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The artificial sweetener aspartame has been the subject of controversy regarding its safety since its initial approval by the U.S. Food and Drug Administration (FDA) in 1974. Some scientific studies, combined with allegations of conflicts of interest in the sweetener's FDA approval process, have been the focus of vocal activism, conspiracy theories and hoaxes regarding postulated risks of aspartame.

A 2007 safety evaluation found that the weight of existing scientific evidence indicates that aspartame is safe at current levels of consumption as a non-nutritive sweetener. The sources and claims of many alleged aspartame dangers and conspiracies have been the subject of critical examination. In 1987, the U.S. Government Accountability Office concluded that the food additive approval process had been followed for aspartame. Based on government research reviews and recommendations from advisory bodies such as the European Commission’s Scientific Committee on Food and the Joint FAO/WHO Expert Committee on Food Additives, aspartame has been found to be safe for human consumption by more than ninety countries world-wide. In 1999, FDA scientists described the safety of aspartame as "clear cut" and stated that the product is "one of the most thoroughly tested and studied food additives the agency has ever approved."

Origins of the aspartame controversy

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

Approval in the United States

Aspartame was originally approved for use in dry foods in 1974 by then FDA Commissioner Alexander Schmidt after review by the FDA's Center for Food Safety and Applied Nutrition. Producer G.D. Searle had initially submitted 168 studies on aspartame, including seven animal studies that were considered crucial by the FDA. Soon after the approval, scientist and anti-MSG activist John Olney and James Turner, a public-interest lawyer who had written a popular anti-food additive book, filed a petition for a public hearing, citing safety concerns. Schmidt agreed, pending an investigation into alleged discrepancies in the aspartame safety studies. During the interim, Searle was not permitted to market aspartame. An FDA task force and a panel of academic pathologists reviewed 15 aspartame studies by Searle, and concluded that, although minor inconsistencies were found, they would not have affected the studies' conclusions.

In 1980, a Public Board of Inquiry (PBOI) heard testimony from Olney and disagreed with his claims that aspartame could cause brain damage, including in the developing fetus. The board decided that further study was needed on a postulated connection between aspartame and brain tumours, and revoked approval of aspartame.

In 1981, FDA Commissioner Arthur Hull Hayes sought advice on the issue from a panel of FDA scientists and a lawyer. The panel identified errors underlying the PBOI conclusion that aspartame might cause brain tumours, and presented arguments both for and against approval. As a result, Hayes approved the use of aspartame in dry foods. Hayes further justified his approval with a Japanese brain tumor study, the results of which, the PBOI chairman later said, would have resulted in an "unqualified approval" from the PBOI panel. Several objections followed, but all were denied. In November 1983, Hayes left the FDA and joined public-relations firm Burson-Marsteller as a senior medical advisor. Because Burson-Marsteller had done public relations work for Searle, this decision would later fuel conspiracy theories.

Because of the approval controversy, Senator Howard M. Metzenbaum requested a report by the U.S. Government Accountability Office (GAO) of aspartame's approval. In 1987, the GAO reported that protocol had been followed and provided a timeline of events in the approval process.

Scientific Studies

Of 67 scientists who responded to a 1987 questionnaire by the US GAO, all but twelve were "generally" or "very confident" in the safety of aspartame. 26 said they were "somewhat concerned" and twelve had "major concerns" about aspartame's safety. Several scientists have recommended further research into postulated connections between aspartame and diseases such as brain tumors, brain lesions, mental disorders, and lymphoma. These disease hypotheses, combined with allegations of conflicts of interest in the approval process—which were refuted by an official US governmental enquiry—have been the focus of vocal activism and conspiracy theories regarding the possible risks of aspartame.

