To: Ms. Griffith-Sackey:
A slogan your agency should use is: "We lie for Big Business!" Why does the United Kingdom Food Standards Agency continuously ignore valid scientific evidence of a deadly neurotoxin in preference to the propaganda of international poisoners. This very question suggests the answers: UKFS is in their pockets.
What is the poison? Aspartame, E951, Canderel, NutraSweet, Equal, Benevia. Who are the poisoners? Ajinomoto, Merisant, Coca Cola, Pepsi and the hundreds of "food" makers who add this toxin into their products to sweeten them.
The reality of this health crisis was proven when 47 members of Parliament signed on to ban it from the UK. It was further certified years ago by the 30-page objection to the approval of aspartame submitted in the US by the National Soft Drink Assoc. You can read this part of the congressional record here: http://www.mpwhi.com/open_letter_dick_adamson.htm Notice how aspartame manufacturers use wrong analysis procedures even when it's available.
NSDA said: "HPLC is a practicable, well-accepted analytical method (3) which is commonly-employed by FDA. When the safety and suitability for use of a food additive such as APM with an acknowledged degradation problem (and anticipated high consumption) is under evaluation, HPLC is clearly the analytical method of choice." Instead they used TLC and NSDA said: "Searle itself has acknowledged the inadequacy of the analytical method that it chose when it described, in the petition, the quantity of degradation products identified using TLC as "estimates." Aspartame manufacturers expertly manipulate science to get the result they want through deception. Aspartic acid, the excitotoxin in aspartame, couldn't even be detected with their outdated procedure. Further they used the wrong solution.
Read the whole objection and see that Searle neglected to identify the breakdown chemicals such as formaldehyde and formic acid, and diketopiperazine, a brain tumor agent. NSDA (now American Beverage) declared "aspartame is uniquely unstable," is adulterated and breaks down at moderate temperature. What a bouquet of poisons! This is first year chemistry - nothing complicated.
Government records present the facts but the manufacturers publish falsehoods. I've sent you this report before. http://www.wnho.net/whopper.htm
My last letter about behavioral problems triggered by aspartame has gone unanswered. http://www.mpwhi.com/letter_on_aspartame_to_uk_food_standards.htm When UKFS can't answer facts they ignore them.
Butchko HH and Stargel WW are flacks defending commercial interests, that in 2002 were employed by NutraSweet. Every line in this misinformation post is from industry in defense of the poison - outright propaganda. Were there 5000 studies showing aspartame toxicity by the aspartame makers would seek to rebut them all, refining lies to sound like truth. Food Standards' loyalty is to aspartame manufacturers not citizens. I will list facts. The aspartame industry would seek to rebut them all.
The Trocho Study showed the formaldehyde converted from aspartame's free methyl alcohol embalms living tissue and damages DNA. http://www.mpwhi.com/formaldehyde_from_aspartame.pdf Tephly attempts to discredit it. He is well known for writing on methanol. Industry scientists have admitted their 1969 testing procedure is not sensitive enough to detect the large increase of plasma methanol levels when aspartame is given at doses of 34 mg/kg (Stegink l948b). They know several superior plasma methanol measurement techniques have been developed since l969.
Below is a web link to a methanol - formaldehyde piece on methanol measurements after aspartame ingestion. It addresses deception in industry-sponsored studies. Eight studies are listed in the chart.
TEPHLY'S GROUP CONDUCTED THE METHANOL MEASUREMENTS IN THESE STUDIES!
Nobody has proved the Trocho Study wrong, but they tried hard. Tephly published a pamphlet in the same journal as Trocho without a trace of experimental work, simply verbalizing inconsistencies to drown in words and lies which could - in a civilized world -- end the use of this weapon of mass destruction that our society is wounded by for greed. One is never wrong when in power. Tephly's slander is "a tale told by an idiot, Full of sound and fury, signifying nothing!" - an insidious attack on solid research that contradicts their greedy lies.
No mention of Trocho is in a recent "final" analysis of aspartame Toxicology that was written by people who don't know how to use pubmed or other tools of the trade in preparing scientific reports. What doesn't coincide with their pre-established "truth" is simply ignored, and their propaganda is publicized as the final definition silencing all the voices proving aspartame is an economic swindle and brutal aggression on world health. The review of aspartame in Toxicology was bought by Ajinomoto, aspartame's largest manufacturer, reviewing its own studies.
Let's analyze the Tephly comments:
"Trocho et al., (l998) demonstrated that aspartame, radio-labelled on the methanol, induced in the liver stable DNA and protein adducts. According to these authors, the accumulation of these adducts after repeated administration of aspartame could pose problems of toxicity and carcinogenicity in the long term."
This part is correct, simply states the main conclusion.
"Besides the fact that aspartame at high doses has never induced liver cancer in rats."
Wrong: aspartame has been found to induce cancer in rats, just look at the literature (the Ramazzini Study (Soffritti) for example). In addition, high-dosing studies of aspartame toxicity have been almost always been short term, and the cancer studies done with low (common usage) doses for the long term. This language is like an assassin saying he "never tortured and killed anybody" because he killed them first, no torture.
"Trocho's studies did not identify the radioactivity found in the proteins and DNA."
This author didn't read what he himself writes: in the opening sentence he defined that "aspartame, radio-labelled on the methanol, induced in the liver stable DNA and protein adducts" - this is as complete as anybody can define the nature of the label found in the proteins and DNA. Here sentences from different sources are glued by lawyers that don't know radioactivity from radio-labelled ... This ignorant editing doesn't merit further comment, except that the compounds identified did not correspond to single -carbon metabolism as was their mantra.
"Consequently, the formation of adducts of formaldehyde on the proteins and nucleic acids from aspartame, in vivo, remains to be proved. (Tephly 1999)"
Weird conclusion to a demonstration of exactly the opposite, since the Trocho Study identified the formation of adducts of formaldehyde and proteins or nucleic acids from aspartame in vivo. The sentence: "remains to be proved" should be changed by "has been proved". That's all. If you lie with a straight face somebody will believe you. In this case what's required isn't a straight face but a straitjacket and a ton of soap to wash the lies out of the mouths of the mass murderers.
Food Standards never corrects their propaganda. See aspartame industry propaganda rebutted with medical evidence and references by Mark Gold of the Aspartame Toxicity Center: http://www.holisticmed.com/aspartame - http://www.dorway.com/offasprt.html
You say: "This Agency is of the view that no additive (including sweeteners) should be permitted unless there is convincing evidence that it will not harm consumers." Then why does Food Standards ignore or attempt to rebut all independent scientific peer reviewed research. Dr. Ralph Walton showed on 60 Minutes 92% of independent scientific peer reviewed research showed the problems aspartame causes. If you eliminate 6 studies having to do with the FDA because of the controversy, and one pro-aspartame summary, 100% of independent scientific peer reviewed research shows the problems. Here is that report: http://www.dorway.com/peerrev.html This revokes industry studies because you can't do a study on a chemical poison like aspartame and have it prove safety. That's why the FDA tried to have Searle, the original manufacturer, indicted for fraud. They got caught. Jerome Bressler wrote the FDA audit about Searle filtering out neoplasms, and excising brain tumors, resurrecting rats on paper after they died, and more: http://www.dorway.com/bressler.txt He further stated to me, Dr. H. J. Roberts and Dr. Russell Blaylock that the studies were so bad when FDA retyped the report they removed the worst 20%. Now FDA refuse to release it. To avoid indictment the defense law firm hired both US Prosecutors.
Since Dr. Walton researched the connection between studies and funding many more studies have showed aspartame's hazards. 13 in the last 24 months show aspartame toxicity: http://www.mpwhi.com/13_aspartame_research_studies.htm How many more have to be done before Food Standards gets interested in protecting consumers instead of defending manufacturers? You claim no additive is permitted if there is convincing evidence it will harm consumers. You have the evidence but ignore it.
You bring up the Scientific Committee on Food (SCF) even after a 2004 assessment by the European Anti-Fraud Agency (OLAF) revealed that the report was written by a single individual who works at the UK Food Safety Agency and not by the entire Scientific Committee on Food (SCF). Here is the rebuttal to that report.
I met with the European Union for two hours providing them with all the damning research on aspartame and they omitted it. I was wired. It was obvious at the meeting they had no interest in anything showing aspartame toxicity. They were given a copy of the Board of Inquiry Report of the FDA revoking the petition for approval. http://www.mpwhi.com/fda_petition1.doc I explained how Rumsfeld got it marketed through political chicanery, and how no studies were done in the UK for its approval. Searle simply made a deal with Professor Paul Turner of Food Standards and he approved it without anyone knowing. Parliament had a big controversy but never rescinded the poison, which story was in the Guardian. Aspartame was never proven safe in the UK either! So when you send out all this propaganda why don't you add the facts above. It's a crime to the public to believe an addictive excitoneurotoxic carcinogenic drug is safe.
Regarding obesity: Why wasn't the study at the University of Texas (Sharon Fowler) which linked diet drinks to obesity with 8 years data included? MSG likewise causes obesity. Food Standards uses industry controlled or funded studies and where there is sound independent research, they resort to rebuttals by industry flacks. It was known two decades ago that aspartame would cause an epidemic of obesity. From the Congressional Record, May 7, l985, page 5511: "Aspartame has been demonstrated to inhibit the carbohydrate-induced-synthesis of the neurotransmitter serotonin (Wurtman affidavit) Serotonin blunts the sensation of craving carbohydrates and thus is part of the body's feedback system that helps limit consumption of carbohydrate to appropriate levels. Its inhibition by aspartame could lead to the anomalous result of a diet product causing increased consumption of carbohydrates." I brought this congressional record to the EU which then ignored it.
Behavioral problems are mentioned on the same page in the congressional record is this statement: "There is scientific evidence suggesting that increases in brain PHE and TYR levels of the order seen in the rat studies can effect synthesis of neurotransmitters, which themselves can effect important physiological functions and potentially behavior." Aspartame triggered behavioral problems have been known for over a quarter of a century. Dr. John Olney's report to the Board of Inquiry also was given to the EU, 49 pages of evidence. Behavioral problems are epidemic from of aspartame.
The 3 year Ramazzini Study in 2005 concluded aspartame is a "multipotential carcinogen" and confirmed FDA's original findings. It was peer reviewed by 7 world experts. Your report says "The EFSA assessment raised a number of concerns regarding this study and concluded "on the basis of all the evidence currently available, that there is no need to further review the safety of aspartame nor to revise the previously established ADI." I see no mention of why it wasn't accepted. Without rebuttal the European Food Safety Authority made up the fairy tale stating the rats got cancer from respiratory disease. Any physician knows respiratory disease is part of the dying process. It's outrageous that a scientific committee would say something so bizarre. Members of EFSA had connections to Ajinomoto. Could it be their paychecks were involved? They were exposed in the UK press.
