewed safety studies from his review of the literature and that most of the research he cites as non-industry funded were actually letters to the editors, case reports, review articles or book chapters rather than published studies. In a rebuttal to Walton's statements, the Aspartame Information Service (a service provided by Ajinomoto, a primary producer and supplier of aspartame), reviewed the publications Walton cites as critical of aspartame, arguing that most of them do not involve aspartame or do not draw negative conclusions, are not peer-reviewed, are anecdotal, or are duplicates.

Internet hoax conspiracy theory

An elaborate health scare, involving a hoax conspiracy theory disseminated on many Internet websites, attributes a host of deleterious medical effects to aspartame. This theory claims that the FDA approval process of aspartame was tainted and cites as its source an email based upon a supposed talk by a "Nancy Markle" (whose existence has never been confirmed) at a "World Environmental Conference". Specifically, the hoax websites allege 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.

The "Markle" email was in large parts identical to many messages posted by Betty Martini (who sometimes writes as "Dr. Betty Martini" based upon an honorary Doctor of Humanities degree awarded by an unaccredited religious institution) to Usenet newsgroups in late 1995 and early 1996 about a talk at a "World Environmental Conference". Although the content was traced back to her, Martini, says that an unknown person plagiarized her original letter, combined with other information, and redistributed it as "Nancy Markle". The email has been described as an "Internet smear campaign ... Its contents were entirely false, misleading, and defamatory to various popular products and their manufacturers, with no basis whatever in fact."

The "Markle" email says that there is a conspiracy between the FDA and the producers of aspartame, and the conspiracy theory has become a canonical example discussed on several Internet conspiracy theory and urban legend websites. Although most of the allegations of this theory contradict the bulk of medical evidence, the misinformation has spread around the world as chain emails since mid-December 1998, influencing many websites as an urban legend that continues to scare consumers. The Media Awareness Network featured one version of it in a tutorial on how to determine the credibility of a web page. The tutorial implied that the "Markle" letter was not credible and stated that it should not be used as an authoritative source of information.

Dean Edell warned very strongly against the "Markle" letter:

Beware The E-Mail Hoax: The Evils Of Nutrasweet (Aspartame)

A highly inaccurate "chain letter" is being circulated via e-mail warning the reader of the health dangers of aspartame (Nutrasweet) diet drinks. There is so much scientific untruth in it, it's scary. Be careful, because others know how to manipulate you by this. Just because something is beyond your comprehension doesn't mean it is scientific. The e-mail is outrageous enough to state that the Multiple Sclerosis Foundation is suing the FDA for collusion with Monsanto ... Bogus, totally bogus. You've got to be careful of these Internet hoaxes. When you read health information online, be sure to know the source of the information you are reading, okay?

Government action and voluntary withdrawals

In 1997, due to public concerns the UK government introduced a new regulation obliging food makers who use sweeteners to state clearly next to the name of their product the phrase "with sweeteners".

In 2007, the Indonesian government considered banning aspartame. 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 the U.S. state of New Mexico a bill to ban aspartame was introduced in 2007, and subsequently rejected. A similar 2008 Hawaiian bill stalled in committee for lack of evidence. In March 2009, the California OEHHA identified aspartame as a chemical for consultation by its Carcinogen Identification Committee, in accordance with California state Proposition 65. So far no conclusions or updates have been published on the OEHHA website.

In 2007, the UK supermarket chains Sainsbury's, M&S, and Wal-Mart subsidiary Asda, announced that they would no longer use aspartame in their own label products. In April 2009, Ajinomoto Sweeteners Europe, one of the makers of aspartame in Europe, responded to Asda's "no nasties" campaign by filing a complaint of malicious falsehood against Asda in the English courts. In July 2009, Asda initially won the legal case after the trial judge construed the "no nasties" labelling to "not mean that aspartame was potentially harmful or unhealthy". The decision was reversed in June 2010, upon appeal, and was settled in 2011 with ASDA removing references to aspartame from its packaging.

In 2009, the South African retailer Woolworths announced it was removing aspartame from its own-brand foods.

In 2010, the British Food Standards Agency launched an investigation into aspartame amid claims that some people experience side-effects after consuming the substance. A significant proportion of volunteers participating in the study are those who have claimed to experience side-effects. The study has not yet been concluded, as the FSA had trouble finding enough volunteers.

In September 2011, the European Food Safety Authority (EFSA), which is due to release the findings of its full re-evaluation of aspartame in May 2013, made all 600 datasets it is using in its full re-evaluation available publicly. This includes previously unpublished scientific data, "including the 112 original studies on aspartame which were submitted to support the request for authorisation of aspartame in Europe in the early 1980s."

Safety and health effects

The safety of aspartame has been studied extensively since its discovery with research that includes animal studies, clinical and epidemiological research, and post-marketing surveillance, with aspartame being one of the most rigorously tested food ingredients to date. Peer-reviewed comprehensive review articles and independent reviews by governmental regulatory bodies have analyzed the published research on the safety of aspartame and have found aspartame is safe for consumption at current levels. Aspartame has been deemed safe for human consumption by over 100 regulatory agencies in their respective countries, including the UK Food Standards Agency, the European Food Safety Authority (EFSA) and Health Canada.