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

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

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

Internet rumors and activism

An elaborate hoax disseminated through the internet attributes deleterious medical effects to aspartame. This conspiracy theory claims that the FDA approval process of aspartame was tainted and cites as its source an email based upon a supposed talk by a "Nancy Markle" at a "World Environmental Conference". Specifically, the hoax websites allege that aspartame is responsible for multiple sclerosis, systemic lupus, and methanol toxicity, causing "blindness, spasms, shooting pains, seizures, headaches, depression, anxiety, memory loss, birth defects" and death.

The dissemination of the Nancy Markle letter was considered so notable that the Media Awareness Network featured one version of it in a tutorial determining the credibility of a web page. The tutorial concluded that the Markle letter was not credible. Betty Martini, who posted similar messages to Usenet newsgroups in late 1995 and early 1996, claims that an unknown person combined her original letter with other information and redistributed it as Nancy Markle. She believes that there is a conspiracy between the FDA and the producers of aspartame.This conspiracy theory has become a canonical example discussed on several internet conspiracy theory and urban legend websites. Although most of the allegations of this theory contradict the bulk of medical evidence, this misinformation has spread around the world as chain emails since mid-December 1998, influencing many websites, such as those citing an association between aspartame and systemic lupus. It has become an urban legend that continues to scare consumers.

Reported effects

Most scientific studies have found no adverse effects of aspartame ingestion, but some have reported adverse effects associated with very high dosages of aspartame, or in certain susceptible groups. One study associated headaches with doses lower than the acceptable daily intake.

The debate over possible adverse health effects has focused mainly on three metabolites of aspartame that occur naturally in the body — methanol, phenylalanine and aspartic acid — and on aspartylphenylalanine diketopiperazine, a breakdown product of aspartame before ingestion.

Methanol and formaldehyde

Approximately 10% of aspartame (by mass) is broken down into methanol in the small intestine. Most of the methanol is absorbed and quickly converted into formaldehyde and then to formic acid. The metabolism of aspartame does not damage the body because: (a) the quantity of methanol produced is too small to disrupt normal physiological processes; (b) methanol and formaldehyde are natural by-products of human metabolism and are safely processed by various enzymes; (c) there is more methanol in some natural fruit juices and alcoholic beverages than is derived from aspartame ingestion; and (d) even large doses of pure methanol have been shown in non-human primate studies to lead to ample accumulation of formic acid (as formate), while no formaldehyde was detected.

In experiments on rodents given radiolabeled aspartame, labeled protein and DNA accumulated in the brain, liver, kidneys and other tissues after ingestion of either 20 mg/kg or 200 mg/kg of aspartame. However, these scientists were not directly measuring formaldehyde, but simply measuring levels of some by-product of the methanol from aspartame.

Phenylalanine

50% of aspartame by mass is broken down into phenylalanine, one of the nine essential amino acids commonly found in foods and precursor to Tyrosine. A rise in blood plasma phenylalanine is negligible in typical use of aspartame and their studies show no significant effects on neurotransmitter levels in the brain or changes in seizure thresholds. Adverse effects of phenylalanine on fetuses have been observed only when blood phenylalanine levels remain at high levels as opposed to spiking occasionally.

Aspartic acid

40% of aspartame by mass is broken down into aspartic acid (aspartate), a natural amino acid of proteins. At high concentrations, aspartic acid can act as an excitotoxin, inflicting damage on brain and nerve cells, but aspartate does not normally cross the blood-brain barrier in most parts of the brain without active uptake by transporters.

Humans and other primates are not as susceptible to excitotoxins as rodents; therefore, it is problematic to make conclusions about human safety from high-dose excitoxin response in rodent studies. Increases in blood plasma levels of aspartic acid after ingestion of aspartame are insufficient to cause concern for human subjects researchers.

Aspartylphenylalanine diketopiperazine

Aspartylphenylalanine diketopiperazine, a type of diketopiperazine (DKP), is created in products as aspartame breaks down over time. For example, researchers found that 6 months after aspartame was put into carbonated beverages, 25% of the aspartame had been converted to DKP.