EFSA never apologized, so I reported them to the Universal Court of Justice. Then Dr. Koeter finally admitted in a press release they were pressured by industry to hijack science:
"Science and politics make poor bedfellows. Just ask Herman Koeter, deputy executive directorat the European Food Safety Authority (EFSA), which has felt the push and pull of national politics ever since the agency began operating four years ago." ----- "Hot decisions that had political repercussions included a review of a controversial aspartame study" . It seems the SCF became inactive after their little stunt of one person making the decision on a review of aspartame that omitted all independent damning research. The entire press release is in my open letter to the EFSA: http://www.mpwhi.com/letter_to_efsa.htm Why was this is not in the report when EFSA is mentioned?
The second Ramazzini Study which showed aspartame is still a multipotential carcinogen even in SMALL doses is ignored. If a pregnant woman uses it, and the baby survives since aspartame is a teratogen causing birth defects and mental retardation, the child can grow up and have cancer. Is the EFSA afraid to review this study because they have run out of excuses and admitted they are pressured by industry?
An accurate summary of these prestigious studies:
The first ERF study (2005) was conducted on 1800 Sprague-Dawley rats (100-150/per sex/per group) In order to simulate daily human intake, aspartame was added to the standard rat diet in quantities of 5000, 2500, 100, 500, 20, 4, and 0 mg/Kg of body weight. Treatment of the animals began at 8 weeks of age and continued until spontaneous death. The results show that APM causes a statistically significant, dose-related increase of lymphomas/leukemias and malignant tumors of the renal pelvis in females and malignant tumors of peripheral nerves in males. These results demonstrate for the first time that APM is a carcinogenic agent, capable of inducing malignancies at various dose levels, including those lower than the current acceptable daily intake (ADI) for humans (50 mg/kg of body weight in the US, 40 mg/kg of body weight in the EU).
The second ERF study (2007) was conducted on 400 Sprague-Dawley rats (70-95/per sex/per group). In order to simulate daily human intake, aspartame was added to the standard rat diet in quantities of 100, 20, and 0 mg/Kg of body weight. Treatment of the animals began on the 12th day of fetal life until natural death. The results of the second study show an increased incidence of lymphomas/leukemias in female rats with respect to the first study. Moreover, the study shows that when lifespan exposure to APM begins during fetal life, the age at which lymphomas/leukemias develop in females is anticipated. For the first time, a statistically significant increase in mammary cancers in females was also observed in the second study. The results of this transplacental carcinogenicity bioassay not only confirm, but also reinforce the first experimental demonstration of APMs multipotential carcinogenicity.
DR. MORANDO SOFFRITTI, was the lead researcher on these two groundbreaking long-term aspartame studies.. Early this year he was honored at New York's Mt Sinai School of Medicine with the Irving J Selikoff Award for his outstanding contributions to the identification of environmental and industrial carcinogens and his promotion of independent scientific research. This is only the third time in history this award has been given. It is obscene and criminal that the EFSA would stoop to fairy tales to defend industry, when the lives of the public are at stake. An excellent review of the 2005 Ramazzini Study was done by Dr. Russell Blaylock, "The Truth About Aspartame" - http://www.atavistik.com
You discuss the "acceptable daily intake" when FDA toxicologist, Dr. Adrian Gross, told Congress in l985 that you could not set an ADI because aspartame causes cancer.
The Delaney Amendment makes it illegal to allow any residues of cancer causing chemicals in foods. In his concluding testimony Gross asked, "Given the cancer causing potential of aspartame how would the FDA justify its position that it views a certain amount of aspartame as constituting an allowable daily intake or 'safe' level of it? Is that position in effect not equivalent to setting a 'tolerance' for this food additive and thus a violation of that law? And if the FDA itself elects to violate the law, who is left to protect the health of the public?" Congressional Record SID835:131 (August 1, l985)
Dr. Gross was the on-site toxicologist who witnessed what Searle was doing and asked for the indictment. Today 12 toxicologists have asked the FDA to ban aspartame, and I have written an amendment to a petition to ban on the basis of an imminent health hazard.
The Food Standards report says for an average 3-year-old child the ADI is of the order of 600 milligrams. Your own regulations in the UK state artificial sweeteners cannot be used in children 3 and under. Yet they are marketed in all kinds of products used by these young children and Food Standards has done nothing about it.
This report admits high levels of phenylalanine can harm an unborn baby but PKU testing is only done when the baby is born. By that time the baby either has some birth defect or mentally retarded if he survives at all. Why is there no warning for pregnant women? It was even established in Congress by Dr. Louis Elsas, Pediatric Professor, genetics, that aspartame is a neurotoxin and teratogen. We have the record on web.
Regarding the investigation by the Center for Disease Control, what they recommended was future investigations regarding neurological and behavioral problems and focus on symptoms such as headaches, mood alterations and behavioral changes. Some of the reported symptoms included aggressive behavior, disorientation, hyperactivity, extreme numbness, excitability, memory loss, loss of depth perception, liver impairment, cardiac arrest, seizures, suicidal tendencies, severe mood swings and death. This is what was going on in the population after aspartame approval and is still going on today except after a quarter of a century there is a medical text documenting the many neurodegenerative diseases, tumors, drug interactions, diabetes, and other horrors triggered by this poison. The text is over 1000 pages - "Aspartame Disease: An Ignored Epidemic", by H. J. Roberts, M.D. http://www.sunsentpress.com He testified before Congress, and treated aspartame victims in the trenches of medical practice since aspartame approval.
The CDC covered up this investigation by allowing an executive summary to the report which conflicted with the information. Frederick L. Trowbridge called these complaints of a mild nature.
Frankly, I've never seen a case of mild cardiac arrest, mild severe mood swings or mild death! When I complained to the CDC of this coverup their answer was: "Frederick Trowbridge has now retired". So on their web page you find the fraudulent summary but on http://www.dorway.com/cdctext.txt you find the entire 146 page investigation. I showed this report in the aspartame documentary: "Sweet Misery: A Poisoned World", http://www.soundandfury.tv
Food Standards even attempts to cover up the 52 week RAO study on 7 infant monkeys fed aspartame. Five had grand mal seizures and 1 died. http://www.dorway.com/raoreport.txt It stated the reason for the seizures was the high serum phenylalanine levels. The FDA report of 92 documented symptoms lists four types of seizures. http://www.mpwhi.com/92_aspartame_symptoms.pdf To make matters worse aspartame interacts with all anti-seizure medication, as discussed in the medical text. Aspartame interacts with all drugs and vaccines, and other additives as well as proven in the Liverpool study. Seizures are discussed in Excitotoxins: The Taste That Kills by neurosurgeon Russell Blaylock, M.D., http://www.russellblaylockmd.com
To fool the public into believing aspartame doesn't cause seizures is obscene. This report lists industry funded and controlled studies which make a mockery of science. This report on Scientific Abuse in Seizure Research relating to aspartame exposes sham studies. http://www.holisticmed.com/aspartame/abuse/seizures.html For example in the Rowen study (funded by Monsanto) they gave 16 of 18 subjects anti-seizure medication because they were so afraid someone would have an aspartame seizure. They used one capsule of aspartame for a one day study. Using this method 10,000 non-smokers could smoke 1 cigarette and report nobody got cancer. How could they get such a sham of study peer reviewed. This reveals the influence of industry even in medical journals.
How many times do we have to give Food Standards the information for it to be disregarded in favor of preposterous unscientific cover-ups?
After reading comments about the Trocho Study I sent them to Dr. Alemany who did this study and here he answered:
"With respect to the Committee evaluation of my work:
"The Committee has also reviewed the study by Trocho et al. (1998), who reported the occurrence of stable DNA and protein adducts in the liver of rats following aspartame administration. The Committee noted that the study used aspartame radiolabelled on the methanol portion, and that during metabolism of aspartame in the gut, radiolabelled methanol will be split off and enter the body's one-carbon pool, with the potential to appear anywhere there is methylation. The Committee therefore agrees with the analysis of Tephly (1999) that formation of DNA adducts has not been demonstrated"
This is amazing, a Committee that does not read the literature they bare reviewing, that disregard experimental proof and gives credit to an abusive interpretation (Tephly's) over the shown and proven experimental data. In addition they show they don't know elementary biochemistry and the metabolism of one-carbon in the body.
Let's go over the details:
a) They state that aspartame was broken up to methanol in the intestine. We demonstrated that this was not the case, since then all aspartame methanol would be carried as such in the portal vein and detoxified by the alcohol dehydrogenase of the liver. How can they explain the very high and cumulative levels of label in the other organs studied? Most of methanol is oxidized to CO2, and only part of it can enter the 1C path, in fact the entry of formaldehyde is minimal, and that of formate almost inexistent, thus the flow of one-carbon from methanol could be deemed vert low (this is also what Tephly and Co say). If this is the case, how can they explain a high percentage of the ingested label in the tissues?, and explain it only with the occasional and limited conversion of a formate unit into a methyl that is used to regenerate methionine (a not specially abundant amino acid) from homocysteine ou used in the pyrimidine synthesis pathway for their entry into nucleic acids. By the way, this is not new, it was already explained in our paper.
b) TLC analysis demonstrated without any doubt that the label was not in any cytidine nor cysteine, which proves false the theory of the one-carbon, and supports the existence of adducts of formaldehyde. How can they simply disregard experimental proof? I would accept it if someone else repeated the experiments and found mine erroneous, inconclusive or false. But nobody did. In fat I believe one of the Tephly's clones did and found us right, then they simply published an attack paper without experimental data (this requires clout and money) to bury our work, so far the most damaging piece of experimental study against the bunch of murderers that peddle this dangerous drug. If so sure are they of their value why not repeat the study? A few years ago an English team was publicized with considerable fanfare that they were going to do our study in humans. The absolute lack of news suggests that either it was done and the scientists subdued or bought or that they were subdued, menaced or bought before the experiment took place.
I think that may be interesting to present a detailed dossier of why the EU Committee on the Protection of Poisonous Food Additives arrived at the solid conclusions they state in the case of my paper. I am sure that this is the same with the other studies. This dossier should present in parallel columns their statements and the parts of the papers in which it is concluded the contrary. Also, the affiliations, degrees and relationship with industries (i.e. grants or contracts) obtained in the last 10 years should be presented. A former collaborator of mine was member of one such Committee and since his funding has skyrocketed with substantial contracts and consultations directly related to his work in the Commission. Sometimes, science loses in front of the mighty euro (and the not so mighty, but powerful enough dollar).
It makes me sad to see this travesty of the defense of the safety in the food of the citizens because of the brutal and callous greed of a few.
Let me know if I can be of further help.
