Aspartame – An Evidence-Based Saftey Review

Aspartame – An Evidence-Based Saftey Review

Of all artificial sweeteners, aspartame is the most controversial and one of the most widely used. It is known by the brand names Equal, NutraSweet, Sugar Twin and AminoSweet and can be found in more than 6,000 products around the world.[1]

From headaches to rare forms of cancer, this sweetener has been accused of quite a bit of malaise. But does aspartame deserve its unfavorable reputation? Internet sources are quick to pass judgment, with popular health news sites going as far as labeling it the “most dangerous” food additive. We’ll look at both sides and examine some of the key evidence on this popular debate.

Approval

approval stamp
Aspartame was first approved for use by the FDA in 1981 for certain uses; table top sweetener, chewing gum, breakfast cereals and various other foods. Two years later, it was approved for use in carbonated beverages, and finally in 1996 it was approved as a general purpose sweetener.[40]

Advantages

There are two main advantages of aspartame over regular sugar.

1. It is roughly 200 times sweeter than table sugar, allowing similar sweetening with a much smaller portion.[40]

2. Aspartame, like all carbohydrates and proteins, has four calories per gram which means based on the levels needed to achieve sweetness, it contributes almost no calories. The aspartame in a diet soda adds less than one calorie.[41 PAGE 2]

The Basic Chemistry of Aspartame

Aspartame

One of the key differences between aspartame and other artificial sweeteners is that aspartame is broken down by the body while all other approved artificial sweeteners are not; they pass through the digestive tract undigested and contribute no calories.[37] The breakdown of aspartame is fundamental to the argument against its safety.

Aspartame is created by combining the amino acids, aspartic acid and phenylalanine. Once ingested, the body converts aspartame back into these same amino acids and one other substance, methanol. Methanol is a substance that has the potential to be toxic in large doses, however, the amounts produced from the breakdown of aspartame are less than many common foods.

According to the American Cancer Society, a liter of fruit juice could result in as much as 680 mg of methanol compared to just 55 mg from a liter of diet soda. The amino acids phenylalanine and aspartic acid are common in foods that contain protein. They present no risk to most individuals, however those with a rare genetic disorder known as phenylketonuria or PKU, can not break down phenylalanine and are advised to avoid aspartame.[27]

Methanol toxicity comes from the fact that it is further metabolized by the body into formaldehyde, a substance identified as a known human carcinogen by the National Toxicology Program.[42] While formaldehyde can be toxic, it is also produced in small quantities by most living organisms – including humans – as part of the natural metabolic process.

According to the the American Chemical Society, the amount of formaldehyde produced from aspartame is one thousand times less than is naturally produced by the body. In addition, the body uses formaldehyde to build amino acids among other purposes, and it does not accumulate in the body.[28]

While different theories exist, it is not known for sure why the metabolites of aspartame would have different or adverse effects when compared to other sources that produce the same substances. However, according to some research, this may be the case.

A study published in 1998 in Life Sciences tested high doses of aspartame on rats and found that the resulting formaldehyde may bond to tissues in the body and accumulate creating a health hazard.[30]

Another study in 2012 published in the Journal of Biosciences found that in rats, chronic exposure to aspartame resulted in detectable methanol blood levels which may have been responsible for the oxidative stress (cellular damage) observed in regions of the brain.[34]

Take Away: Aspartame breaks down into its harmless amino acids and methanol. Though methanol is produced in greater amounts from other common dietary sources, there is some scientific evidence showing that methanol from aspartame may be unsafe.

Institutions that Maintain Aspartame is Safe

A group known as the Calorie Control Council, which represents “manufacturers and suppliers of low- and reduced-calorie foods and beverages”[2] owns the domain, Aspartame.org. On this website, the group lists all the of the regulatory and scientific organizations that approve the use of aspartame. The list includes:

Scientific:

Alzheimer’s Association
American Academy of Family Physicians
American Council on Science and Health
American Diabetes Association
Academy of Nutrition and Dietetics
American Heart Association
Asthma and Allergy Foundation of America
British Medical Journal (editorial)
Canadian Diabetes Association
Diabetes U.K.
Lupus Foundation of America
Massachusetts Institute of Technology
Mayo Clinic
Multiple Sclerosis Society of Canada
Multiple Sclerosis Foundation
National Cancer Institute
National Multiple Sclerosis Society
National Parkinson Foundation
The Nemours Foundation
U.K. Ministry of Agriculture, Fisheries and Food (MAFF)
U.S. Consumer Information Center