Concern among some scientists has been expressed that this form of DKP would undergo a nitrosation process in the stomach producing a type of chemical that could cause brain tumors. However, the nitrosation of aspartame or the DKP in the stomach likely does not produce chemicals that cause brain tumors. In addition, only a minuscule amount of the nitrosated chemical can be produced. There are very few human studies on the effects of this form of DKP. However, a (one-day) exposure study showed that the DKP was tolerated without adverse effects.

Insulin resistance and weight gain

Some aspartame critics, particularly those in weight loss communities, claim that aspartame contributes to weight gain and obesity due to purported spikes in the insulin level. The argument holds that the taste of sweetness or perhaps some chemical peculiarity of aspartame causes the body to secrete excess insulin even though aspartame is non-caloric. If true, this would lead to insulin resistance and eventually type II diabetes, which is ironic given that most aspartame is consumed in diet foods and sodas by people looking to monitor their weight and prevent diabetes and other health concerns. However, recent studies have shown that aspartame does not increase glucose nor insulin blood levels. Aspartame can not be directly linked to insulin resistance or diabetes.

A related claim is that aspartame causes weight gain indirectly by increasing cravings for, and hence consumption of, sweets and carbohydrates. A study of 14 women dieters found that compared to drinking a sugar beverage, drinking an aspartame-sweetened beverage caused higher caloric consumption the next day despite no reported increase in appetite. Any results from studies with a larger or broader sample size have not been published since.

Major research studies

Mario Negri research institute

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

National Cancer Institute

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

Ramazzini Foundation

In 2006, a study of the long-term effects of eating aspartame in rats by the European Ramazzini Foundation Institute was published. The study of 1,800 rats found that aspartame administered at varying levels in feed led to slight, dose-independent, but statistically significant increase of lymphomas-leukemias and malignant tumors of the kidneys in female rats and malignant tumors of peripheral nerves in male rats, and malignant brain tumors in male and female rats. The authors concluded that aspartame is "a multipotential carcinogenic agent, even at a daily dose of 20 mg/kg body weight, much less than the current acceptable daily intake".

Reviews of the Ramazzini claims found numerous problems with the study, including:

1. The rats had chronic lung infections that are associated with lymphomas; thus the increase was not related to aspartame
2. The aspartame dosages were not given properly: "The doses are 'estimates' based on assuming constant food consumption of 20 g/day and constant body weights of 400 g for each rat from in utero (fetal day 12) to death."
3. The rats entered the study prenatally, but the researchers did not provide necessary information on the parents, the pregnancies, the condition of the pups at birth, food consumption by mother rats while pregnant and nursing -- all important to figuring out if the control and treatment groups are properly matched. No data substantiating in utero exposure were provided.
4. The lymphoma/leukemia incidences and the breast cancer rates in the high-dose group were in or near historical control ranges
5. The kidney tumors found at high doses were not relevant to humans

As a result, the European Food Safety Authority (EFSA) the US FDA discounted the study results and found no reason to revise their previously established acceptable daily intake levels for aspartame.

Various accusations of conflicts of interest were leveled at scientists who criticised the Ramazzini studies, and the Ramazzini Foundation continued to claim carcinogenic effects.

The New Zealand Food Safety Authority (NZFSA) questioned the significance of the Ramazzini studies:

These studies were conducted in a way that could not possibly have provided any information about the toxicity of aspartame – or in fact anything else in the rats’ diet. ... If aspartame was as horrendously toxic as is being claimed, it would be logical to expect the rats dosed with it to have shortened life-spans. The conclusions drawn by the researchers were clearly not backed up by their own data.

Other scientists stated that the Ramazzini researchers ought to have improved upon the methodologic and conceptual weaknesses that had been present in their earlier paper., although some supported the Ramazzini group.

Attempted political bans and voluntary withdrawals

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

Due to public concerns over artificial sweeteners, in 1997, the UK government introduced a new regulation obliging food makers who use sweeteners to state clearly next to the name of their product the phrase "with sweeteners". In 2007, the UK supermarket chains Sainsbury's, M&S and ASDA announced that they would no longer use aspartame in their own label products.