Dr. Maria' Alemany
Departament de Nutrici Bromatologia
Facultat de Biologia, Universitat de Barcelona
Av. Diagonal, 645
08028 Barcelona. Espanya / Espa Spain
tel. 34 93 403 4606; fax 34 93 403 7064
End of comments by Dr. Alemany -
People are sick and dying the world over from this toxin because of the propaganda spread by government agencies controlled by manufacturers. Here is the history of what was done to mass poison the world with aspartame. http://www.mpwhi.com/ecologist_september_2005.pdf
The brains of babies and children are being destroyed as these reports by experts reveal: http://www.mpwhi.com/report_on_aspartame_and_children.htm This 8 month investigation by United Press International exposes that in the beginning how far aspartame manufacturers would go to cover up the facts. Even scientists were threatened. http://www.dorway.com/upipaper.txt
It's a sad commentary when those responsible to solve the problem ARE the problem. Worthless studies should be replaced by accurate "independent" scientific research. As long as Food Standards pitch propaganda and falsehood citizens will continue to be disabled or die. When you damage DNA as the Trocho Study proved, you destroy humanity. Is industry influence worth our biological future?
Dr. Betty Martini, D.Hum.
Founder, Mission Possible World Health International
9270 River Club Parkway
Duluth, Georgia 30097
Aspartame Toxiocity Center: http://www.holisticmed.com/aspartame
Dear Mr --
Thank you for your email of 16 October 2007 to Alan Johnson concerning the safety of aspartame. Your letter has been forwarded to the Food Standards Agency for reply as we have policy responsibility for sweeteners (and other additives) and flavourings.
The Agency is of the view that no additive (including sweeteners) should be permitted unless there is convincing evidence that it will not harm consumers. Furthermore, all approvals of food additives should be kept under review as and when new scientific information becomes available.
Aspartame is one of the most widely tested food additives approved for use in foods and its safety has been reviewed on several occasions by the Joint Expert Committee on Food Additives (JECFA) of the United Nations' Food and Agriculture Organization and the World Health Organization; the UK Committee on Toxicity, Consumer Products and the Environment (COT); and the European Commission's former Scientific Committee on Food (SCF). In Europe, aspartame was first reviewed in 1982 by the COT. The SCF also gave a positive opinion on aspartame in its 1988 review of the sweetener. The COT fully reviewed aspartame again in 1992 and after studying all the available scientific information confirmed that it is suitable for human consumption.
You refer to various health issues which you attribute to the consumption of aspartame. With regards to obesity, the effect of aspartame in obese subjects has been studied and no differences were found between the subjects given aspartame and those given a placebo. Investigations considered by the SCF in 2002 showed that aspartame was not associated with increased energy intake or increased body weight. In addition, a recent review (Nutrition Bulletin, June 2006) suggests that consuming foods and drinks sweetened with aspartame rather than sugar may be an effective means of weight control.
The incidence of obesity is rising in the whole population, including children, but this is a problem with many underlying causes, such as dietary changes and more sedentary lifestyles.
During the 1980s a number of anecdotal reports of adverse reactions to aspartame were reported. Some of these reports were of effects on behaviour. As a result of these reports a number of controlled scientific studies were performed in human volunteers, including the general human population and potentially more vulnerable groups such as children and people claiming to have adverse reactions to consuming aspartame. These included controlled, double-blind studies to assess whether aspartame consumption could have effects on behaviour, mood or learning, or on brain EEG patterns. These studies did not identify any effects resulting from aspartame administration.
Studies have also been performed on aspartame prior to its approval to assess whether it can cause cancer in animals, and to assess whether it is able to damage DNA, the genetic material in the cells of our body, which is one mechanism by which a chemical may cause cancer. Independent experts, both internationally and in the UK, assessed the results of these studies and concluded that aspartame is not cancer-causing and is not able to damage DNA. Subsequent re- assessments of the safety of aspartame as more studies have been performed have confirmed that opinion.
The Agency has prepared a note which summarises our opinion on the safety of aspartame (attached). This note contains information on safety evaluations, intake levels and labelling issues in relation to this substance. The note also refers to the most recent opinion on aspartame published by the SCF in 2002 (also attached).
I hope this information will provide you with the assurance that the safety of aspartame and other additives have been thoroughly assessed by scientific experts at both UK and EC level, and as with all additives, are kept under constant review.
Food Standards Agency
Novel Foods, Additives and Supplements Division
Aspartame is an intense sweetener, approximately 200 times sweeter than sugar, which has been used in soft drinks and other low-calorie or sugar-free foods throughout the world for over 25 years. It is sometimes referred to by its original trade name of Nutrasweet and it appears on ingredient lists either as "aspartame" or "E951".
Sweeteners and other food additives are tightly regulated and may only be used once their safety has been rigorously assessed.
Aspartame was first approved in the UK in 1982 following the review of its safety by the UK's Committee on Toxicity, Consumer Products and the Environment (COT), a committee of independent experts who advise the Government on the safety of food chemicals. In 1988 the European Commission's former Scientific Committee on Food (SCF) also gave a positive opinion on aspartame. This was later reaffirmed in 1992 when the COT considered new literature on aspartame and confirmed their original findings that aspartame was acceptable for use in food.
Following the publication of a number of anecdotal reports, which cast doubt on the safety of this sweetener, the Food Standards Agency pressed the European Commission in 2001 to revisit its previous safety assessment of aspartame (1988) at the earliest opportunity; and provided assistance in preparing a summary report for consideration by the former Scientific Committee on Food (SCF).
The SCF reviewed over 500 papers published in the scientific literature between 1988 and 2001 on the safety of aspartame, including studies supporting the safety of aspartame and others pointing to potential adverse effects. Included as an annex to the summary report presented to the SCF was the outcome of a review of the safety of aspartame by the French Agency for Food Health and Safety (AFSSA). The AFSSA review focussed primarily on the possible link between aspartame and brain tumours.
Following this extensive review, the SCF published a revised opinion in 2002, which concluded that there was no evidence to suggest a need to revise the outcome of their earlier risk assessment or the Acceptable Daily Intake (ADI) previously established for aspartameof 40 milligrams per kilogram of body weight per day (40 mg/kg bw/day).
The European Food Safety Authority (EFSA), who assumed the role of the SCF in providing the European Commission with independent scientific advice, published a further review on the safety of aspartame in May 2006. This was in response to a study published by the Ramazzini Foundation in Bologna, Italy in July 2005. The study claimed to have shown that rats given dosages of aspartame equivalent to the Acceptable Daily Intake (ADI) may develop tumours.The EFSA assessment raised a number of concerns regarding this study and concluded "on the basis of all the evidence currently available, that there is no need to further review the safety of aspartame nor to revise the previously established ADI."
The Agency supports the conclusions of these reviews and also reiterates that all approvals of food additives should be kept under review as and when new scientific information becomes available.
Intake of aspartame
Like many food additives, the safety assessment for aspartame has led to the setting of an Acceptable Daily Intake, or ADI. This is an estimate of the amount of an additive that could be routinely consumed every day over a lifetime with no appreciable health risk. In the case of aspartame, the ADI is set at 40 milligrams per kilogram of body weight. This is equivalent to 2800 milligrams for an average British adult. For an average 3-year-old child the amount is of the order of 600 milligrams.
The ADI applies to all sections of the population, including children and infants from the age of 12 weeks. The only exception is for people suffering from a rare genetic disease phenylketonuria (PKU) (see below).
It is not necessary, however, for each person to calculate their intake of additives in order to make sure that they keep within the ADI. Indeed, it would be extremely complicated and time-consuming to do so. Instead, legislation on food additives specifies the categories of foods in which aspartame can be used and the levels that can be added. These levels are set after considering food consumption patterns and the likelihood of exceeding the ADI, combined with knowledge of the amount that is actually needed in the food to have the desired sweetening effect. In the case of aspartame, an adult would have to consume 14 cans of a sugar-free drink every day before reaching the ADI, assuming the sweetener was used in the drink at the maximum permitted level. In practice most drinks use aspartame in combination with other sweeteners so that the level is considerably lower.
It is the responsibility of government to monitor the exposure to all food additives and to check that consumers do not regularly exceed the ADI. Previous work by the former Ministry of Agriculture, Fisheries and Food and the Department of Health showed that aspartame intakes were considerably below the recommended maximum level, even among children and diabetics who consume large quantities of sugar-free drinks.
There is a small group of people who cannot safely consume aspartame. These are the sufferers of the inherited disease phenylketonuria (PKU), who are unable to metabolise the amino acid phenylalanine effectively, leading to the accumulation of potentially harmful levels. PKU is a serious, metabolic disorder, affecting 1 in 10,000 individuals and if untreated, it can cause serious brain damage. Sufferers are normally diagnosed shortly after birth by a routine blood test and need to follow a very strict diet in order to limit their intake of phenylalanine, which is a normal constituent of proteins in food. Since aspartame is also a source of phenylalanine, all food products containing aspartame are clearly labelled to indicate the presence of phenylalanine so that those people who suffer from PKU can avoid consuming these products. This labelling is a legal requirement.
Because high levels of phenylalanine can harm an unborn baby, women who have PKU and are actively planning a family follow a pre-conception phenylalanine controlled diet. In the UK, all new born babies have been screened for PKU since 1969. It is highly improbable that anyone born prior to 1969 would have PKU and been unaware of their condition, especially if there is no family history of PKU. However, women who are actively planning a family who have concerns about PKU should contact their doctor.
Whilst satisfied as to the safety of aspartame, we recognise that some consumers may wish to avoid those foods containing this sweetener. One important aim of food labelling legislation is to enable consumers to make an informed choice. As well as the general requirement for foods to carry a list of food additives and other ingredients, products containing sweeteners such as aspartame must show the statement "with sweetener(s)" on the label close to the main product name. Foods that contain both sugar and sweetener must carry the statement "with sugar and sweetener(s)". In addition, foods that contain aspartame must be labelled with a warning "contains a source of phenylalanine". This warning is specifically to aid individuals who suffer from phenylketonuria (PKU), so that they can avoid such foods (see above).
Novel Foods, Additives and Supplements Division Phone: 020 7276 8581
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June 2006 email: firstname.lastname@example.org
The SCF's opinion on aspartame can be seen on their website at: http://europa.eu.int/comm/food/fs/sc/scf/out155_en.pdf
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EUROPEAN COMMISSIONHEALTH & CONSUMER PROTECTION DIRECTORATE-GENERAL
Directorate C - Scientific OpinionsC2 - Management of scientific committees II; scientific co-operation and networks Scientific Committee on Food SCF/CS/ADD/EDUL/222 Final10 December 2002Opinion of the Scientific Committee on Food:Update on the Safety of Aspartame (expressed on 4 December 2002)
Opinion of the Scientific Committee on Food:
Update on the Safety of Aspartame
Terms of Reference
The Committee is asked to review all new scientific information on aspartame not having been examined by the SCF previously, taking into account, notably, theliterature search carried out in the UK.