Regulatory:

Brazilian Health Ministry
Centers for Disease Control & Prevention (CDC)
Health Canada
Food Standards Australia New Zealand (FSANZ)
French Food Safety Agency (AFSSA)
New Zealand Food Safety Authority (NZFSA)
Scientific Committee on Food of the European Commission
U.K. Food Standards Agency
U.S. Food and Drug Administration (FDA)
U.S. FDA’s Center for Food Safety and Applied Nutrition
Specific Quotes from Regulatory Authorities

While it is true that each of these organizations maintain that aspartame is completely safe, they have also come to this conclusion using the same available scientific evidence.

That evidence is in the form of studies completed by both independent labs as well as industry sponsored studies (i.e. paid for by manufacturers or sellers of aspartame and products containing aspartame)

The Center for Science in the Public Interest

CSPIlogo

One of the most outspoken critics of aspartame is the consumer advocate group Center for Science in the Public Interest.

CSPI has a 40-year history of successfully influencing public policy as well as corporate decision-making regarding food additives, nutrition labeling and other issues that affect public health.[5]

According to CSPI, major regulatory bodies have overlooked important studies while giving credence to less important studies in making their final decisions about aspartame.

Three of the most referenced studies as evidence against aspartame are animal studies (using rats and mice) all conducted by the same institution, the European Ramazzini Foundation. These are the primary studies that CSPI bases their “everyone should avoid” rating on.[38]

Take Away: The Center for Science in the Public Interest is a non-profit consumer advocate group that disagrees with aspartame’s current “safe” status.

The European Ramazzini Foundation

Europena ramazzini foundation logoThe European Ramazzini Foundation (ERF) is an independent non-profit lab in Italy that has conducted animal testing since 1970 in order to evaluate the potential cancer-causing effects of chemicals.

RI has tested over 200 compounds and concluded that 10 of these compounds increase the risk for cancer as the dose increases. These 10 compounds include aspartame, chlorinated drinking water, di-isopropyl-ether (DIPE), formaldehyde, mancozeb, methanol, MTBE, tert-amyl methyl-ether (TAME), toluene and vinylidene chloride.

Of these 10 compounds, other laboratories have tested 7 (aspartame, chlorinated drinking water, formaldehyde, methanol, MTBE, toluene, and vinylidene chloride) and have determined that just 3 of these (chlorinated drinking water, methanol and MTBE) are linked to blood cell cancers.[7 PAGE 3]

Some of the findings coming out of the ERF are controversial. In addition to aspartame, ERF also found that sucralose, another artificial sweetener deemed safe by the FDA and EFSA, increases the incidence of cancer, though that study remains unpublished.

While the FDA and EFSA disagree with the Ramazzini aspartame findings, CSPI notes that the European Ramazzini Foundation along with the National Toxicology Program (NTP) are the two “largest and longest-existing, and most well-established bioassay (experiments that use living things to test the toxicity of chemicals) programs in the world.”[4 – PAGE 6]

Take Away: The European Ramazzini Foundation (ERF) is the largest and most highly-regarded scientific organization to test and determine aspartame to have adverse health effects on animals.

EPA Review of The European Ramazzini Foundation

EPA logoThe Environmental Protection Agency (EPA) and the National Center for Environmental Assessment published a review of Ramazzini bioassays in Environmental Health Perspectives in 2013, to investigate the discrepancies between ERF and other laboratories.

The authors concluded that Ramazzini results are generally consistent with other laboratories as well as the NTP, though the authors believe it is possible that cancers in some studies may have been caused by unrelated respiratory infections, thus providing false positives.[7 PAGES 1, 9] The review also examines study designs and protocols used by the ERF.

Key Differences Between ERF and Other Laboratories

The authors included a table comparing ERF studies with non-ERF studies. One of the key differences between the ERF and other studies was that the Ramazzini researchers monitored the animals throughout their entire lifespan – three years for rats and 2 ½ years for mice – whereas other labs monitored the animals for two years – or roughly two-thirds of their lifespan.[7 PAGE 4]

CSPI argues that because 2-year-old rats are equivalent to 65-year-old humans, later-in-life tumors could have been missed in these studies.