Alleged conflict of interest prior to 1996

A 2006 New York Times article mentions Ralph G. Walton, then a psychologist at Northeastern Ohio Universities College of Medicine, who claims that funding sources may have affected the conclusions of aspartame-related research. Walton alleges that researchers with ties to industry find no safety problems, while many of those without ties to aspartame find toxicities. In a rebuttal to Walton's statements, the 'Aspartame Information Service' (a service provided by Ajinomoto, a producer of aspartame and supplier to well known food and drink makers), reviews the publications Walton cites as critical of aspartame, finding that most of them do not involve aspartame or do not draw negative conclusions, are not peer-reviewed, are anecdotal, or are duplicates.

See also

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

References

1. ^ GAO 1987. "Food Additive Approval Process Followed for Aspartame" United States General Accounting Office, GAO/HRD-87-46, June 18, 1987 Cite error: The named reference "GAO87" was defined multiple times with different content (see the help page).
2. Sugarman, Carole (1983-07-03). "Controversy Surrounds Sweetener". Washington Post. pp. D1-2. Retrieved 2008-11-25. {{cite news}}: Italic or bold markup not allowed in: |publisher= (help)
3. ^ Falsifications and Facts about Aspartame - An analysis of the origins of aspartame disinformation, by the University of Hawaii
4. ^ Aspartame Warning About.com - the Nancy Markle chain email.
5. Magnuson BA, Burdock GA, Doull J; et al. (2007). "Aspartame: a safety evaluation based on current use levels, regulations, and toxicological and epidemiological studies". Crit. Rev. Toxicol. 37 (8): 629–727. doi:10.1080/10408440701516184. PMID 17828671. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
6. ^ GAO 1986. "Six Former HHS Employees' Involvement in Aspartame's Approval." United States General Accounting Office, GAO/HRD-86-109BR, July 1986.
7. ^ Health Canada: "Aspartame - Artificial Sweeteners". Retrieved 2008-11-08.
8. ^ Food Standards Australia New Zealand: "Food Standards Australia New Zealand: Aspartame (September 2007)". Retrieved 2008-11-08.
9. Henkel, John (November–December 1999). "Sugar Substitutes: Americans Opt for Sweetness and Lite". FDA Consumer. Retrieved January 29, 2009. {{cite news}}: Check date values in: |date= (help)
10. "Aspartame (NutraSweet) Warning - Netlore Archive". Retrieved 2009-01-18. The "aspartame scare" hit the mainstream media when the Associated Press moved a Jan. 29, 1999 article debunking the rumor.
11. "A Web of Deceit - TIME". Retrieved 2009-01-19. In this and similar cases, all the Nancy Markles of the world have to do to fabricate a health rumor is post it in some Usenet news groups and let ordinary folks, who may already distrust artificial products, forward it to all their friends and e-mail pals.
12. Cockburn A. (2007). Rumsfeld: His Rise, Fall, and Catastrophic Legacy, pp. 63-4. Simon and Schuster.
13. FDA Statement on Aspartame, November 18, 1996
14. ^ "The Lowdown on Sweet?" The New York Times, 12 February 2006
15. Most Scientists in Poll Doubt NutraSweet's Safety, Washington Post, 17 July 1987
16. ^ Olney JW, Farber NB, Spitznagel E, Robins LN (1996). "Increasing brain tumor rates: is there a link to aspartame?". J. Neuropathol. Exp. Neurol. 55 (11): 1115–23. doi:10.1097/00005072-199611000-00002. PMID 8939194. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
17. Humphries P, Pretorius E, Naudé H (2008). "Direct and indirect cellular effects of aspartame on the brain". European Journal of Clinical Nutrition. 62 (4): 451–62. doi:10.1038/sj.ejcn.1602866. PMID 17684524. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