The intense sweetener, aspartame, is used in a wide range of food products in many countries around the world and is authorised for use in the EU (E951). It has the following structure:
The Scientific Committee for Food (SCF) initially evaluated aspartame (L-aspartyl- L-phenylalanine methyl ester) during 1984 (SCF, 1985) and subsequently during 1988 (SCF, 1989). At its 107th meeting in June 1997, the SCF also examined the issue of an alleged connection between aspartame and increase in incidence of brain tumours in the USA (SCF, 1997).Aspartame has also been considered by other bodies including the Joint FAO/WHO Expert Committee on Food Additives (JECFA, 1980) the US Food and Drug Administration (FDA, 1984), and the UK Committee on Toxicity (COT, 1992). The toxicity data on aspartame were used by the JECFA, SCF and COT to establish an Acceptable Daily Intake (ADI) of 40 mg/kg body weight/day and an ADI of 50 mg/kgbw/d was established by the FDA. An ADI of 7.5 mg/kg bw/d was alsoestablished for a minor cyclic dipeptide derivative of aspartame, a diketopiperazine (DKP), which is formed in some aqueous solutions (JECFA, 1980; SCF, 1985).The safety issues that have been raised in the past about aspartame have included: (1) the possibility of toxicity from methanol, one of the breakdown products of aspartame; (2) elevations in plasma concentrations of phenylalanine (Phe) and aspartic acid, which could result in increased transport of these amino acids into the brain, altering the brain's neurochemical composition; (3) the possibility of neuroendocrine changes, particularly increased concentrations in the brain, synaptic ganglia and adrenal medulla of catecholamines derived from Phe and its hydroxylation product, tyrosine; and (4) a postulated link with epilepsy and brain tumours. All these areas have been addressed in the pre-1988 literature and in more recent reviews (Meldrum, 1993; Lajtha et al., 1994; Tschanz et al., 1996).
The safety of aspartame and its metabolic breakdown products (phenylalanine, aspartic acid and methanol) has been assessed in humans generally and in several subgroups, including healthy infants, children, adolescents, adults, obese individuals, diabetics, lactating women, and individuals heterozygous for the genetic disease, phenylketonuria (PKU), who have a compromised ability to metabolise the essential amino acid, Phe.
Since its approval, aspartame has undergone further investigation through clinical and laboratory research, intake studies and postmarketing surveillance of anecdotal reports of adverse health effects. The present review updates the previous SCF opinions in the light of new reports on the consumption of aspartame in relation to the onset of brain tumours and seizures, headaches, allergies, and changes in behaviour and cognitive function. Information on the safety of aspartame was available from a variety of sources including scientific papers, conference proceedings, abstracts and magazine articles.
This review focuses on papers published in the open scientific literature from 1988 to 2001 and draws on the recent extensive review by the Agence Fran se de S rit Sanitaire des Aliments (AFSSA, 2002), which covered mutagenic, carcinogenic and neurological effects.
European Commission report on Food Additive Intake
In the European Commission report on Dietary Food Additive Intake in the European Union (EC, 2001), estimates of intake were calculated using a tiered approach. Tier 1 is based on theoretical food consumption data and maximum usage levels for additives as permitted by relevant Community legislation. The second and third tiers refer to assessment at the level of individual Member States, combining national data on food consumption with the maximum permitted usage levels for the additive (Tier 2) and with its actual usage patterns (Tier 3). Aspartame has been examined at Tier 1 for adults and at Tier 2 for children.
Aspartame intakes for adults were estimated at Tier 1 to be 21.3 mg/kg bw/day in the European Union. The Tier 1 approach is likely to be an overestimate of actual intake even by high level consumers of aspartame-sweetened foods. More refined intake 4 estimates (Tier 2) were performed for children. Information from individual member states showed that the refined estimated intake for children was 1-40% of the ADI. Therefore aspartame was excluded from further consideration as both adults and children were shown to be unlikely to exceed the ADI of 40 mg/kg bw.
Other published intake estimates for European countries
In addition to the Commission report, a number of reports have been published from 1990 onwards with estimates of aspartame intake in European countries (B and Biermann, 1992; Butchko and Stargel, 2001; Garnier-Sagne et al., 2001; Hinson and Nicol, 1992; Leclercq et al., 1999; MAFF, 1990 and 1995; Renwick, 1990; Salminen and Penttil 1999). The table below shows the highest reported intake estimates for different age groups of the general population and people with diabetes. The data are based on actual food consumption combined with the actual sweetener levels present in the foods (equivalent to Tier 3 in the Commission report) or the maximum permitted aspartame levels (Tier 2). The estimates of intake by mean and high level consumers are fairly consistent between European countries even though slightly different approaches were used. High level consumers, both adults and children, are unlikely to exceed the ADI of 40 mg/kg bw for aspartame. Special groups such as diabetics that are likely to be high consumers of foods containing aspartame are also well below the ADI. Therefore, from the available data it appears that no group is likely to exceed the ADI for aspartame on a regular basis.
Table: Highest reported intake estimates for aspartame Consumer group Country Mean consumer intake in mg/kg bw/d High level consumer in take in mg/kg bw/d (percentile quoted) Reference Children 1-5 years old UK - 2.8 (90) Hinson & Nicol, 1992 Children 1-6 years old Finland - < 4 (-) Salminen & Penttil 1999 All ages Netherlands 2.4 7.5 (95) Butchko & Stargel, 2001 All ages Norway 3.4 - Butchko & Stargel, 2001 Diabetics* 2-20 years oldFrance 2.4 7.8 (97.5) Garnier-Sagne et al., 2001 Diabetics 2-65 years old UK - 10.1 (97.5) MAFF, 1995
* Using maximum permitted level of sweeteners in different food categories (Tier 2 approach). All theother figures are derived using actual sweetener levels present in foods. 5 Absorption, distribution, metabolism and excretion The metabolism of aspartame and its metabolic breakdown products in animals, healthy individuals and in PKU subjects has been comprehensively reviewed by Lajtha et al. (1994). Aspartame is metabolised by gut esterases and peptidases to three common dietary components - two amino acids (aspartic acid and Phe) and methanol.Animal studies have demonstrated that the metabolic breakdown products of aspartame are absorbed and metabolised similarly whether they are given alone or derived from aspartame. The extensive presystemic metabolism of aspartame results in little or no parent compound reaching the general circulation. Initial studies focused on the effects of ingesting single bolus doses of aspartame on plasma aspartate and Phe levels and blood methanol concentrations in normal adults. These studies were done with doses of aspartame approximating current levels ofdietary exposure (4 and 10 mg/kg bw), doses representative of premarketing projections of the high level intake and the ADI (34 and 40 mg/kg bw respectively), and `abuse' doses of 100, 150 and 200 mg/kg bw (Stegink and Filer 1996). The plasma Phe concentrations in healthy adults administered various doses of aspartame have been compared to values obtained: (1) in the fasting and postprandialstate; (2) in individuals who are heterozygous for PKU; and (3) in subjects with various forms of hyperphenylalaninaemia other than PKU (Stegink et al 1990;Stegink and Filer, 1996). The data indicated that the plasma Phe concentrations after single bolus doses (ranging between 4 and 50 mg/kg bw) and repeated doses (30 and 69 mg/kg bw given as 3 and 8 divided doses respectively) of aspartame were generally within the normal postprandial range for this amino acid and well below those measured in subjects homozygous for PKU after ingestion of aspartame. The aspartate component is rapidly metabolised and thus the plasma aspartate concentrations are not significantly elevated following aspartame doses of 34 to 50 mg/kg bw, whereas plasma Phe concentrations may increase depending on dose (Stegink, 1984). Methanol is also rapidly metabolised and blood levels are usually not detectable unless large bolus doses of aspartame (>50 mg/kg bw) are administered. Genotoxicity and carcinogenicity The available mutagenicity and long-term carcinogenicity studies on aspartame were recently reviewed by AFSSA (2002). AFSSA noted that: "Aspartame is not genotoxic in a reverse mutation test on S. typhimurium, in two chromosome aberration tests in vivo on somatic cells and in Rodent 6 dominant lethal test on germ cells (JECFA, 1980). Recently, two studies have confirmed the absence of clastogenic potential (Durnev et al., 1995; Mukhopadhyay et al., 2000) of the compound." The AFSSA report also noted: "Trocho et al., (1998) demonstrated that aspartame, radio-labelled on the methanol, induced in the liver stable DNA and protein adducts. According to these authors, the accumulation of these adducts after repeated administrationof aspartame could pose problems of toxicity and carcinogenicity in the long term. Besides the fact that aspartame at high doses has never induced liver cancer in rats, Trocho's studies did not identify the radioactivity found in the proteins and DNA. Consequently, the formation of adducts of formaldehyde on the proteins and nucleic acids from aspartame, in vivo, remains to be proved (Tephly, 1999)."
As regards the long-term studies, the AFSSA report noted that: "In a carcinogenicity study on CD-1 mice (FDA, FR 1981), aspartame administered in feed at doses of 1, 2 and 4 g/kg bw/day for 110 weeks, showed no carcinogenic potential." "Three carcinogenicity studies were conducted in Sprague Dawley and Wistar rats. In the first study (1973), post-weaning Sprague Dawley rats were fed doses of aspartame corresponding to 1, 2, 4, 6/8 g/kg bw/day for 104 weeks (6/8 i.e. dose of 6 was increased during the study to 8 g/kg bw/day). In the second study (1974), male and female Sprague Dawley rats, from a two generation study, were exposed during gestation, lactation and after weaning for 104 weeks, to doses of 0, 2 and 4 g/kg bw/day in their food. The results of these two studies have been widely discussed by the scientific community and the regulatory authorities (FDA). In the first study, the incidence of brain tumours in the treated animals was higher than in the control animals but without any dose-response relationship. In contrast, in the second study the incidence of tumours in the treated rats was lower than in the control group.
For these reasons, a third study was conducted under conditions of Good Laboratory Practice in order to ensure the reliability of the experimental data. In this third study (Ishii, 1981), groups of male and female Wistar rats were given doses of aspartame of 0, 1, 2, 4 g/kg bw/day for 104 weeks. Under theseconditions, aspartame did not cause any increase in the incidence of brain tumours."
AFSSA concluded as follows on carcinogenicity: "Taking into account all the studies that have been conducted, the frequency of spontaneous tumours in laboratory rats, the types of tumours observed and the absence of a dose-response relationship, it was concluded that aspartame had no carcinogenic potential on the brain in experimental animals (FDA FR, 1981-1984; Koestner, 1984; Cornell et al., 1984; Flamm, 1997)."