In actuality, a 2-year-old rat is closer to a 53-year-old human, based on the current average life expectancy of 79 years. This makes the final one-third of life even more important for monitoring, as about 78 percent of all cancers in humans are diagnosed after the age of 55.[43]

The EFSA counters by pointing out that when studies are carried out until, or close to, natural death, faulty conclusions are often observed due to the fact that older animals are more susceptible to spontaneous tumors.[6 – PAGE 2]

Another key difference between ERF and other laboratories is that ERF studies use a strain of rat known as Sprague-Dawley. The NTP and the National Cancer Institute used Sprague-Dawley rats until the late 1970s but then switched to a strain known as Fischer F344N.

However, the FDA still primarily uses Sprague-Dawley for drug safety testing and the NTP switched back to Sprague-Dawley in 2009 after concerns about a higher incidences of certain types of leukemia and other health issues in the F344N colony.

Questions about Sprague-Dawley rats having naturally higher than normal incidences of certain types of cancer have also been raised. In some ERF studies, the same types of lymphomas observed in treated Sprague-Dawley rats have also been found in untreated (control group) rats.

These same cancers have rarely been found in treated or untreated F344N rats. Similarly, the type of cancers seen commonly in F344N rats are rare in Sprague-Dawley.[7 PAGE 5]

As is the case with genetic differences in humans, genetic differences between strains of rats can result in varying rates of different types of cancer. There is, however, no clear evidence suggesting that Sprague-Dawley rats are not appropriate for carcinogenic testing.

Take Away: ERF monitors their animals longer than other laboratories and uses a strain of rats not used by some other laboratories, which may account for some discrepancies, according to the EPA.

2005 Ramazzini Aspartame Mega-Experiment

lab rat

The first and most widely referenced aspartame study out of ERF, which was first published online in 2005 and appeared in Environmental Health Perspectives in March of 2006, concluded that aspartame was a multi-carcinogen even at 20 mg/kg of body weight per day, which is below the acceptable daily intake of 40 mg/kg by the EFSA and WHO and 50 mg/kg by the FDA.

The authors recommend an urgent re-evaluation of current aspartame consumption guidelines.

One of the reasons this study is referenced so often is the number of rats used, the duration of the study and the number of doses tested. The study tested 6 doses of aspartame with one control group, with each of the doses being tested on 100 – 150 males and 100 – 150 females, all until natural death. The researchers refer to it as a mega-experiment.[8]

FDA Review of 2005 Mega-Experiment

FDA Logo

Upon review of this mega-experiment, the FDA issued a statement, which concluded that the study did not provide sufficient evidence to alter its stance on the safety of aspartame. Before issuing this statement, the FDA requested the data from ERF for review, but only received a portion of the data requested.

The FDA then made a second request for the remainder of the data along with the pathology slides. ERF did not submit this data, nor did they agree to submit pathology slides.

Therefore, the FDA was forced to make a determination based on the available data – “Based on the available data, however, we have identified significant shortcomings in the design, conduct, reporting, and interpretation of this study — FDA finds no reason to alter its previous conclusion that aspartame is safe as a general purpose sweetener in food.”

The statement also mentions that among the large number of studies already performed on aspartame, there are five long-term carcinogenic studies demonstrating aspartame’s safety. The only shortcoming mentioned specifically in the statement issued by the FDA was the presence of infection in test animals.[14]

According to ERF, the type of pulmonary inflammation (infections) observed in the study is common in the dying process and this inflammation was observed in both control groups as well as those rats treated with aspartame.

In regards to the FDA’s request for pathology slides, Scientific Director of the European Ramazzini Foundation and primary author of the aspartame study, Dr. Morando Soffritti, M.D. believes the external review of a small subset of the 34,000 slides in the study is not appropriate, particularly given the statistical power of such a large experiment.[12]

Take Away: The FDA did not change its stance based on the ERF mega-study, citing major shortcomings.

ERF Follow-Up Studies

ERF published two follow-up studies on aspartame published in 2007 and 2010. The objective of both studies was to test aspartame for carcinogenic effects beginning during prenatal life through natural death, given that pregnant women and children are among the major consumers of aspartame. Both studies which started treatment at the 12th day of gestation determined aspartame to be cancerous.

First Follow-up Study

The first, published in 2007 in Environmental Health Perspectives found a significant increase in leukemias and lymphomas in both male and female Sprague-Dawley rats and a significant increase in mammary cancer in females at 2,000 ppm, a dose close to the ADI for humans.