Intake

The acceptable daily intake (ADI) value for aspartame, as well as other food additives studied, is defined as the "amount of a food additive, expressed on a body weight basis, that can be ingested daily over a lifetime without appreciable health risk." The Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the European Commission's Scientific Committee on Food has determined this value is 40 mg/kg of body weight for aspartame, while FDA has set its ADI for aspartame at 50 mg/kg.

The primary source for exposure to aspartame in the United States is diet soft drinks, though it can be consumed in other products, such as pharmaceutical preparations, fruit drinks, and chewing gum among others in smaller quantities. A 12 US fluid ounce (355 ml) can of diet soda contains 180 milligrams (0.0063 oz) of aspartame, and for a 75 kg (165 lb) adult, it takes approximately 21 cans of diet soda daily to consume the 3,750 milligrams (0.132 oz) of aspartame that would surpass the FDA's 50 milligrams per kilogram of body weight ADI of aspartame from diet soda alone.

Reviews have analyzed studies which have looked at the consumption of aspartame in countries worldwide, including the United States, countries in Europe and Australia, among others. These reviews have found that the even high levels of intake of aspartame, studied across multiple countries and different methods of measuring aspartame consumption, is well below the ADI for safe consumption of aspartame. Reviews have also found that populations that are believed to be especially high consumers of aspartame such as children and diabetics are below the ADI for safe consumption, even considering very conservative worst-case scenario calculations of consumption.

Metabolites

Hypotheses of adverse health effects have focused on the three metabolites of aspartame, which are aspartic acid, methanol and phenylalanine. Aspartame is rapidly hydrolyzed in the small intestines. Even with ingestion of very high doses of aspartame (over 200 mg/kg), no aspartame is found in the blood due to the rapid breakdown. These metabolites have been studied in a wide range of populations including infants, children, adolescents, and healthy adults. In healthy adults and children, even enormous doses of aspartame do not lead to plasma levels of metabolites that are a concern for safety.

Aspartate

Aspartic acid (aspartate) is one of the most common amino acids in the typical diet. As with methanol and phenylalanine, intake of aspartic acid from aspartame is less than would be expected from other dietary sources. At the 90th percentile of intake, aspartame provides only between 1% and 2% of the daily intake of aspartic acid. There has been some speculation that aspartame, in conjunction with other amino acids like glutamate, may lead to excitotoxicity, inflicting damage on brain and nerve cells. However, clinical studies have shown no signs of neurotoxic effects, and studies of metabolism suggests it is not possible to ingest enough aspartic acid and glutamate through food and drink to levels that would be expected to be toxic.

Methanol

The methanol produced by the metabolism of aspartame is absorbed and quickly converted into formaldehyde and then completely converted to formic acid, which, due to its long half life, is considered the primary mechanism of toxicity in methanol poisoning. The methanol from aspartame is unlikely to be a safety concern for several reasons. The amount of methanol in aspartame is less than that found in fruit juices and citrus fruits, and there are other dietary sources for methanol such as fermented beverages. Therefore, the amount of methanol produced from aspartame is likely to be less than that from natural sources. With regards to formaldehyde, it is rapidly converted in the body, and the amounts of formaldehyde from the metabolism of aspartame is trivial when compared to the amounts produced routinely by the human body and from other foods and drugs. At the highest expected human doses of consumption of aspartame, there are no increased blood levels of methanol or formic acid, and ingesting aspartame at the 90th percentile of intake would produce 25 times less methanol than would be considered toxic.

Phenylalanine

People with the genetic disorder phenylketonuria are advised to avoid aspartame as they have a decreased ability to metabolize phenylalanine. Common foods such as milk, meat, and fruits provide far greater amounts of these metabolites in a diet than aspartame.

Phenylalanine is one of the essential amino acids and is required for normal growth and maintenance of life. Concerns about the safety of phenylalanine from aspartame center largely around hypothetical changes in neurotransmitter levels as well as ratios of neurotransmitters to each other in the blood and brain that could lead to neurological symptoms. Reviews of the literature have found no consistent findings to support such concerns, and while high doses of aspartame consumption may have some biochemical effects, these effects are not seen in toxicity studies to suggest aspartame can adversely affect neuronal function. Like methanol, the typical diet will lead to ingestion of significantly higher amounts of phenylalanine than would be expected from aspartame consumption.

Cancer

Reviews have found no association between aspartame and cancer. These reviews have looked at numerous carcinogenicity studies in animals, epidemiologic studies in humans, as well as in vitro genotoxicity studies. These studies have found no significant evidence that aspartame causes cancer in animals, damages the genome, or causes cancer in humans at doses currently used. This position is supported by multiple regulatory agencies like the FDA and EFSA as well as scientific bodies such as the National Cancer Institute.