Epidemiological data Concerning the epidemiological data on brain tumours, the AFSSA (2002) report noted that: "In 1996, Olney et al. published an article on a possible link between the increase in the frequency of brain tumours in humans and the consumption of aspartame in the United States. Based on the data from the National Cancer Institute (10% of the population) from 1975-1992, the authors concluded that there was a significant increase in the frequency of brain tumours in the mid- 1980s, that is to say the period following aspartame came onto the market. The conclusions of this epidemiological study have been criticised by a number of scientists who questioned the methodology, the use of the data and their interpretation (Levy et al., 1996; Linet et al., 1999; Ross, 1998; Seife, 1999; Smith et al., 1998). One of the major criticism is that the authors only took into account the frequency of brain tumours during a selected period (1975- 1992). When all the epidemiological data are used (1973-1992) a different conclusion is reached, as the frequency of brain cancers began to increase in 1973 and stabilised from the mid-1980s (Levy et al., 1996). Furthermore, Olney et al. did not provide any quantitative or qualitative relationship between the exposure of the population to aspartame and the observedfrequency of brain tumours. Finally, an increase in the incidence of the tumours can have many causes including, among others, improvements in diagnostic methods (Modan et al., 1992)." "More recently, Gurney et al., (1997) published the results of a case-control study on the relationship between the consumption of aspartame and the frequency of brain tumours. The study covered 56 patients affected by tumours in childhood and 94 controls. According to these authors, no relationship could be established between the consumption of aspartame and the frequency of brain tumours." "In France, data on the incidence of and mortality from brain cancers were supplied by the FRANCIM network (F. M goz et al., 2001). These cancers include meninges tumours and tumours of the brain itself. Between 1980 and 1997, the incidence (number of new cases appearing each year) of cerebral tumours was relatively stable in men and showed a slight increase in women. The trend towards an increase in mortality from cancer of the brain and other parts of the nervous system is a longstanding one, as it first appeared in 1950and continues to the present day, for both sexes. However, during the lastdecade, mortality in men stabilised and the increase in mortality from braincancer in women was less pronounced than during the preceding period."
"In France, the epidemiological data from the cancer registers do not enable a definitive indication to be given on a possible aspartame-brain tumour relationship, but they do show that, at the present time, the sale of this food additive in France is not being accompanied by an increase in the frequency of brain tumours or increased mortality from this disease in the general population."
Reproduction and Developmental toxicity
The derivation of an ADI for aspartame by JECFA (1980) and the SCF (1985) included assessment of single- and multi-generation studies in animals that were specifically designed to examine the possible effects of aspartame and its metabolic conversion products on reproduction, and development, including neuro-development. The data used by JECFA (1980) were discussed in more recent reviews (Kotsonis and Hjelle, 1996; London and Rorick, 1996; Shaywitz, 1997; AFSSA, 2002), but no additional studies were identified which would impact on the no-observed-adverse effect level (NOAEL).
Much of the recent interest in the safety of aspartame has explored whether its consumption is linked with neurological effects. Therefore this end point has been given special consideration in this review. Shortly after the widespread marketing of aspartame, there were a number of anecdotal reports of health effects, which some consumers related to their consumption of aspartame-containing products (Hull, 1999). Most of the earlier complaints and reports of aspartame-related adverse reactions were analysed by experts at the Centres for Disease Control (CDC) in Atlanta on behalf of the FDA, who concluded that there was no symptom complex that could be assigned to the ingestion of aspartame (Janssen and Van der Heijden, 1988; Tollefson, 1988). A number of complaints were of a neurological or behavioural type (Tollefson, 1988) and these received special consideration, in part because experiments in animals haveshown that high doses (1000mg/kg bw and above in rats) can alter the concentrations of neurotransmitters and their precursors within the central nervous system (Lajtha et al., 1994). As regards the potential effect of aspartame on neurotransmitter levels, the underlying hypothesis was that aspartame, as a source of Phe without the other large neutral amino acids (LNAA) (i.e. tryptophan, valine, leucine, methionine, histidine) which compete for transport across the blood-brain barrier, would increase the serum ratio of Phe to the other LNAA, thereby selectively increasing Phe concentrations in brain. It was further suggested that such increased entry of Phe into the brain may result in disturbances in monoaminergic neurotransmission (Wurtman, 1985).
A number of animal studies were conducted to determine whether increases in plasma Phe concentrations secondary to large doses of aspartame may result in changes in 9 brain concentrations of norepinephrine, dopamine, or serotonin and their metabolites (reviewed by Schomer et al., 1996; Lajtha et al., 1994). Although effects on neurotransmitter levels were noted in some acute and repeat-dose studies at high doses in rodents, it was apparent that these effects were not consistent or reproducible. For instance, acute doses of up to 2000 mg/kg bw/d and repeated doses of up to 863 mg/kg bw/d (for 28 days) failed to induce significant changes in brain serotonin or dopamine levels and had no effect on seizure severity in rats genetically prone to epilepsy (Dailey et al., 1991).
Some changes in neurotransmitter levels in rodents were also identified in some of the older studies on aspartame (Lajtha et al., 1994). In mice given aspartame orally at 13,130 and 650 mg/kg bw, increases of 12, 49 and 47% respectively innorepinephrine were found after 3 hours in the hypothalamus; significant increases innorepinephrine in the medulla oblongata (in the low- and high-dose group animals) and corpus striatum (in the low-dose group animals) were also observed (Coulombe and Sharma, 1986). However, these increases were not dose-related and were accompanied by non-significant changes in serotonin levels. Lack of any significant effects on biogenic amine levels, following higher bolus doses (1000 mg/kg bw) of aspartame, have also been reported in both Sprague-Dawley and Fischer 344 rats (Freeman et al., 1990).Glutamic and aspartic acids act as excitatory neurotransmitters at glutamate receptor sites to which aspartic acid also shows affinity. A more recent study evaluated brain glutamatergic receptor kinetics following perinatal exposure to large doses of aspartame (500 mg/kg bw/day) (Reilly and Lajtha, 1995). In this study aspartame indrinking water was administered to Sprague-Dawley rats throughout gestation and lactation. The kinetics of the N-methyl-D-aspartate receptor and total glutamatergic binding in cerebral cortex and hippocampus of the offspring (20-22 days old) were found to be unaffected by perinatal exposure to aspartame. However, statistically significant but reversible reductions in glutamic acid levels in both brain regions and of aspartate in the hippocampus were noted. The same group of workers reported an absence of effects on dopaminergic, adrenergic and serotonergic receptor bindingkinetics in adult rat brain with chronic exposure to aspartame (Reilly et al., 1989).Behaviour, Cognition and Mood Some years ago, it was hypothesised that aspartame, primarily due to its content of Phe, could have an effect on human behaviour, cognition, and possibly on measures of physiological function (Wurtman, 1985). However, no consistent and reproducible effects were observed in a number of older animal studies investigating the effects of aspartame on neurotransmitter levels. Only a limited number of studies on behavioural aspects in animals have been published in the last ten years. A proportion of these focused on seizure activity but a causal link with aspartame could not be established; no adverse effects on other aspects of behaviour and cognition were reported in experimental animals when aspartame was given at oral dose levels of up to 2000 mg/kg bw/day (Yirmiya et al., 1989; Tilson et al., 1991; Mullenix et al., 1991; Vitulli et al., 1996; LaBuda and Hale, 2000; Goerss et al., 2000).
A number of anecdotal reports in humans were received by the manufacturers of aspartame in early to mid 1980's relating to a variety of symptoms following the marketing of aspartame in the USA. About two-thirds of these symptoms fell into the neurobehavioural category (Butchko and Stargel, 2001). These consisted mostly of headaches (see below), mood alterations, insomnia, and dizziness. More than 500 reports were received by CDC, and almost half underwent follow-up and evaluation.
A post-marketing surveillance system was developed by the NutraSweet company (Butchko and Kotsonis, 1994; Butchko et al., 1996), which was followed by scientific research on these neurological symptoms (see below). A number of scientific studies were carried out in healthy and potentially sensitive individuals, including children, to test whether the consumption of aspartame was associated with behavioural and cognitive changes. The potentially sensitive individuals studied were, heterozygotes for PKU, individuals suffering from depression, Attention Deficit Disorder (ADD), Parkinson's Disease, epilepsy or othersuspected seizures. They included double-blind studies in children (Saravis et al.,1990; Shaywitz et al., 1994) in which no effects were observed on behaviour, mood or learning when aspartame was given as a drink at single and multiple doses of 34 mg/kg bw/day for up to two weeks. The longer-term study of Shaywitz et al. (1994) examined the effect of aspartame in children with ADD and included an assessment of liver function as well as measurement of plasma levels of amino acids, serotonin andmonoamine metabolites. Treatment-related effects were also absent in a study of preschoolchildren who were given aspartame at 32 mg/kg bw/day and described as sugarsensitive by their parents (Wolraich et al., 1994).
A number of double-blind behavioural studies of variable quality in healthy adults, involving single and repeated administrations of aspartame have also been conducted. No treatment-related effects were noted in tests on a range of cognitive parameters in studies employing single administrations of aspartame at doses of up to 60 mg/kgbw/day (Lieberman et al., 1988; Lapierre et al., 1990; Pivonka and Grunewald, 1990;Stokes et al., 1991, 1994). However, it can be argued that single dosing studies employing high amounts of aspartame do not reflect typical consumption patterns. A number of longer term studies with a double-blind design involving multiple dosing in healthy individuals also failed to highlight any treatment-related adverse effects on 11behaviour (Spiers et al., 1998; Leon et al., 1989). As noted with shorter-term studies ,no treatment-related effects on behaviour were noted even when aspartame was tested at 74 mg/kg bw/day for periods extending up to 24 weeks. Although Phe concentrations increased significantly as a result of treatment with aspartame, there were no significant effects noted on behaviour, mood or electroencephalogram (EEG) patterns, nor on a comprehensive battery of clinical laboratory tests. Headache was the most frequently reported adverse effect in placebo- and aspartame-treated groupsbut there were no significant differences noted between groups.