At 2,000 ppm the rate of cancer was nearly twice that of the control group. The authors of the study concluded that when exposure begins during fetal life, aspartame is more likely to cause cancer.[15]

Food toxicologist Bernadene Magnuson, PhD., who authored a safety review on aspartame, criticized this study for not addressing important details related to the pregnancies and for publishing conclusions for a period for which they provide no data.

She also believes that the colony of rats used, which was the same colony from the first study, was infected, which led to faulty conclusions, particularly related to cancers of the lung. She further pointed out the that the authors observed no significant effects at the low-level diet. Finally, Magnuson noted that there was no difference between cancer rates in high dose groups and those in historical control groups.[25]

Soffritti rejected Magnuson’s claim that the cancers were caused by unrelated infections by noting that such an infection would not only affect those in the treated groups, but the control groups as well.[9] 

A 2008 review published in Environmental and Molecular Mutagenesis also determined that lymphomas/leukemias observed in ERF studies were not the result of general infections, but were rather chemical specific, in other words, they were caused by aspartame and other substances being evaluated.[10]

Soffritti also argued that ignoring concurrent control group data is “contrary to the widely accepted standard of good laboratory science.”[9]

Second Follow-up Study

The 2010 study published in the American Journal of Industrial Medicine tested higher doses, from 2000 ppm up to 32000 ppm, on Swiss mice. This study found aspartame to induce dose-related liver and lung cancer only in the male mice, while females remained unaffected.[16]

Upon review, EFSA pointed out that cancer rates in high-dose groups were within historical controls for the type of Swiss mice used, which bear a high incidence of spontaneous liver and lung tumors. The agency additionally noted that the type of tumor observed is not relevant to humans when it’s caused by substances such as aspartame that do not damage genetic information or cause cell mutation.[6]

Other Aspartame Studies Showing Adverse Results

Side Effects

Although ERF studies are the most highly publicized due to their size and duration, other studies using both humans and animals have found aspartame to have adverse effects on health.

In 1993 a study was published in Biological Psychiatry to determine the effects of aspartame on individuals with depression and healthy individuals. Subjects received 30 mg/kg/day (which is below the U.S. ADI of 50 mg/kg/day) for 7 days.

The study had to be halted early because of the severe reactions in the participants with depression. The authors concluded that individuals with mood disorders are particularly sensitive to the affects of aspartame.[22]

A small study published in 1994 in Neurology used a total of 32 participants to test whether aspartame is linked to headaches. The authors concluded that some individuals may be particularly susceptible to headaches caused by aspartame and may want to limit their consumption.[18]

In 2014 a study published in Research in Nursing & Health tested low and high-aspartame diets both for 8 days on healthy adults in an attempt to evaluate any potential neurobehavioral effects.

The authors concluded that when participants consumed high aspartame diets, they were more irritable and depressed and performed worse on spatial orientation tests. Memory did not appear to be affected. The high aspartame diet was well below the ADI of 50 mg/kg of bodyweight.[19]

A study published in 2013 in Drug and Chemical Toxicology tested the effects of long-term aspartame exposure on the rat brain. The results of the 6-month experiment indicated that aspartame reduces concentrations of an important antioxidant known as glutathione, which prevents cellular damage.[21]

Another study published in a 2012 issue of the European Review for Medical and Pharmacological Sciences also found reduced glutathione concentrations in the brains of mice treated with aspartame. The authors of the study concluded that aspartame may cause impaired memory performance and increased brain oxidative stress.[23]

Anecdotal Evidence

Side effects of aspartame, both self-reported and observed by medical professionals have been reported. Examples include:

A 1988 survey published in the Journal of Applied Nutrition surveyed 551 individuals who reported adverse effects from aspartame. The most common complaints were headaches, dizziness, blurred vision, confusion, memory loss, eye pain, depression, irritability, anxiety heart palpitations, nausea, diarrhea and tinnitus (ringing in the ears).[26]

In a 2004 letter to the Texas Heart Institute Journal, H.J. Roberts MD of the Palm Beach Institute for Medical Research describes cases of female patients who were affected by Graves’ disease (an immune disorder common in women that causes overproduction of thyroid hormones) and pulmonary hypertension.

Symptoms of these disorders improved significantly upon ceasing aspartame consumption and returned upon reintroduction of aspartame to the diet.