18. ^ Soffritti M, Belpoggi F, Degli Esposti D, Lambertini L, Tibaldi E, Rigano A (2006). "First experimental demonstration of the multipotential carcinogenic effects of aspartame administered in the feed to Sprague-Dawley rats". Environ. Health Perspect. 114 (3): 379–85. PMC 1392232. PMID 16507461. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
19. Food Standards Australia New Zealand: "Food Standards Australia New Zealand: Aspartame – what it is and why it's used in our food". Retrieved 2008-12-09.
20. ^ "Aspartame and Cancer: Questions and Answers", National Cancer Institute
21. "Aspartame monograph addendum, 1981". Retrieved 2008-12-08.
22. "Monograph on Aspartame, 1980, [[JECFA]]". Retrieved 2008-12-08. {{cite web}}: URL–wikilink conflict (help)
23. Tsang, Wing-Sum, et al., 1985. "Determination of Aspartame and Its Breakdown Products in Soft Drinks by Reverse-Phase Chromatography with UV Detection," Journal Agriculture and Food Chemistry, Vol. 33, No. 4, page 734-738.
24. Husøy T, Mangschou B, Fotland TØ; et al. (2008). "Reducing added sugar intake in Norway by replacing sugar sweetened beverages with beverages containing intense sweeteners - a risk benefit assessment". Food Chem. Toxicol. 46 (9): 3099–105. doi:10.1016/j.fct.2008.06.013. PMID 18639604. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
25. Chung MS, Suh HJ, Yoo W; et al. (2005). "Daily intake assessment of saccharin, stevioside, D-sorbitol and aspartame from various processed foods in Korea". Food Addit Contam. 22 (11): 1087–97. doi:10.1080/02652030500202092. PMID 16332631. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
26. Garnier-Sagne I, Leblanc JC, Verger P (2001). "Calculation of the intake of three intense sweeteners in young insulin-dependent diabetics". Food Chem. Toxicol. 39 (7): 745–9. doi:10.1016/S0278-6915(01)00003-5. PMID 11397521. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
27. "Update on the Safety of Aspartame, 4 December 2002" (PDF). Retrieved 2008-12-08.
28. ""Scientific Facts on Aspartame", a peer-reviewed summary of the 2002 assessment by the [[European Commission]]'s Scientific Committee on Food, 2004". Retrieved 2008-12-08. {{cite web}}: URL–wikilink conflict (help)
29. Examining the Safety of Aspartame, Multiple Sclerosis Foundation
30. ^ Deconstructing Web Pages - An exercise deconstructing a web page to determine its credibility as a source of information, using the aspartame controversy as the example.
31. Betty Martini (2001). "Not Nancy Markle". Retrieved 2009-01-30.
32. Betty Martini (1995-12-03). "WORLD ENVIRONMENTAL CONFERENCE & MULTIPLE SCLEROSIS". Retrieved 2009-01-30.
33. ^ Kiss My Aspartame. False. Snopes.com
34. The World's Best Ant Poison. False. Snopes.com
35. Bandyopadhyay A, Ghoshal S, Mukherjee A (2008). "Genotoxicity testing of low-calorie sweeteners: aspartame, acesulfame-K, and saccharin". Drug Chem Toxicol. 31 (4): 447–57. doi:10.1080/01480540802390270. PMID 18850355.{{cite journal}}: CS1 maint: multiple names: authors list (link)
36. http://www.neurology.org/cgi/gca?allch=&SEARCHID=1&TITLEABSTRACT=aspartame&FIRSTINDEX=0&hits=10&RESULTFORMAT=1&gca=neurology%3B44%2F10%2F1787&allchb= Neurology 44: 1787
37. Spiers PA, Sabounjian L, Reiner A, Myers DK, Wurtman J, Schomer DL (1998). "Aspartame: neuropsychologic and neurophysiologic evaluation of acute and chronic effects". Am. J. Clin. Nutr. 68 (3): 531–7. PMID 9734727. Retrieved 2008-12-08. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
38. Schiffman SS, Buckley CE, Sampson HA; et al. (1987). "Aspartame and susceptibility to headache". N. Engl. J. Med. 317 (19): 1181–5. PMID 3657889. {{cite journal}}: |access-date= requires |url= (help); Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