Several sub-populations of individuals who may potentially be sensitive to aspartame have also been studied. From a double-blind study with a cross-over design in 13 depressed patients, Walton et al. (1993) concluded that aspartame (30 mg/kg bw/day for 7 days) increased the frequency and severity of adverse experiences in these individuals. These authors concluded that the use of aspartame in individuals with mood disorder should be discouraged. However, it is difficult to interpret this study since the authors numerically combined unrelated adverse effects to show a statistically significant result in depressed patients and only a limited number of subjects were available for evaluation due to premature termination of the study. The effect of aspartame on behaviour, cognition and EEG patterns has also been investigated in PKU heterozygotes. Older studies in PKU homozygotes and those heterozygous for the condition have been reviewed elsewhere (de Sonneville and Benninger, 1996, and references therein). Overall, the authors concluded that aspartame did not affect cognitive function and EEG profiles in either the general population or those heterozygous for PKU. In a more recent double-blind study, which included assessment of plasma amino acid levels and EEG patterns (Trefz etal., 1994), the subjects ingested aspartame (15 or 45 mg/kg bw/day) and placebo for12 weeks. The battery of behavioural tests included tests for short-term memory, reaction time and various attention tasks. Although headaches were among the mild adverse symptoms reported, there was no statistically significant difference between treatments. There was a significant rise in Phe in the high-dose group in contrast to the low-dose group and this was also the case for the ratio of Phe to LNAA. However,aspartame had no significant effect on cognitive function or EEG profiles.
Headache was one of the more common symptoms that was reported to the FDA and evaluated by the CDC (Janssen and Van der Heijden, 1988; Tollefson, 1988). Several studies were carried out to test the potential association between aspartame intake and the onset of headaches. Although the results of a questionnaire-based study (Lipton et al., 1989) and two double-blind out-patient investigations (Koehlerand Glaros, 1988; Van Den Eeden et al., 1994) employing daily doses of up to 30 mg/kg bw/day indicated a potential association between aspartame intakes and 12 headache, it was not possible to deduce causality as the effect of diet had not been adequately controlled for and the interpretation of the data was complicated by a high drop out rate and a limited experimental design.
Another study employing a controlled environment, which was also a randomised double-blind placebo-controlled cross-over trial, concluded that aspartame was no more likely than placebo to trigger headaches (Schiffman et al., 1987). This study consisted of 40 subjects who complained of aspartame-related headaches. Subjects received aspartame challenges on days three or five at a total dose of 30 mg/kg bw (for a 70 kg person); subjects received placebo on the other days.
While 35% of subjects developed headaches while on aspartame, 45% developed headaches while on placebo. In addition, no treatment related effects were detected in blood pressure, or plasma concentrations of cortisol, insulin, glucagon, histamine, epinephrine or norepinephrine. The subjects who had headaches had lower plasma concentrations of norepinephrine and epinephrine just before the development of headache. This study has been criticised for using tightly controlled experimental conditions which did not mimic normal life (Edmeads, 1988), but Schiffman et al. (1987) argued that the nature of the study and the primary focus of the questions raised by CDC dictated that they use carefully controlled conditions at a hospital setting.
The AFSSA (2002) report noted that"Among the possible adverse effects of aspartame, researchers have paid particular attention to seizures. Several studies have suggested a relationship between the consumption of large amounts of aspartame and the triggering of epileptic seizures. In an old study (1972), on new-born monkeys (2-3 animals per group) treated with doses of aspartame of 1, 3 and 4g/kg bw/day for 52 weeks, epileptic seizures were recorded at the highest doses, after 218 days of treatment. Thereafter, sporadic convulsions were observed during handling of the animals. These symptoms were identical with those observed in young monkeys treated with phenylalanine."
"In contrast, in a similar study also conducted on young monkeys, no effect was observed at doses of aspartame of 2 and 2.7 g/kg bw/day. The different results observed in the two studies could be explained by differences in the exposure conditions, the food and the state of health of the animals (JECFA, 1980)."
"Walton et al. (1993) reported, in a study conducted on 13 patients suffering from depression, that the administration of 30 mg/kg bw/day of aspartame for 7 days caused severe side effects in these patients which led the authors to conclude that the use of this sweetener in depressive patients should be avoided. The same author (Walton, 1986) reported a case of 7 epileptic 13 seizures and serious behavioural problems in a woman being treated with antidepressants who ingested large quantities of tea containing aspartame."
"Wurtman (1985) indicated that the administration of aspartame, due to an increase in phenylalanine absorption in the brain, could affect the synthesis of catecholamines or serotonin and cause seizures. He based his findings on three examples of heavy consumers of "diet" drinks and on experimental studies on animals demonstrating that the consumption of aspartame reduced the threshold of sensitivity to chemically induced seizures (Maher et al., 1987; Guiso et al., 1988; Pinto et al., 1988). Finally Camfield et al. (1992) demonstrated that aspartame could increase the duration of certain types of epileptic seizure in children." "The ATIC on the Internet reported a large amount of evidence from people who have identified aspartame as the cause of their health problems and in particular of seizures. These statements should be taken into account but with the reservation that they have not been examined according to any academic standard. They may, however, in certain cases, reflect the hypersensitivity of certain individuals to aspartame or its metabolites. Effects on seizures have been reported with phenylalanine, aspartic acid and methanol but these were under specific conditions (high doses, individual sensitivity, types of seizures, etc.) which are not representative of the general population and of current use of this sweetener in food (Anderson et al., 1996). This causal relationship between aspartame and epileptic seizures has been refuted by a large number of scientists who base their opinions on numerous experimental studies conducted on laboratory animals or on clinical or tolerance studies in humans (Anderson et al., 1996; Gaull, 1985; Rowan et al., 1995; Shaywitz et al., 1994;Tollefson et al., 1992; 1993; Dailey et al., 1991; Zhi et al., 1989; Sze, 1989;Tilson et al., 1989)." "The Epilepsy Institute in the USA has also concluded that aspartame is not the cause of epileptic seizures (Congressional Record, June 20, 1986). In the United States various consumer complaints about aspartame have been collected by the Special Nutritionals Adverse Event Monitoring System (SN/AEMS). The sources of these reports were the FDA, federal and local health agencies, consumers and health professionals. Of 2621 side effects reported, concerning 3451 products, some ten cases concerned preparations concerning aspartame (mixtures also containing vitamins, amino acids and various nutritional supplements). The effects reported included seizures, death, nervous and cardiac symptoms, oedema and fever. Still in the United States, the Center for Disease Control assessed 517 complaints about aspartame (1983). The symptoms reported were headaches, mood changes, insomnia, abdominal pain, nausea, convulsions, etc These symptoms are observed frequently in the general population. Although it might be possible that certain individuals are particularly sensitive to aspartame, these data, which relate to a large number of people, have not enabled any relationship to be demonstrated between the consumption of aspartame and the occurrence of convulsive seizures." Other effects 14Idiosyncratic reactions described as allergic-like (hives, rashes) were reported by some consumers to CDC in response to aspartame (Tollefson, 1988). However, the results of a multi-centre, randomised, double-blind, placebo-controlled, cross-over study in individuals who were convinced they were allergic to aspartame indicated that aspartame and its conversion products are no more likely than placebo to cause urticaria and angio-oedema (Geha et al., 1993). This finding was supported by the outcome of another study, which also demonstrated that alleged allergic reactions to aspartame were not reproducible under blinded conditions (Garriga et al., 1991).However as with the Geha et al. (1993) study, the authors reported major difficultiesin enrolling subjects with a history of allergy/hypersensitivity reactions to aspartame.A number of other studies focused on the effects of aspartame on hunger and food intake (Rolls and Shide, 1996) and in the control of body weight (Kanders et al.,1996). Sensory and post-ingestion experience with aspartame was reported by these reviewers not to be associated with increased energy intake or increases in body weight.
Since the SCF's extensive reviews of aspartame were carried out in 1984 and 1988 (SCF, 1985, 1989), the objective of the present review was to identify any more recent data suggesting there might be additional endpoints requiring evaluation or effects at lower doses than those previously considered. To this end, consideration has been given to aspects of metabolism and toxicity as well as to clinical studies conducted to address the reported adverse effects of aspartame in healthy and potentially sensitive individuals. Consideration has also been given to recent estimates of intake.
Aspartame is unique among the intense sweeteners in that the intake of its componentparts can be compared with intakes of the same substances from natural foods. It is clear that the consumption of aspartame represents only a minor source of aspartic acid, Phe or methanol in the diet (Renwick, 1990). The available estimates of intake of aspartame by mean and high level consumers are fairly consistent among European countries, even though different approaches were used for the assessment. They show that intakes in high level consumers, including adults, children, and diabetics of all ages, range up to 10 mg/kg bw/day and thus are unlikely to exceed the current ADI for aspartame of 40 mg/kg bw established by the SCF (1985, 1989).
Studies both in healthy subjects and in PKU heterozygotes confirm the SCF's earlier conclusion (SCF, 1989) that despite the plasma variations in Phe levels following single and repeated administrations of aspartame, Phe levels generally remain within normal postprandial limits.
In 1996, a report suggesting a connection between aspartame and an increase in the incidence of brain tumours in the USA was published (Olney et al., 1996). The SCF considered this report and concluded that the data did not support the proposed biphasic increase in the incidence of brain tumours (SCF, 1997). The issue had also been considered earlier by the FDA and by the UK Committee on Carcinogenicity of Chemicals in Food, Consumer Products and the Environment (COC). The FDA stated that analysis of the National Cancer Institute database on cancer incidence in the USA did not support an association between the use of aspartame and increased incidence of brain tumours (FDA, 1996). The COC agreed that the findings provided no evidence of the proposed biphasic increase in the incidence or either all brain tumours or selected tumour types in the USA during the 1980's and concluded that the data published by Olney et al. did not raise any concerns with regard to the use of aspartame in the UK (COC, 1996). The recent review by AFSSA (2002) covered all the original experimental studies and concluded that aspartame and DKP are notgenotoxic and that none of the carcinogenicity tests on rodents indicate a relationship between treatment with aspartame and the appearance of brain tumours. The Committee agrees with this conclusion concerning the experimental studies.
AFSSA also reviewed more recent publications on the human epidemiological data and concluded that "The epidemiological study by Olney et al., which suggested a link between the placing on the market of aspartame and a possible increase in the frequency of brain cancers in humans, did not provide any scientific evidence to justify or demonstrate a basis for this suggestion; to date it has not been confirmed." (AFSSA, 2002). The Committee agrees with this view and reaffirms its conclusion of 1997 (SCF, 1997). The Committee has also reviewed the study by Trocho et al. (1998), who reported the occurrence of stable DNA and protein adducts in the liver of rats following aspartame administration. The Committee noted that the study used aspartame radiolabelled on the methanol portion, and that during metabolism of aspartame in the gut, radiolabelled methanol will be split off and enter the body's one- carbon pool, with the potential to appear anywhere there is methylation. The Committee therefore agrees with the analysis of Tephly (1999) that formation of DNA adducts has not been demonstrated. AFSSA (2002) has also evaluated the scientific literature on epilepsy and EEG anomalies and concluded that there is a lack of evidence, based on the current state of knowledge, which would enable a causal link to be established between the consumption of aspartame and the occurrence of epileptic seizures or anomalies on an electro-encephalogram. The Committee agrees with this conclusion of AFSSA.