Concern about possible carcinogenic properties of aspartame was originally raised and popularized in the mainstream media by John Olney in the 1970s and again in 1996 by suggesting that aspartame may be related to brain tumors. Reviews have found that these concerns were flawed, due to reliance on the ecological fallacy and the purported mechanism of causing tumors being unlikely to actually cause cancer. Independent agencies such as the FDA and National Cancer Institute have reanalyzed multiple studies based on these worries and found no association between aspartame and brain cancer.

Ramazzini studies

The Cesare Maltoni Cancer Research Center of the European Ramazzini Foundation of Oncology and Environmental Sciences has released several studies which claim that aspartame can increase several malignancies in rats, concluding that aspartame is a potential carcinogen at normal dietary doses. Although thirteen occupational safety and health experts signed an open letter from CSPI to the FDA expressing that the 2007 ERF study merited a reevaluation of aspartame's safety in humans, these studies have been widely criticized and discounted by the FDA and other food safety agencies:

After reviewing the foundation's claims, the EFSA and the FDA discounted the study results and found no reason to revise their previously established acceptable daily intake levels for aspartame. Reported flaws were numerous and included, but were not limited to, the following: comparing cancer rates of older aspartame-consuming rats to younger control rats; unspecified composition of the "Corticella" diet and method of adding aspartame, leading to possible nutritional deficiencies; unspecified aspartame storage conditions; lack of animal randomization; overcrowding and a high incidence of possibly carcinogenic infections; and the U.S. National Toxicology Program's finding that the ERF had misdiagnosed hyperplasias as malignancies. Reviews by the FDA and EFSA were hampered by the refusal of the Ramazzini Foundation to release all data and pathology slides, but from the materials received, the FDA and EFSA found that the data did not support the researcher's published conclusions. Evaluation of this research by Health Canada and the British government's Committee on Carcinogenicity of Chemicals in Food, Consumer Products and the Environment likewise found methodological problems with the research and did not recommend any further reconsideration of the recommended intake of aspartame in their respective countries.

A review of the literature concurred with these evaluations, finding many possible flaws in the study's design and conclusions. These conclusions are also contradicted by other carcinogenicity studies which found no significant danger. This review therefore concluded this research did not constitute credible evidence for the carcinogenicity of aspartame. Another review criticized the Ramazzini Foundation for relying on "science by press conference" with its release of results through the media before being published in a proper peer-reviewed journal, thus helping fuel the controversy and publicity about the study in the media.

Another carcinogenicity study in rodents published by this foundation in 2010 was evaluated by the EFSA and was found to have multiple significant design flaws and could not be interpreted. The EFSA therefore concluded this study did not provide enough evidence to reconsider previous evaluation of aspartame safety.

Neurological and psychiatric symptoms

Numerous allegations have been made on the Internet and in consumer magazines purporting neurotoxic effects of aspartame leading to neurological or psychiatric symptoms such as seizures, headaches, and mood changes. Review of the biochemistry of aspartame have found no evidence that the doses consumed would plausibly lead to neurotoxic effects. Comprehensive reviews have not found any evidence for aspartame as a cause for these symptoms. One review did provide a theoretical biochemical background of neurotoxicity and suggested further testing. However, a panel of EFSA experts noted that this review's conclusions were partially based on Internet sources and therefore were not scientifically robust. These experts also concurred with a critique that significant scientific errors were made in the critical review that led to unsubstantiated and misleading interpretations. A review of the pediatric literature did not show any significant findings for safety concerns with regards to neuropsychiatric conditions such as panic attacks, mood changes, hallucinations or with ADHD or seizures.

Headaches

Headaches are the most common symptom reported by consumers. While one small review noted aspartame is likely one of many dietary triggers of migraines, in a list that includes "cheese, chocolate, citrus fruits, hot dogs, monosodium glutamate, aspartame, fatty foods, ice cream, caffeine withdrawal, and alcoholic drinks, especially red wine and beer," other reviews have noted conflicting studies about headaches and still more reviews lack any evidence and references to support this claim.

Weight change and hunger

Since the caloric contribution of aspartame is negligible, it has been used as a means for weight loss through its role as a sugar substitute, with reviews finding that aspartame may aid in weight loss as part of a multidisciplinary weight loss program. Claims that aspartame contributes to weight gain and obesity are not supported by the medical literature. Although there have also been claims that aspartame contributes to hunger or increased appetite, there have been few studies directly addressing the effect of aspartame on appetite. The data show no increased appetite with aspartame use, and this is an area of possible future research. Studies looking at caloric intake found that aspartame consumers consumed as many calories as or fewer calories than non-aspartame consumers, but not more.

See also

• Canderel
• Equal (sweetener)
• NutraSweet

External links

• Centers for Disease Control: Evaluation of Consumer Complaints Related to Aspartame Use
• International Programme on Chemical Safety: Aspartame toxicology evaluation and further evaluation