Dr. Roberts, who has written about aspartame for over 20 years, believes the sweetener can cause severe “adverse neurologic, cardiopulmonary, endocrine, and allergic effects” and recommends only introducing drugs aimed at treating pulmonary hypertension after an aspartame-free trial period.[20]

Aspartame Safety Evaluation

evaluation checklistThe safety review completed by Magnuson and nine others which was published in a 2007 issue of Critical Reviews in Toxicology noted that toxicity studies on aspartame have found no adverse effects in various animals, including rats, mice, dogs and hamsters, even at 4000 mg/kg of bodyweight per day, which is 100 times the acceptable daily intake recommended by the EFSA and the WHO.

The researchers concluded that there is no association between aspartame and cancer in any tissue and that aspartame is safe at current levels of consumption.[11]

Soffritti points out that this review was entirely sponsored by Ajinomoto, the world’s largest manufacturer of aspartame.[9] In addition, the Ramazzini Institute notes that (other than its own studies) the only four long-term studies of aspartame carcinogenicity were conducted over 20 years ago using small numbers of animals and paid for by manufacturers of the sweetener.

According to ERF, these studies provide the basis for the current belief that aspartame is safe.[12]

Select Aspartame Studies Showing No Risk

A study published in 2006 in Cancer Epidemiology Biomarkers & Prevention concluded that aspartame is not linked to brain and hematopoietic cancers. This study used previous data from a 1999 – 2000 self-reported survey of AARP members. Participants were asked to recall eating habits over a 12-month period.

Three sources of beverages that may contain aspartame were identified as fruit drinks, soft drinks and iced teas. Participants were asked to report on how often they consumed diet or sugar-free forms of these drinks. They were also asked to report on any aspartame added to coffee or tea.[17]

Even with a large study population (285,079 men and 188,905 women ages 50 to 71) there are many limitations to data based on a self-reported survey. This study in particular also has no way of identifying whether the sugar-free drinks reported were sweetened using aspartame or other artificial sweeteners.

An often referenced study demonstrating no side effects from high levels of aspartame consumption was published in 1989 in Archive of Internal Medicine.

In this double-blind, randomized, placebo-controlled trial, 108 volunteers received either a placebo or a capsule three times daily which totaled 75 mg/kg/day of aspartame, for a 24-week period. This dosage represents 1.5 times the ADI for aspartame. In terms of diet soft drink, this equals nearly 10 liters per day.

The authors recorded no significant difference in the number of symptoms or the number of subjects experiencing symptoms.[29]

In 2015 the Public Library of Science published a double-blind randomized study to test the effects of aspartame in individuals who claimed to have aspartame sensitivity. The study utilized 96 individuals, half of whom claimed sensitivity to aspartame.

Participants were given an aspartame containing cereal bar (100 mg) or a control bar randomly at least 7 days apart. None of the participants symptoms differed between aspartame and the control group. The authors used a comprehensive series of tests and were unable to detect any acute response to aspartame.[31]

In this study the 100 milligram dosage used is just over half the amount in one can of diet soft drink (185 mg) and far below the ADI of 40/mg/kg/day. In addition, the exposure was not ongoing, but intermittent.

This trial demonstrates that some individual’s perceived sensitivity to aspartame may be psychological, however, it can not be used to demonstrate the long-term safety of aspartame, nor the safety of aspartame at acceptable daily intakes.

DAGC Report

The U.S. Dietary Advisory Guidelines Committee is a group of medical professionals that reviews the most current scientific and medical literature and prepares a report that provides evidence-based recommendations for the next edition of the U.S. Dietary Guidelines.[13]

In the case of Aspartame, the group reviewed its association with cancer, preterm delivery, headaches and negative effects on behavior and cognition. The group concluded that there are no safety concerns for those without PKU (a rare disorder) at 40 mg/kg, which is slightly lower than the U.S. ADI of 50 mg/kg.[24]

DGAC also noted that, while limited and inconsistent, there is research that suggests a link between aspartame and increased risk of some blood cell cancers in men, which means more long-term human studies are needed.

DGAC also concluded that limited and inconsistent evidence suggests that pregnant women who use aspartame heavily may be at increased risk for preterm delivery. [24]

Recommended Aspartame Intake Levels

girl drinks sodaThe World Health Organization, The European Food Safety Authority and Health Canada have all assigned aspartame an acceptable daily intake of 40 mg/kg of bodyweight per day while the U.S. FDA has set the ADI at 50 mg/kg bw/day.[44]

By U.S. standards a 50-pound child could safely consume 1150 mg of aspartame each day, a 100-pound adolescent or teen could consume 2250 mg, a 150-pound adult could consume 3400 mg and a 200-pound adult could consume 4500 mg.