The present review also addressed the data on other neurological endpoints including cognition, mood and behaviour. Although the data varied in quality, evidence for a causal relationship between aspartame consumption and these endpoints could not be established. The Committee noted that despite targeted animal studies, no consistent effects of aspartame on neurotransmitters or their precursors have been observed. Studies have also been specifically designed to follow up individuals reporting that they were sensitive to aspartame during post-marketing surveillance, together with studies on individuals, including children, who, because of underlying medical conditions, might be considered sensitive to aspartame. Aspartame administration did not induce changes in behaviour, cognition, mood or learning. The data on headaches received special consideration as this was a commonly reported symptom during postmarketing surveillance. The data on headaches vary in quality, but the one well, controlled double-blind, cross-over trial showed that aspartame was no more likely than placebo to be associated with headaches. Studies on allergic-like reactions in individuals who themselves reported such reactions to aspartame have not confirmed their occurrence when later studied under controlled conditions.
AFSSA (2002). Assessment Report: Opinion on a possible link between exposition to aspartame and the incidence of brain tumours in humans. Agence Fran se de S rit anitaire des Aliments, Maisons-Alfort. Report in French, available at http://www.afssa.fr
ATIC - Aspartame (Nutrasweet) Toxicity Info Center (1998). Thiswebsite as updated06/26/98. Available at http://www.holisticmed.com/aspartame
Anderson GM, Novotny EJ and Shaywitz BA (1996). Evaluation of seizures. In: The Clinical Evaluation of a Food Additive: Assessment of Aspartame.
Eds. Tschanz C, Butchko HH, Stargel WW, Kotsonis FN, CRC Press, Boca Raton, New York, London, Tokyo, pp 205-216.B A and Biermann C (1992). Intake of intense sweeteners in Germany. ZErn ungswiss 31: 25-39. Butchko HH and Kotsonis FN (1994).
Postmarketing surveillance in food industry: the aspartame case study. In: Nutritional Toxicology. Eds. Kotsonis FN, Mackay M, and Hjelle J. Raven Press, New York, pp 235-250. Butchko HH, Tschanz C and Kotsonis FN (1996).
Post-marketing surveillance of anecdotal medical complaints. In: The Clinical Evaluation of A Food Additive:Assessment of Aspartame. Eds. Tschanz C, Butchko HH, Stargel WW, and KotsonisFN. CRC Press, Boca Raton, FL, pp 183-193.
Butchko HH and Stargel WW (2001), Aspartame: scientific evaluation in the postmarketing period. Regul Toxicol Pharmacol 34: 221-233. Camfield PR, Camfield CS, Dooley JM, Gordon K, Jollymore S and Weaver DF(1992). Aspartame exacerbates EEG spike wave discharge in children withgeneralised absence epilepsy: a double blind controlled study.Neurology 42: 1000-1003.
Coulombe RA Jr and Sharma RP (1986). Neurobiochemical alterations induced bythe artificial sweetener aspartame (NutraSweet). Toxicol Appl Pharmacol 83: 79-85.
COT (1996). Committee on Toxicity of Chemicals in Food, Consumer Products and The Environment.
1992 Annual Report of The Committees on Toxicity, Mutagenicity and Carcinogenicity. HMSO, London, pp12-15.
COC (1996). Aspartame. Committee on Carcinogenicity of Chemicals in Food, Consumer Products and The Environment (1996). Annual Report of The Committees on Toxicity, Mutagenicity and Carcinogenicity. The Stationery Office, London, pp 56-57.
Cornell RG, Wolfe RA and Sanders PG (1984). Aspartame and brain tumours: statistical issues. In: Aspartame: Physiology and Biochemistry. Eds. Stegink LD and Filer LJ Jr. Marcel Dekker Inc., New York and Basel, pp 459-479.
Dailey JW, Lasley SM, Burger RL, Bettendorf AF, Mishra PK and Jobe PC (1991).Amino acids, monoamines and audiogenic seizures in genetically epilepsy-prone rats: effects of aspartame. Epilepsy Res 8: 122-33 De Sonneville LMJ and Benninger C (1996). Evaluation of behaviour, cognition and electrocardiograms in PKU heterozygotes.
In: The Clinical Evaluationof a Food Additive: Assessment of Aspartame. Eds. Tschanz C, Butchko HH,Stargel WW, Kotsonis FN. CRC Press, Boca Raton, FL, pp 235-254.
Durnev AD, Oreshchenko AV, Kulakova AV, Beresten NF and Seredenin SB(1995). Clastogenic activity of dietary sugar substitutes. Vopr Med Khim 41(4): 31-33. EC (2001). Dietary Food Additive Intake in the European Union. Available at http://europa.eu.int/comm/food/fs/sfp/addit_flavor/flav15_en.pdf
Edmeads J (1988). Aspartame and headache. Headache 28: 64-65.
Flamm WG (1997). Increasing brain tumour rats: is there a link to aspartame? J Neurpathol Exp Neurol 56: 105-106.
FDA (1984). Food additives permitted for direct addition to food for human consumption: aspartame. Food and Drug Administration. Federal Register 49: 6672. FDA (1981-1984). Food additives permitted for direct addition to food for human consumption; aspartame, Food and Drug Administration. Federal Register, 46FR38285, 1981; 48FR31376, 1983; 49FR6672, 1984.
FDA (1996). Food and Drug Administration Statement on Aspartame. Talk Paper T96-74, November 18, 1996. Freeman G, Sobotka T and Hattan D (1990). Acute effects of aspartame on concentrations of brain amines and their metabolites in selected brain regions of Fischer-344 and Sprague-Dawley rats. Drug and Chem Tox 13: 113-133.
Garnier-Sagne I, Leblanc JC and Verger Ph (2001). Calculation of the intake of three intense sweeteners in young insulin-dependent diabetics. Food and Chemical Toxicology 39: 745-749.Garriga MM, Berkebile C and Metcalfe DD (1991). A combined single- blind, doubleblind, placebo-controlled study to determine the reproducibility of hypersensitivityreactions to aspartame. J Allergy Clin Immunol 87: 821-827.
Gaull GE (1985). Aspartame and seizures. Lancet 2 (8469-70): 1431.
Geha R, Buckley CE, Greenberger P, Patterson R, Polmar S, Saxon A, Rohr A, Yang W and Drouin M (1993). Aspartame is no more likely than placebo to cause urticaria/angioedema: results of a multicenter, randomized, double-blind, placebocontrolled, crossover study. J Allergy Clin Immunol 92: 513-520.
Goerss AL, Wagner GC and Hill WL (2000). Acute effects of aspartame on aggression and neurochemistry of rats. Life Sciences 67: 1325-1329.
Guiso G, Caccia S, Vezzani A, Stasi MA, Salmona M, Romano M and Garattini S (1988). Effect of aspartame on seizures in various models of experimental epilepsy. Toxicol Appl Pharmacol 96: 485-493.
Gurney JG, Pogoda JM, Holly EA, Hecht SS and Preston-Martin S (1997). Aspartame consumption in relation to childhood brain tumour risk: results from a case-control study. J Nat Cancer Inst 89: 1072-1074.
Hull JS (1999). Sweet Poison-How the world's most popular artificial sweetener is harming us. New Horizon Press, London.
Hinson AL and Nicol WM (1992). Monitoring sweetener consumption in Great Britain. Food Additives and Contaminants 9: 669-681. Ishii H (1981). Incidence of brain tumours in rats fed aspartame. Toxicol Lett 7: 433-437. Janssen PJ, and van der Heijden CA (1988). Aspartame: review of recent experimental and observational data. Toxicology 50: 1-26.
JECFA (1980). Aspartame; Evaluation of certain food additives. Joint FAO/WHO Expert Committee on Food Additives. Technical Report Series 653. World Health Organization, Geneva. Kanders BS, Blackburn GL Lavin PT and Kienholz M (1996). In: The Clinical Evaluation of a Food Additive. Assessment of Aspartame. Eds. Tschanz C, Butchko HH, Stargel WW, and Kotsonis FN. CRC Press, Boca Raton, FL, pp 289-299. Koestner A (1984). Aspartame and brain tumours: pathology issues. In Aspartame: Physiology and Biochemistry. Eds. Stegink LD and Filer LJ Jr, Marcel Dekker Inc., New York and Basel, pp 447-457. Kotsonis FN and Hjelle JJ (1996). The safety assessment of aspartame: Scientific and regulatory considerations. In: The Clinical Evaluation of a Food Additive: Assessment of Aspartame. Eds. Tschanz C, Butchko HH, Stargel WW, Kotsonis FN, Boca Raton, CRC Press. Pp 23-41. Koehler SM and Glaros A (1988). The effect of aspartame on migraine headache. Headache 28: 10-14.
LaBuda CJ and Hale RL (2000). Anxiety in mice following acute aspartame and ethanol exposure. Alcohol 20: 69-74.
Lajtha A, Reilly MA, and Danlop DS (1994). Aspartame consumption: Lack of effects on neural function. J Nutr Biochem 5: 226-283.
Lapierre KA, Greenblatt DJ, Goddard JE, Harmatz JS and Shader RI (1990). The neuropsychiatric effects of aspartame in normal volunteers. J Clin Pharmacol 30: 454-60.Leclercq C, Berardi D, Sorbillo MR and Lambe J (1999). Intake of saccharin,aspartame, acesulfame K and cyclamate in Italian teenagers: present levels andprojections. Food Additives and Contaminants 16: 99-109.
Lieberman HR, Caballero B, Emde GG, and Bernstein JG (1988). The effects of aspartame on human mood, performance, and plasma amino acid levels. In: Dietary Phenylalanine and Brain Function. Eds. Wurtman RJ and Ritter-Walker E. Birkh er, Boston, pp 196-200.
Leon AS, Hunninghake DB, Bell C, Rassin DK and Tephly TR (1989). Safety of long-term large doses of aspartame. Arch Int Med 149: 2318-2324. Levy P and Hedeker D (1996). Statistical and epidemiological treatment of the SEER incidence data. J Neuropathol Exp Neurol 55: 1280.
Linet MS, Ries LA, Smith MA, Tarone RE and Devesa SS (1999). Cancer surveillance series: recent trends in childhood cancer incidence and mortality in the United States. J Natl Cancer Inst 91: 1382-1390.
Lipton RB, Newman LC, Cohen JS and Solomon S (1989) Aspartame as a dietary trigger of headache. Headache 29: 90-92. London RS and Rorick JT (1996). Safety evaluation in pregnancy. In: The Clinical Evaluation of a Food Additive: Assessment of Aspartame. Eds.