39. Gurney JG, Pogoda JM, Holly EA, Hecht SS, Preston-Martin S (1997). "Aspartame consumption in relation to childhood brain tumor risk: results from a case-control study". J. Natl. Cancer Inst. 89 (14): 1072–4. doi:10.1093/jnci/89.14.1072. PMID 9230890. Retrieved 2008-12-08. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
40. Walton RG, Hudak R, Green-Waite RJ (1993). "Adverse reactions to aspartame: double-blind challenge in patients from a vulnerable population". Biol. Psychiatry. 34 (1–2): 13–7. doi:10.1016/0006-3223(93)90251-8. PMID 8373935. Retrieved 2008-12-08.{{cite journal}}: CS1 maint: multiple names: authors list (link)
41. Koehler SM, Glaros A (1988). "The effect of aspartame on migraine headache". Headache. 28 (1): 10–4. doi:10.1111/j.1365-2524.1988.hed2801010.x. PMID 3277925. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |month= ignored (help)
42. Smith JD, Terpening CM, Schmidt SO, Gums JG (2001). "Relief of fibromyalgia symptoms following discontinuation of dietary excitotoxins". Ann Pharmacother. 35 (6): 702–6. doi:10.1345/aph.10254. PMID 11408989. Retrieved 2008-12-08. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
43. Van den Eeden SK, Koepsell TD, Longstreth WT, van Belle G, Daling JR, McKnight B (1994). "Aspartame ingestion and headaches: a randomized crossover trial". Neurology. 44 (10): 1787–93. PMID 7936222. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
44. ^ EFSA EU, afc_opinions, 1471 en
45. ^ Trocho C, Pardo R, Rafecas I, Virgili J, Remesar X, Fernández-López JA, Alemany M (1998). "Formaldehyde derived from dietary aspartame binds to tissue components in vivo". 63 (5): 337–349. PMID 9714421. {{cite journal}}: Cite has empty unknown parameter: |month= (help); Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link) Cite error: The named reference "PubMed9714421" was defined multiple times with different content (see the help page).
46. ^ Butchko HH, Stargel WW, Comer CP; et al. (2002). "Aspartame: review of safety". Regul. Toxicol. Pharmacol. 35 (2 Pt 2): S1–93. doi:10.1006/rtph.2002.1542. PMID 12180494. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
47. Abel Lajtha, Margaret A. Reilly and David S. Dunlop (June 1994). "Aspartame consumption: lack of effects on neural function". The Journal of Nutritional Biochemistry. 5 (6). Elsevier Science Inc.: 266–283. doi:10.1016/0955-2863(94)90032-9.
48. McMartin KE, Martin-Amat G, Noker PE, Tephly TR (1979). "Lack of a role for formaldehyde in methanol poisoning in the monkey". Biochem. Pharmacol. 28 (5): 645–9. doi:10.1016/0006-2952(79)90149-7. PMID 109089. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
49. Stegink LD, Filer LJ, Bell EF, Ziegler EE, Tephly TR, Krause WL (1990). "Repeated ingestion of aspartame-sweetened beverages: further observations in individuals heterozygous for phenylketonuria". Metabolism: clinical and experimental. 39 (10): 1076–81. PMID 2215254. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
50. Koeppe RA, Shulkin BL, Rosenspire KC; et al. (1991). "Effect of aspartame-derived phenylalanine on neutral amino acid uptake in human brain: a positron emission tomography study". Journal of neurochemistry. 56 (5): 1526–35. doi:10.1111/j.1471-4159.1991.tb02047.x. PMID 2013754. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
51. Romano M, Diomede L, Guiso G, Caccia S, Perego C, Salmona M (1990). "Plasma and brain kinetics of large neutral amino acids and of striatum monoamines in rats given aspartame". Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 28 (5): 317–21. doi:10.1016/j.asr.2007.02.043. PMID 2379890. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
