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The [[artificial sweetener]] '''[[aspartame]]''' has been the subject of public [[controversy]] regarding its safety<ref name=pmid17684524>{{cite journal |author=Humphries P, Pretorius E, Naudé H |title=Direct and indirect cellular effects of aspartame on the brain |journal=European journal of clinical nutrition |volume=62 |issue=4 |pages=451–62 |year=2008 |month=April |pmid=17684524 |doi=10.1038/sj.ejcn.1602866 |url=}}</ref> and the circumstances around its approval.{{Fact|date=October 2008}} Many studies have recommended further investigation into the possible connection between aspartame and diseases such as [[brain tumor]]s, [[lesion|brain lesions]], and [[lymphoma]].<ref>Olney, J.W., N.B. Farber, E. Spitznagel, L.N. Robins, 1996. "Increasing Brain Tumor Rates: Is There a Link to Aspartame?" ''Journal of Neuropathology and Experimental Neurology'', Volume 55, pages 1115&ndash;1123.</ref><ref>Soffritti, Morando, et al., [http://www.ehponline.org/members/2005/8711/8711.pdf "First Experimental Demonstration of the Multipotential Carcinogenic Effects of Aspartame Administered in the Feed to Sprague-Dawley Rats."] ''Environmental Health Perspectives'', Volume 114(3): 379-385, 2006. </ref><ref>Roberts, H.J., "Does Aspartame Cause Human Brain Cancer," ''Journal of Advancement in Medicine'', Volume 4(4):231-241, 1991.</ref> These findings, combined with alleged [[Conflict of interest|conflicts of interest]] in the approval process, have engendered vocal activism regarding the possible risks of aspartame.<ref>GAO 1986. [http://archive.gao.gov/d4t4/130780.pdf "Six Former HHS Employees' Involvement in Aspartame's Approval."] United States General Accounting Office, GAO/HRD-86-109BR, July 1986.</ref><ref>Gordon, Gregory, United Press International Investigation, [http://www.dorway.com/upipaper.txt "NutraSweet: Questions Swirl."] 1987.</ref> In 1987 the US Government Accountability Office concluded that the food additive approval process had been followed for aspartame.<ref>{{Cite web | title = U.S. GAO - HRD-87-46 Food and Drug Administration: Food Additive Approval Process Followed for Aspartame, June 18, 1987 | accessdate = 2008-09-05 | url = http://www.gao.gov/docdblite/info.php?rptno=HRD-87-46 }}</ref> The [[U.S. Food and Drug Administration]] asserts that the safety of aspartame is "clear cut" and "one of the most thoroughly tested and studied food additives the agency has ever approved."<ref>[http://www.fda.gov/fdac/features/1999/699_sugar.html FDA Consumer magazine November - December 1999]</ref>
The [[artificial sweetener]] '''[[aspartame]]''' has been the subject of public [[controversy]] regarding its safety<ref name=pmid17684524>{{cite journal |author=Humphries P, Pretorius E, Naudé H |title=Direct and indirect cellular effects of aspartame on the brain |journal=European journal of clinical nutrition |volume=62 |issue=4 |pages=451–62 |year=2008 |month=April |pmid=17684524 |doi=10.1038/sj.ejcn.1602866 |url=}}</ref> and the circumstances around its approval.{{Fact|date=October 2008}} Many studies have recommended further investigation into the possible connection between aspartame and diseases such as [[brain tumor]]s, [[lesion|brain lesions]], and [[lymphoma]].<ref>Olney, J.W., N.B. Farber, E. Spitznagel, L.N. Robins, 1996. "Increasing Brain Tumor Rates: Is There a Link to Aspartame?" ''Journal of Neuropathology and Experimental Neurology'', Volume 55, pages 1115&ndash;1123.</ref><ref>Soffritti, Morando, et al., [http://www.ehponline.org/members/2005/8711/8711.pdf "First Experimental Demonstration of the Multipotential Carcinogenic Effects of Aspartame Administered in the Feed to Sprague-Dawley Rats."] ''Environmental Health Perspectives'', Volume 114(3): 379-385, 2006. </ref><ref>Roberts, H.J., "Does Aspartame Cause Human Brain Cancer," ''Journal of Advancement in Medicine'', Volume 4(4):231-241, 1991.</ref> These findings, combined with alleged [[Conflict of interest|conflicts of interest]] in the approval process, have engendered vocal activism regarding the possible risks of aspartame.<ref>GAO 1986. [http://archive.gao.gov/d4t4/130780.pdf "Six Former HHS Employees' Involvement in Aspartame's Approval."] United States General Accounting Office, GAO/HRD-86-109BR, July 1986.</ref><ref>Gordon, Gregory, United Press International Investigation, [http://www.dorway.com/upipaper.txt "NutraSweet: Questions Swirl."] 1987.</ref> In 1987 the US Government Accountability Office concluded that the food additive approval process had been followed for aspartame.<ref>{{Cite web | title = U.S. GAO - HRD-87-46 Food and Drug Administration: Food Additive Approval Process Followed for Aspartame, June 18, 1987 | accessdate = 2008-09-05 | url = http://www.gao.gov/docdblite/info.php?rptno=HRD-87-46 }}</ref> The [[U.S. Food and Drug Administration]] asserts that the safety of aspartame is "clear cut" and "one of the most thoroughly tested and studied food additives the agency has ever approved."<ref>[http://www.fda.gov/fdac/features/1999/699_sugar.html FDA Consumer magazine November - December 1999]</ref>