Tschanz C, Butchko HH, Stargel WW, Kotsonis FN. CRC Press, Boca Raton, FL, pp115-124. MAFF (1990), Intake of Intense and Bulk Sweeteners in the UK 1987- 1988, Food Surveillance Paper No. 29, Ministry of Agriculture, Fisheries and Food. HMSO, London. MAFF (1995), Survey of the Intake of Sweeteners by Diabetics. Food Surveillance Information sheet No. 76. Ministry of Agriculture, Fisheries and Food, London. Maher TJ and Wurtman RJ (1987). Possible neurologic effects of aspartame, a widelyused food additive. Environ Health Perspect 75: 53-57.
Meldrum BS (1993). Amino acids as dietary excitotoxins: a contribution tounderstanding neurodegenerative disorders. Brain Res 18: 293-314.
M goz F, Grosclaude P et le groupe FRANCIM des registres fran s des cancers (2001). Data on the incidence of and mortality from brain cancers in France, were supplied by the FRANCIM network "Incidence des tumeurs c brales en France - Situation en Juillet 2000. Rapport 'Agence Fran se de S rit br> Sanitaire des Aliments. Juillet 2001".
Modan B, Wagener DK, Feldman JJ, Rosenberg HM and Feinleib M (1992). Increased mortality from brain tumours: a combined outcome of diagnostic technology and change of attitude towards the elderly. Am J Epidemiol 135: 1349-1357.
Mullenix PJ, Tassinari MS, Schunior A and Kernan WJ (1991). No change in spontaneous behavior of rats after acute oral doses of aspartame, phenylalanine, and tyrosine. Fundam Appl Toxicol 16: 495-505.
Mukhopadhyay M, Mukherjee A and Chakrabarti J (2000). In vivo cytogenetic studies on blends of aspartame and acesulfame-K. Food Chem Toxicol 38: 75-77.
Olney JW, Farber NB, Spitznagel E and Robins LN (1996). Increasing brain tumor rates: is there a link to aspartame? J Neuropathol Exp Neurol 55:1115-1123.
Pardridge WM (1986). Potential effects of the dipeptide sweetener aspartame on the brain. In: Nutrition and the Brain 7. Eds. Wurtman RJ and Wurtman JJ, Raven Press, New York.
Pinto JM and Maher TJ (1988). Administration of aspartame potentiates pentenetrazole- and fluorothyl-induced seizures in mice. Neuropharmacology 27: 51-55.
Pivonka EE and Grunewald KK (1990). Aspartame- or sugar-sweetened beverages: effects on mood in young women. J Am Diet Assoc 90: 250-254.
Reilly MA, Debler EA, Fleischer A and Lajtha A (1989). Lack of effect of chronic aspartame ingestion on aminergic receptors in rat brain. Biochem Pharmacol 38:4339-41.
Reilly MA and Lajtha A (1995). Glutamatergic receptor kinetics are not altered by perinatal exposure to aspartame. Neurochem Int 26: 217-222.
Renwick AG (1990). Intake of Intense Sweeteners, Low-Calorie Sweeteners: Present and Future. Ed. Corti A. World Rev Nutr Diet. Basel, Karger, vol 85, 178-200.
Rolls BJ and Shide DJ (1996). Evaluation of hunger, food intake and body weight. In: The Clinical Evaluation of A Food Additive: Assessment of Aspartame. Eds.
Tschanz C, Butchko HH, Stargel WW, and Kotsonis FN, CRC Press, Boca Raton, FL, pp 275-288.
Ross JA (1998). Brain tumours and artificial sweeteners? A lesson on not getting soured on epidemiology. Med Pediatr Oncol 30: 7-8.
Rowan AJ, Shaywitz BA, Tuchman L, French JA, Luciano D and Sullivan CM (1995). Aspartame and seizure susceptibility: results of a clinical study in reportedly sensitive individuals. Epilepsia 36: 270-275.
Salminen M and Penttil L (1999) Intake of food additives by 1-6 year-old children, National Food Administration/Research notes 4, Helsinki.
Saravis S, Schachar R, Zlotkin S, Leiter LA and Anderson GH (1990).
Aspartame: effects on learning, behavior, and mood. Pediatrics 86: 75-83. SCF (1985). Sweeteners. Reports of the Scientific Committee for Food (Sixteenth Series), EUR 10210 EN, Commission of the European Communities, Luxembourg.
SCF (1989). Sweeteners. Reports of the Scientific Committee for Food (Twenty-first Series), EUR 11617 EN, Commission of the European Communities, Luxembourg.
SCF (1997). Minutes of the 107th Meeting of the Scientific Committee for Food, held on 12-13 June 1997 in Brussels. Available at: http://europa.eu.int/comm/food/fs/sc/oldcomm7/out13_en.html
Schiffman SS, Buckley CE, Sampson HA, Massey EW, Baraniuk JN, Follett JV, and Warwick ZS (1987). Aspartame and susceptibility to headache. N Engl J Med 317:1181-1185.
Schomer DL, Spiers PA and Sabounjian LA (1996). Evaluation of behaviour, cognition, mood and electroencephalograms in Normal adults and potentially vulnerable populations. In: The Clinical Evaluation of a Food Additive: Assessment of Aspartame. Eds. Tschanz C, Butchko HH, Stargel WW, Kotsonis FN, Boca Raton, CRC Press, pp 217-234.
Seife C (1999). Increasing brain tumour rates: is there a link to deficit spending. J Neuropathol Exp Neurol 58: 404-405.
Shaywitz BA, Anderson GM, Novotny EJ, Ebersole JS, Sullivan CM and Gillespie SM (1994). Aspartame has no effect on seizures or epileptiform discharges in epileptic children. Ann Neurol 35: 98-103.
Shaywitz BA (1997). Aspartame and development. In: Environmental Toxicology and Pharmacology of Human Development, eds Kacew S and Lambert G, Taylor and Francis, London, pp 161-173.
Smith MA, Freidlin B, Ries LA and Simon R (1998). Trends in reported incidence of primary malignant brain tumours in children in the United States. J Natl Cancer Inst 90: 1269-1277.
Spiers PA, Sabounjian L, Reiner A, Myers DK, Wurtman J and Schomer DL (1998) Aspartame: neuropsychologic and neurophysiologic evaluation of acute and chronic effects. Am J Clin Nutr 68: 531-537.
Stegink LD (1984). Aspartame metabolism in humans: acute dosing studies, In: Aspartame: Physiology and Biochemistry. Eds. Stegink LD, Filer LJ Jr, Marcel Dekker, New York and Basel, pp 509-553. Stegink LD, Filer LJ, Bell EF, Ziegler EE, Tephly TR and Krause WL (1990). Repeated ingestion of aspartame sweetened beverages; further observations in individuals heterozygous for phenylketonuria. Metabolism 39: 1076-1081.
Stegink LD and Filer J (1996). Effects of aspartame ingestion on plasma aspartate, phenylalanine, and methanol concentrations in normal adults. In: The Clinical Evaluation of a Food Additive: Assessment of Aspartame. Eds. Tschanz C, Butchko HH, Stargel WW, Kotsonis FN, Boca Raton, CRC Press. Pp 67-86.
Stokes AF, Belger A, Banich MT and Taylor H (1991). Effects of acute aspartame and acute alcohol ingestion upon the cognitive performance of pilots. Aviat Space Environ Med 62: 648-653.
Stokes AF, Belger A, Banich MT and Bernadine E (1994). Effects of alcohol and chronic aspartame ingestion upon performance in aviation relevant cognitive tasks. Aviat Space Environ Med 65: 7-15.
Sze PY (1989). Pharmacological effects of phenylalanine on seizure susceptibility: an overview. Neurochem Res 14: 103-111.
Tilson HA, Thai L, Zhao D, Sobotka TJ and Hong JS (1989). Oral administration of aspartame is not proconvulsant in rats. Neurotoxicology 10: 229-238.
Tilson HA, Hong JS and Sobotka TJ (1991). High doses of aspartame have no effects on sensorimotor function or learning and memory in rats. Neurotoxicol Teratol 13:27-35.
Tollefson L. (1988) Monitoring adverse reactions to food additives in the U.S. Food and Drug Administration. Regul Toxicol Pharmacol 8: 438-446. Tollefson L and Barnard RJ (1992). An analysis of FDA passive surveillance reports of seizures associated with consumption of aspartame. J Am Diet Assoc 92: 598-601.
Tollefson L (1993). Multiple chemical sensitivity: controlled scientific studies as proof of causation. Regul Toxicol Pharmacol 18: 32-43. Tephly TR (1999). Comments on the purported generation of formaldehyde and adduct formation from the sweetener aspartame. Life Sci 65 (13): 157-160. Trefz F, de Sonneville L, Matthis P, Benninger C, Lanz-Englert B and Bickel H (1994). Neuropsychological and biochemical investigations in heterozygotes for phenylketonuria during ingestion of high dose aspartame (a sweetener containing phenylalanine). Hum Genet 93: 369-374.
Trocho C, Pardo R, Rafecas I, Virgili J, Remesar X, Fernandez-Lopez JA and Alemany M (1998). Formaldehyde derived from dietary aspartame binds to tissue components in vivo. Life Sci 63: 337-349. Tschanz C, Butchko HH, Stargel WW and Kotsonis FN (Editors) (1996). The ClinicalEvaluation of a Food Additive: Assessment of Aspartame. Boca Raton, CRC Press, pp 308. 24 Van den Eeden SK, Koepsell TD, Longstreth WT Jr, van Belle G, Daling JR and McKnight B (1994). Aspartame ingestion and headaches: a randomized crossover trial.
Neurology 44: 1787-1793. Vitulli WF, McAleer JE, Rockwell AC, Granade CR, Parman DL, Benoit C and Quinn JM (1996). Aspartame's effects on behavioral thermoregulation in albino rats.
Percept Mot Skills 83: 15-20. Walton RG, Hudak R and Green-Waite RJ (1993). Adverse reactions to aspartame: double-blind challenge in patients from a vulnerable population. Biol Psychiatry 34:13-17. Walton RG (1986). Seizure and mania after high intake of aspartame. Psychosomatics 27: 218-220. Wolraich ML, Lindgren SD, Stumbo PJ, Stegink LD, Appelbaum MI and Kiritsy MC (1994). Effects of diets high in sucrose or aspartame on the behavior and cognitive performance of children. N Engl J Med 330: 301-307. Wurtman RJ (1985). Neurochemical changes following high-dose aspartame with dietary carbohydrate. N Engl J Med 309: 429-430.
Yirmiya R, Levin ED and Chapman Garcia J (1989). Morphological and behavioral effects of perinatal exposure to aspartame Nutrasweet on rat pups. Bull Psychon Soc 27: 153-156. Zhi JQ and Levy G (1989). Aspartame and phenylalanine do not enhance theophylline-induced seizures in rats. Res Commun Chem Pathol Pharmacol 66: 171-174.