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The safety of aspartame has been studied extensively since its discovery with research that includes animal studies, clinical and epidemiological research, and postmarketing surveillance.[36] Aspartame is one of the most rigorously tested food ingredients.[37] Peer-reviewed comprehensive review articles and independent reviews by governmental regulatory bodies have analyzed the published research on the safety of aspartame and have found aspartame is safe for consumption at current levels.[8][36][38][39] Aspartame has been deemed safe for human consumption by over 100 regulatory agencies in their respective countries,[39] including the UK Food Standards Agency,[40] the European Food Safety Authority (EFSA)[41] and Health Canada.[42]

Intake[edit]
The acceptable daily intake (ADI) value for aspartame, as well as other food additives studied, is defined as the "amount of a food additive, expressed on a body weight basis, that can be ingested daily over a lifetime without appreciable health risk."[43] The Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the European Commission's Scientific Committee on Food has determined this value is 40 mg/kg of body weight for aspartame,[44] while FDA has set its ADI for aspartame at 50 mg/kg.[45]

The primary source for exposure to aspartame in the United States is diet soft drinks, though it can be consumed in other products, such as pharmaceutical preparations, fruit drinks, and chewing gum among others in smaller quantities.[8] A 12 US fluid ounce (355 ml) can of diet soda contains 180 milligrams (0.0063 oz) of aspartame, and for a 75 kg (165 lb) adult, it takes approximately 21 cans of diet soda daily to consume the 3,750 milligrams (0.132 oz) of aspartame that would surpass the FDA's 50 milligrams per kilogram of body weight ADI of aspartame from diet soda alone.[45]

Reviews have analyzed studies which have looked at the consumption of aspartame in countries worldwide, including the United States, countries in Europe and Australia, among others. These reviews have found that even the high levels of intake of aspartame, studied across multiple countries and different methods of measuring aspartame consumption, are well below the ADI for safe consumption of aspartame.[8][36][39][44] Reviews have also found that populations that are believed to be especially high consumers of aspartame such as children and diabetics are below the ADI for safe consumption, even considering extreme worst-case scenario calculations of consumption.[8][36]

In a report released on 10 December 2013, the EFSA said that, after an extensive examination of evidence, it ruled out the "potential risk of aspartame causing damage to genes and inducing cancer," and deemed the amount found in diet sodas an amount safe to consume.[46]

Metabolites[edit]
Aspartame is rapidly hydrolyzed in the small intestines. Even with ingestion of very high doses of aspartame (over 200 mg/kg), no aspartame is found in the blood due to the rapid breakdown.[8] These metabolites have been studied in a wide range of populations including infants, children, adolescents, and healthy adults. In healthy adults and children, even enormous doses of aspartame do not lead to plasma levels of metabolites that are a concern for safety.

Upon ingestion, aspartame breaks down into residual components, including aspartic acid, phenylalanine, methanol,[47] in ratio of 4:5:1 by mass[48] and further breakdown products including formaldehyde[49] and formic acid, accumulation of the latter being suspected as the major cause of injury in methanol poisoning. Human studies show that formic acid is excreted faster than it is formed after ingestion of aspartame. In some fruit juices, higher concentrations of methanol can be found than the amount produced from aspartame in beverages.[15]

Aspartate[edit]
Aspartic acid (aspartate) is one of the most common amino acids in the typical diet. As with methanol and phenylalanine, intake of aspartic acid from aspartame is less than would be expected from other dietary sources. At the 90th percentile of intake, aspartame provides only between 1% and 2% of the daily intake of aspartic acid. There has been some speculation[50][51] that aspartame, in conjunction with other amino acids like glutamate, may lead to excitotoxicity, inflicting damage on brain and nerve cells. However, clinical studies have shown no signs of neurotoxic effects,[8] and studies of metabolism suggest it is not possible to ingest enough aspartic acid and glutamate through food and drink to levels that would be expected to be toxic.[39]

Methanol[edit]
The methanol produced by the metabolism of aspartame is absorbed and quickly converted into formaldehyde and then completely oxidized to formic acid, which, due to its long half life, is considered the primary mechanism of toxicity in methanol poisoning. The methanol from aspartame is unlikely to be a safety concern for several reasons. The amount of methanol in aspartame is less than that found in fruit juices and citrus fruits, and there are other dietary sources for methanol such as fermented beverages. Therefore, the amount of methanol produced from aspartame is likely to be less than that from natural sources. With regard to formaldehyde, it is rapidly converted in the body, and the amounts of formaldehyde from the metabolism of aspartame are trivial when compared to the amounts produced routinely by the human body and from other foods and drugs. At the highest expected human doses of consumption of aspartame, there are no increased blood levels of methanol or formic acid,[8] and ingesting aspartame at the 90th percentile of intake would produce 25 times less methanol than what would be considered toxic.[39]

Phenylalanine and phenylketonuria[edit]
High levels of the naturally-occurring essential amino acid phenylalanine are a health hazard to those born with phenylketonuria (PKU), a rare inherited disease that prevents phenylalanine from being properly metabolized. Since individuals with PKU must consider aspartame as an additional source of phenylalanine, foods containing aspartame sold in the United States must state "Phenylketonurics: Contains Phenylalanine" on their product labels.[52]