52. Dailey JW, Lasley SM, Mishra PK, Bettendorf AF, Burger RL, Jobe PC (1989). "Aspartame fails to facilitate pentylenetetrazol-induced convulsions in CD-1 mice". Toxicology and applied pharmacology. 98 (3): 475–86. doi:10.1016/0041-008X(89)90176-2. PMID 2470165. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
53. London RS (1988). "Saccharin and aspartame. Are they safe to consume during pregnancy?". The Journal of reproductive medicine. 33 (1): 17–21. PMID 3351801. {{cite journal}}: Unknown parameter |month= ignored (help)
54. Olney, J. (1994). "Excitotoxins in Foods". Neurotoxicology. 15 (3): 535–544. PMID 7854587.
55. Olney JW, Ho OL (1970). "Brain damage in infant mice following oral intake of glutamate, aspartate or cysteine". Nature. 227 (5258): 609–11. doi:10.1038/227609b0. PMID 5464249. {{cite journal}}: Unknown parameter |month= ignored (help)
56. Smith, QR (2000). "Transport of glutamate and other amino acids at the blood-brain barrier". The Journal of nutrition. 130 (Supplement 4S). The American Society for Nutritional Sciences: 1016S – 1022S. PMID 10736373. Retrieved 2007-01-31.
57. Abraham R, Swart J, Golberg L, Coulston F (1975). "Electron microscopic observations of hypothalami in neonatal rhesus monkeys (Macaca mulatta) after administration of monosodium-L-glutamate". Experimental and molecular pathology. 23 (2): 203–13. doi:10.1016/0014-4800(75)90018-0. PMID 810365. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
58. Reynolds WA, Butler V, Lemkey-Johnston N (1976). "Hypothalamic morphology following ingestion of aspartame or MSG in the neonatal rodent and primate: a preliminary report". Journal of toxicology and environmental health. 2 (2): 471–80. PMID 827619. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
59. Stegink LD, Filer LJ, Baker GL (1977). "Effect of aspartame and aspartate loading upon plasma and erythrocyte free amino acid levels in normal adult volunteers". The Journal of nutrition. 107 (10): 1837–45. PMID 903828. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
60. Stegink LD, Filer LJ, Baker GL; et al. (1989). "Repeated ingestion of aspartame-sweetened beverage: effect on plasma amino acid concentrations in individuals heterozygous for phenylketonuria". Metabolism: clinical and experimental. 38 (1): 78–84. PMID 2909831. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
61. Wing Sum Tsang, Margaret A. Clarke, and Frederick W. Parrish (1985). "Determination of aspartame and its breakdown products in soft drinks by reverse-phase chromatography with UV detection". Journal of Agricultural and Food Chemistry. 33: 734–738. doi:10.1021/jf00064a043.{{cite journal}}: CS1 maint: multiple names: authors list (link)
62. Shephard SE, Wakabayashi K, Nagao M (1993). "Mutagenic activity of peptides and the artificial sweetener aspartame after nitrosation". Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 31 (5): 323–9. PMID 8505016. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
63. Flamm WG (1997). ""Increasing brain tumor rates: is there a link to aspartame?"". Journal of neuropathology and experimental neurology. 56 (1): 105–6. doi:10.1097/00005072-199701000-00014. PMID 8990134. {{cite journal}}: Unknown parameter |month= ignored (help)
64. Geha R, Buckley CE, Greenberger P; et al. (1993). "Aspartame is no more likely than placebo to cause urticaria/angioedema: results of a multicenter, randomized, double-blind, placebo-controlled, crossover study". The Journal of allergy and clinical immunology. 92 (4): 513–20. doi:10.1016/0091-6749(93)90075-Q. PMID 8409113. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
65. http://www.rense.com/general3/asper.htm
66. http://forums.studentdoctor.net/archive/index.php/t-257051.html