According to the American Cancer Society, one 12-ounce diet soda usually contains about 192 mg of aspartame,[27] meaning respectively, these groups could consume approximately 6, 12, 18 and 23 cans of diet coke per day, safely.

According to the Ramazzini study, however, aspartame is a multicarcinogen at even 20 mg/kg of bodyweight per day[8] meaning 50, 100, 150 and 200-pound individuals would not be safe drinking 2 ½, 5, 7, and 10 cans of diet coke per day, respectively.

Pepsi Drops Aspartame

Diet_Pepsi_CanDue to public pressure, in April 2015 PepsiCo Inc. announced it would no longer use aspartame in Diet Pepsi, Caffeine Free Diet Pepsi and Wild Cherry Diet Pepsi, beginning in August 2015. The drinks will instead be sweetened with two other popular but less controversial sweeteners, sucralose and acesulfame potassium.[39] Despite the change, Pepsi maintains that aspartame is completely safe.

Conclusions

Although the European Ramazzini Foundation has been highly criticized and even delegitimized by some for their findings, particularly regarding aspartame, the fact remains that ERF is one of the largest and most prestigious bioassay institutions in the world, whose findings have previously been used in policy-making decisions.

Therefore, the results of the ERF studies should not be simply overlooked or discredited due to the many regulatory agencies that disagree with their conclusions.

Pregnant women, infants and children should avoid aspartame as much as possible, as some research shows the risks may be greater for these groups.[15][16][24]

Some individuals have shown more sensitivity to the effects of aspartame.[18][19][20][22][26]

Those with the rare genetic disease phenylketonuria (PKU) should always avoid aspartame because they are unable to metabolize the amino acid phenylalanine, one of aspartame’s components.[32]

Aspartame may be more likely to cause cancer in older adults after years of use. Available evidence points to long-term use of aspartame as an important factor in the onset of cancerous growths and other adverse health effects.[8][21]

Regulatory agencies agree that more long-term human studies are needed to further demonstrate aspartame’s safety.[24][36]

While ERF and other animal studies on aspartame have shown links to cancer, currently no human studies have shown a clear link between aspartame and cancer or any other disease.[33]

Though an abundance of evidence demonstrates aspartame’s safety, considerable evidence to the contrary also exists, linking the man-made sweetener to adverse health effects. In addition, a significant number of scientists and health professionals disagree with aspartame’s current safety status.[12][20][35]

The effects of aspartame are not fully understood, which warrants further research on this popular food additive.

For cautious individuals, it may be best to avoid aspartame until a greater scientific consensus is reached. Other artificial sweeteners, and naturally-derived sweeteners like stevia, may be safer options.

 

References:

1. “Aspartame Safety: ADI, Metabolism and Common Concerns …” 2014. 19 Aug. 2015 <https://www.beverageinstitute.org/article/aspartame-safety-adi-metabolism-estimated-intakes-and-common-concerns/>
2. “About the Council | The Calorie Control Council.” 2009. 19 Aug. 2015 <http://www.caloriecontrol.org/about-the-council>
3. “Update on Ramazzini Institute Data in IRIS Assessments …” 2012. 19 Aug. 2015 <http://www.epa.gov/iris/ramazzini.htm>
4. “Evaluation of Ramazzini Institute Aspartame Studies.” 2015. 19 Aug. 2015 <http://www.efsa.europa.eu/sites/default/files/event/documentset/130409-p06.pdf>
5. “CSPI Accomplishments ~ Center for Science in the Public …” 2007. 19 Aug. 2015 <http://cspinet.org/about/accomplishments.html>
6. “Statement of EFSA on the Scientific Evaluation of Two Studies …” 2011. 19 Aug. 2015 <http://www.efsa.europa.eu/de/efsajournal/doc/2089.pdf>
7. Gift, Jeffrey S et al. “Scientific Considerations for Evaluating Cancer Bioassays Conducted by the Ramazzini Institute.” Environmental health perspectives 121.11-12 (2013): 1253. <http://ehp.niehs.nih.gov/wp-content/uploads/121/11-12/ehp.1306661.pdf>
8. Soffritti, Morando et al. “First Experimental Demonstration of the Multipotential Carcinogenic Effects of Aspartame Administered in the Feed to Sprague-Dawley Rats.” Environmental Health Perspectives (2006): 379-385. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1392232/>
9. Soffritti, M. “Carcinogenicity of Aspartame: Soffritti Responds.” 2008. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2430255/>
10. Caldwell, Jane C et al. “Evaluation of Evidence for Infection as a Mode of Action for Induction of Rat Lymphoma.” Environmental and Molecular Mutagenesis 49.2 (2008): 155-164. <http://www.ncbi.nlm.nih.gov/pubmed/18095346>
11. Magnuson, BA et al. “Aspartame: A Safety Evaluation Based on Current Use Levels, Regulations, and Toxicological and Epidemiological Studies.” Critical Reviews in Toxicology 37.8 (2007): 629-727. <http://www.ncbi.nlm.nih.gov/pubmed/17828671>
12. “ERF Stands Behind Aspartame Study Results, Announces …” 2013. 19 Aug. 2015 <http://www.ramazzini.org/comunicato/erf-stands-behind-aspartame-study-results-announces-ongoing-research-on-artificial-sweeteners-response-to-efsas-afc-panel-decision/>
13. “Dietary Guidelines for Americans Committee | Health.gov …” 2014. 19 Aug. 2015 <http://health.gov/dietaryguidelines/committee/>
14. “Food Additives & Ingredients > FDA Statement on European …” 2013. 19 Aug. 2015 <http://www.fda.gov/Food/IngredientsPackagingLabeling/FoodAdditivesIngredients/ucm208580.htm>
15. Soffritti, Morando et al. “Life-span Exposure to Low Doses of Aspartame Beginning During Prenatal Life Increases Cancer Effects in Rats.” Environmental Health Perspectives (2007): 1293-1297. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1964906/>
16. Soffritti, Morando et al. “Aspartame Administered in Feed, Beginning Prenatally Through Life Span, Induces Cancers of the Liver and Lung in Male Swiss Mice.” American Journal of Industrial Medicine 53.12 (2010): 1197-1206. <http://www.ncbi.nlm.nih.gov/pubmed/20886530>
17. Lim, Unhee et al. “Consumption of Aspartame-containing Beverages and Incidence of Hematopoietic and Brain Malignancies.” Cancer Epidemiology Biomarkers & Prevention 15.9 (2006): 1654-1659. <http://cebp.aacrjournals.org/content/15/9/1654.long>
18. Van den Eeden, SK et al. “Aspartame Ingestion and Headaches A Randomized Crossover Trial.” Neurology 44.10 (1994): 1787-1787. <http://www.ncbi.nlm.nih.gov/pubmed/7936222>
19. Lindseth, Glenda N et al. “Neurobehavioral Effects of Aspartame Consumption.” Research in Nursing & Health 37.3 (2014): 185-193. <http://www.ncbi.nlm.nih.gov/pubmed/24700203>
20. Roberts, HJ. “Aspartame Disease: A Possible Cause for Concomitant Graves’ Disease and Pulmonary Hypertension.” Texas Heart Institute Journal 31.1 (2004): 105. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC387446/>
21. Roberts, HJ. “Aspartame Disease: A Possible Cause for Concomitant Graves’ Disease and Pulmonary Hypertension.” Texas Heart Institute Journal 31.1 (2004): 105. <http://www.ncbi.nlm.nih.gov/pubmed/22385158>