In the UK, foods that contain aspartame are legally required by the country's Food Standards Agency to list the substance among the product's ingredients and carry the warning "Contains a source of phenylalanine" – this is usually at the foot of the list of ingredients. Manufacturers are also required to print '"with sweetener(s)" on the label close to the main product name on foods that contain "sweeteners such as aspartame" or "with sugar and sweetener(s)" on "foods that contain both sugar and sweetener".[53]

In Canada, foods that contain aspartame are legally required by the country to list the substance among the product's ingredients and include a measure of the amount of aspartame per serving. As well, labels must state that the product contains phenylalanine – this is usually in the order of ingredients, contained in brackets.[54]

Phenylalanine is one of the essential amino acids and is required for normal growth and maintenance of life. Concerns about the safety of phenylalanine from aspartame center largely on hypothetical changes in neurotransmitter levels as well as ratios of neurotransmitters to each other in the blood and brain that could lead to neurological symptoms. Reviews of the literature have found no consistent findings to support such concerns,[39] and while high doses of aspartame consumption may have some biochemical effects, these effects are not seen in toxicity studies to suggest aspartame can adversely affect neuronal function.[8] Like methanol, the typical diet will lead to ingestion of significantly higher amounts of phenylalanine than would be expected from aspartame consumption.[39] People with the genetic disorder phenylketonuria are advised to avoid aspartame as they have a decreased ability to metabolize phenylalanine. Common foods such as milk, meat, and fruits provide far greater amounts of these metabolites in a diet than does aspartame.[39]

Lactation[edit]
In a study done in 1979, the effect of aspartame ingestion on blood and milk amino acid levels in lactating women was tested.[55] In this study, six women from the ages of 20 to 29 with established lactation were studied after oral administration of aspartame or lactose (50 mg/kg body weight) in a random order, with the intent to study the differences in breast milk between the two. The study resulted with the conclusion that aspartame administration at 50 mg/kg body weight has a small effect upon the milk aspartate levels and although a small increase in aspartate time-effect scores was noted over the four-hour postabsorptive period, no significant difference was noted over the entire 24-hour watching period.[55]

Cancer[edit]
Reviews have found no association between aspartame and cancer. These reviews have looked at numerous carcinogenicity studies in animals, epidemiologic studies in humans, as well as in vitro genotoxicity studies. These studies have found no significant evidence that aspartame causes cancer in animals, damages the genome, or causes cancer in humans at doses currently used.[8][36][39][56] This position is supported by multiple regulatory agencies like the FDA[57] and EFSA as well as scientific bodies such as the National Cancer Institute.[45]

Concern about possible carcinogenic properties of aspartame was originally raised and popularized in the mainstream media by John Olney in the 1970s and again in 1996 by suggesting that aspartame may be related to brain tumors. Reviews have found that these concerns were flawed, due to reliance on the ecological fallacy[58] and the purported mechanism of causing tumors being unlikely to actually cause cancer. Independent agencies such as the FDA and National Cancer Institute have reanalyzed multiple studies based on these worries and found no association between aspartame and brain cancer.[39]

As discussed in the article on controversies around aspartame, the Cesare Maltoni Cancer Research Center of the European Ramazzini Foundation of Oncology and Environmental Sciences released several studies which claimed that aspartame can increase several malignancies in rodents, concluding that aspartame is a potential carcinogen at normal dietary doses.[59][60] The EFSA[61] and the FDA[57] discounted the study results due to lack of transparency and numerous flaws in the study, finding no reason to revise their previously established acceptable daily intake levels for aspartame.

Neurological and psychiatric symptoms[edit]
Numerous allegations have been made via the Internet and in consumer magazines purporting neurotoxic effects of aspartame leading to neurological or psychiatric symptoms such as seizures, headaches, and mood changes.[8] Review of the biochemistry of aspartame has found no evidence that the doses consumed would plausibly lead to neurotoxic effects.[62] Comprehensive reviews have not found any evidence for aspartame as a cause for these symptoms.[8][36][39] One review did provide a theoretical biochemical background of neurotoxicity and suggested further testing.[63] However, a panel of EFSA experts noted that this review's conclusions were partially based on Internet sources and therefore were not scientifically robust. These experts also concurred with a critique that significant scientific errors were made in the critical review that led to unsubstantiated and misleading interpretations.[36] A review of the pediatric literature did not show any significant findings for safety concerns with regard to neuropsychiatric conditions such as panic attacks, mood changes, hallucinations or with ADHD or seizures.[64]

Headaches[edit]
Headaches are the most common symptom reported by consumers.[8] While one small review noted aspartame is likely one of many dietary triggers of migraines, in a list that includes "cheese, chocolate, citrus fruits, hot dogs, monosodium glutamate, aspartame, fatty foods, ice cream, caffeine withdrawal, and alcoholic drinks, especially red wine and beer,"[65] other reviews have noted conflicting studies about headaches[8][66] and still more reviews lack any evidence and references to support this claim.[36][39][64]

Weight change and hunger[edit]
Since the caloric contribution of aspartame is negligible, it has been used as a means for weight loss through its role as a sugar substitute, with reviews finding that aspartame may aid in weight loss as part of a multidisciplinary weight loss program. On its own, aspartame is not known by medical literature to cause weight gain or weight loss.[8][39] Although some researchers have stated that aspartame contributes to weight gain, hunger and increase in appetite,[8][67] broad reviews and regulators conclude that aspartame has no appreciable effect on appetite.[8][36][68]


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