67. Smeets P; et al. (2005). "Functional magnetic resonance imaging of human hypothalamic responses to sweet taste and calories". American Journal of Clinical Nutrition. 82 (5): 1011–1016. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)
68. Template:Cite journal=Nature
69. Gallus S (2007). "Artificial sweeteners and cancer risk in a network of case–control studies". Annals of Oncology. 18 (1): 40–44. doi:10.1093/annonc/mdl346. PMID 17043096. Retrieved 2007-03-01. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help); Unknown parameter |quotes= ignored (help)
70. Seattle PI, NWSource, 265559_soda "No cancer risk found in diet soda's aspartame", Seattle Post-Intelligencer, 5 April 2006
71. Lim U, Subar AF, Mouw T; et al. (2006). "Consumption of aspartame-containing beverages and incidence of hematopoietic and brain malignancies". Cancer Epidemiol. Biomarkers Prev. 15 (9): 1654–9. doi:10.1158/1055-9965.EPI-06-0203. PMID 16985027. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
72. ^ Bernadene Magnuson, Gary M. Williams (2008). "Carcinogenicity of Aspartame in Rats Not Proven". Environ Health Perspect. 116 number=6: A239 – A240. PMID 18560494. {{cite journal}}: Missing pipe in: |volume= (help); line feed character in |volume= at position 4 (help)
73. ^ CFSAN. (April 2007). FDA Statement on European Aspartame Study. FDA
74. Felicity Lawrence. "Food safety authority says aspartame not linked to cancer". Guardian Unlimited. Retrieved 2006-12-31.
75. Soffritti, M. et. al (2007) "Lifespan Exposure to Low Doses of Aspartame Beginning During Prenatal Life Increases Cancer Effects in Rats", Environmental Health Perspectives (115:6) June 2007
76. Food Safety Authority challenges activists’ views on aspartame
77. http://www.sciencemag.org/cgi/content/summary/sci;317/5834/29c?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=Souring+on+Fake+Sugar&searchid=1&FIRSTINDEX=0&issue=5834&resourcetype=HWCIT Science 6 July 2007
78. Honolulu Advertiser: "Legislators consider aspartame ban" Feb 10, 2008
79. State of New Mexico Legislature House bill 391: Relating to food; Banning the use of the artificial sweetener Aspartame in food products 2007
80. Organic Consumers Association: New Mexico State Senator Calls for Ban on Aspartame Artificial Sweetener Sept 28, 2006
81. American Bakers Association: New Mexico - Bill Introduced to Ban Aspartame in Foods 2007
82. SunStar (Philippines): "Lawmaker wants artificial sweeteners banned" Sep 04, 2008
83. Saudi Food and Drug Authority: Indonesia consults on aspartame, sweetener use in food 16 Jan 2007
84. AP-Foodtechnology.com: Indonesia consults on aspartame, sweetener use in food 09-Jan-2007
85. BBC: Sweeteners, sweeteners everywhere Oct 16, 1998
86. Daily Telegraph: M&S and Asda to axe E-numbers 17 May 2007
87. Daily Mail: Sainsbury's takes the chemicals out of cola 23 april 2007
88. Daily Mail: Asda becomes first supermarket to axe all artificial flavourings and colours in own brand foods 14 maj 2007
89. Daily Mail: M&S joins race to ban artificial additives from their food 15 maj 2007
90. "Aspartame Information replies to the New York Times". Aspartame Information Service. 2006-02-16.

External links

• Deconstructing Web Pages - An exercise deconstructing a web page to determine its credibility as a source of information, using the aspartame controversy as the example.
• Sugar Substitutes (U.S. FDA web page)
• Centers for Disease Control: Evaluation of Consumer Complaints Related to Aspartame Use
• International Programme on Chemical Safety: Aspartame toxicology evaluation and further evaluation

• Misplaced Pages neutral point of view disputes from November 2008
• Medical controversies
• Food safety