22. Walton, Ralph G, Robert Hudak, and Ruth J Green-Waite. “Adverse Reactions to Aspartame: Double-blind Challenge in Patients From a Vulnerable Population.” Biological Psychiatry 34.1 (1993): 13-17. <http://www.ncbi.nlm.nih.gov/pubmed/8373935>
23. Abdel-Salam, OM et al. “Studies on the Effects of Aspartame on Memory and Oxidative Stress in Brain of Mice.” Eur Rev Med Pharmacol Sci 16.15 (2012): 2092-2101. <http://www.ncbi.nlm.nih.gov/pubmed/23280025>
24. “Download PDF – Health.gov.” 2015. 19 Aug. 2015 <http://www.health.gov/dietaryguidelines/2015-scientific-report/PDFs/10-Part-D-Chapter-5.pdf>
25. Magnuson, Bernadene, and Gary M Williams. “Carcinogenicity of Aspartame in Rats Not Proven.” Environmental Health Perspectives 116.6 (2008): A239. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2430246/>
26. “Reported Aspartame Toxicity Effects – Food and Drug …” 2013. 19 Aug. 2015 <http://www.fda.gov/ohrms/dockets/dailys/03/jan03/012203/02p-0317_emc-000199.txt>
27. “Aspartame – American Cancer Society.” 2010. 19 Aug. 2015 <http://www.cancer.org/cancer/cancercauses/othercarcinogens/athome/aspartame>
28. “Is Aspartame Safe? (Video) – American Chemical Society.” 2015. 19 Aug. 2015 <http://www.acs.org/content/acs/en/pressroom/newsreleases/2015/june/is-aspartame-safe-video.html>
29. Leon, Arthur S et al. “Safety of Long-term Large Doses of Aspartame.” Archives of Internal Medicine 149.10 (1989): 2318-2324. <http://www.ncbi.nlm.nih.gov/pubmed/2802896>
30. Trocho, C et al. “Formaldehyde Derived from Dietary Aspartame Binds to Tissue Components in Vivo.” Life Sciences 63.5 (1998): 337-349. <http://www.ncbi.nlm.nih.gov/pubmed/9714421>
31. Sathyapalan, Thozhukat et al. “Aspartame Sensitivity? A Double Blind Randomised Crossover Study.” PloS One 10.3 (2015): e0116212. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4364783/>
32. “Phenylketonuria: MedlinePlus Medical Encyclopedia.” 2002. 19 Aug. 2015 <http://www.nlm.nih.gov/medlineplus/ency/article/001166.htm>
33. “Artificial Sweeteners and Cancer – National Cancer Institute.” 2015. 19 Aug. 2015 <http://www.cancer.gov/about-cancer/causes-prevention/risk/diet/artificial-sweeteners-fact-sheet>
34. Iyyaswamy, Ashok, and Sheeladevi Rathinasamy. “Effect of Chronic Exposure to Aspartame on Oxidative Stress in Brain Discrete Regions of Albino Rats.” Journal of Biosciences 37.4 (2012): 679-688. <http://www.ncbi.nlm.nih.gov/pubmed/22922192>
35. “FDA Should Reconsider Aspartame Cancer Risk, Say Experts.” 2007. 19 Aug. 2015 <https://www.cspinet.org/new/200706251.html>
36. “Sweeteners – Sugar Substitutes: MedlinePlus Medical …” 2011. 19 Aug. 2015 <http://www.nlm.nih.gov/medlineplus/ency/article/007492.htm>
37. “Low-Calorie Sweeteners: American Diabetes Association®.” 2014. 19 Aug. 2015 <http://www.diabetes.org/food-and-fitness/food/what-can-i-eat/understanding-carbohydrates/artificial-sweeteners/>
38. “European Safety Review of Aspartame a Whitewash, Says …” 2013. 19 Aug. 2015 <http://cspinet.org/new/201312101.html>
39. “PepsiCo to Drop Aspartame From Diet Pepsi – WSJ.” 2015. 19 Aug. 2015 <http://www.wsj.com/articles/pepsico-to-replace-aspartame-with-sucralose-in-diet-pepsi-in-u-s-1429885941>
40. “Food Additives & Ingredients > Additional Information About …” 2014. 3 Sep. 2015 <http://www.fda.gov/Food/IngredientsPackagingLabeling/FoodAdditivesIngredients/ucm397725.htm>
41. “Aspartame Brochure – International Food Information …” 2011. 3 Sep. 2015 <http://www.foodinsight.org/Content/3848/FINAL_Aspartame%20Brochure_Web%20Version_11-2011.pdf>
42. “Formaldehyde – National Toxicology Program.” 2015. 4 Sep. 2015 <https://ntp.niehs.nih.gov/ntp/roc/content/profiles/formaldehyde.pdf>
43. “Questions People Ask About Cancer.” 2011. 3 Sep. 2015 <http://www.cancer.org/cancer/cancerbasics/questions-people-ask-about-cancer>
44. Butchko, Harriett H, and Frank N Kotsonis. “Acceptable Daily Intake vs Actual Intake: The Aspartame Example.” Journal of the American College of Nutrition 10.3 (1991): 258-266. <http://www.ncbi.nlm.nih.gov/pubmed/1894884>