Revision as of 06:06, 31 October 2008


The artificial sweetener aspartame has been the subject of public controversy regarding its safety[1] and the circumstances around its approval.[citation needed] Many studies have recommended further investigation into the possible connection between aspartame and diseases such as brain tumors, brain lesions, and lymphoma.[2][3][4] These findings, combined with alleged conflicts of interest in the approval process, have engendered vocal activism regarding the possible risks of aspartame.[5][6] In 1987 the US Government Accountability Office concluded that the food additive approval process had been followed for aspartame.[7] The U.S. Food and Drug Administration asserts that the safety of aspartame is "clear cut" and "one of the most thoroughly tested and studied food additives the agency has ever approved."[8]

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.[9]

Some human and animal studies have found adverse effects associated with aspartame[10][11][12] and some have found no adverse effects.[13][14][15] It is not only the results of the research that have been questioned, but the design of the research that led to specific outcomes.[16]

The US Air Force issued an alert in 1992, warning air force pilots about drinking diet drinks containing aspartame before flying[17].

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 research has indicated formaldehyde accumulation from aspartame ingestion. [18] 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.[19][20] 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.[21]

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.[18] However, these scientists were not directly measuring formaldehyde, but simply measuring levels of some by-product of the methanol from aspartame.[19]

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.[22][23] Scientists have reported that a rise in blood plasma phenylalanine is negligible in typical use of aspartame[24] and their studies show no significant effects on neurotransmitter levels in the brain or changes in seizure thresholds.[25][26][27] 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.[28]

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.[22][29]

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.[30] 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.[31] The debate among scientists has been raging since the early 1970s, when researcher John Olney found that high levels of aspartic acid caused damage to the brains of infant mice.[32] Olney and consumer attorney James Turner filed a protest with the FDA to block the approval of aspartame. 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.[33]

Humans and other primates are not as susceptible to excitotoxins as rodents and therefore comparisons to human safety are problematic.[34][35] 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.[citation needed][36][37] One group was concerned with potential effects in infants and young children,[38] the potential long-term neurodegenerative effects of small-to-moderate spikes on plasma excitotoxin levels,[31] 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[39][40] 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.[41] 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.[42][43] 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.[44] 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.[45]

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".[46]

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.[42] The results of a large seven-year study into the long-term effects of eating aspartame in rats by the European Ramazzini Foundation Institute 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,[47] published in Environmental Health Perspectives,[48] 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,[49] the European Food Safety Authority (EFSA) issued a press release about the Ramazzini study on 5 May 2006.[50] It 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.[51] FDA later submitted its findings based on the evidence, and replied:[52]

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.[52]

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.[citation needed] As the EFSA felt it had already addressed this in their 5 May 2006 press release, no further press release was made.[50]

The Guardian on 15 May 2006[53] 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.[54]
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.[55] The results of the study have been published in the academic journal Environmental Health Perspectives on June 14, 2007.[56] 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."[57]

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."[58]

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.[59] 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."

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.[60] 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.[61]

Conflict of interest prior to 1996

In 1996, Ralph G. Walton, then Professor of Clinical Psychiatry, Northeastern Ohio Universities College of Medicine (NEOUCOM) [62], surveyed 166 studies of aspartame in peer reviewed medical literature prior to 1996.[63] 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.[64]

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:[65]

  • 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

References

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  2. ^ Olney, J.W., N.B. Farber, E. Spitznagel, L.N. Robins, 1996. "Increasing Brain Tumor Rates: Is There a Link to Aspartame?" Journal of Neuropathology and Experimental Neurology, Volume 55, pages 1115–1123.
  3. ^ Soffritti, Morando, et al., "First Experimental Demonstration of the Multipotential Carcinogenic Effects of Aspartame Administered in the Feed to Sprague-Dawley Rats." Environmental Health Perspectives, Volume 114(3): 379-385, 2006.
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  49. ^ FDA Statement on European Aspartame Study, May 8, 2006
  50. ^ a b EFSA EU, press release 1472 EN
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  54. ^ "List of International Life Sciences Institute members" (PDF). Retrieved 2006-12-31.
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  65. ^ "Aspartame Information replies to the New York Times". Aspartame Information Service. 2006-02-16.

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