Aspartame deemed safe after a mammoth effort

Aspartame - EFSA's most comprehensive risk assessment ever

Aspartame – EFSA’s most comprehensive risk assessment ever

After its most extensive effort ever the European Food Safety Authority (EFSA) deemed aspartame to be safe at current use levels in an opinion just published in December 2013. This is a mammoth effort not only reviewing most of the available literature on aspartame and its breakdown products, but also consulting widely with the public before finalising the opinion. It will be seen as a breakthrough effort in improving consumer confidence in the scientific process of evaluating controversial food additives. But of course not everyone will be pleased, that is the nature of the beast.

The question could be raised why EFSA didn’t do as thorough a job in its previous evaluations of aspartame, but why be critical now when it is done. The work raises the bar for future opinions and I am thinking in particular of the Bisphenol A opinion in the immediate pipeline. That issue will be even more difficult to resolve with the low-dose hypothesis causing considerable angst among scientists. Another question is if EFSA can spend so much time on only one opinion without hampering overall progress on the many issues on EFSA’s plate. But that is an issue for their political masters.

So what did EFSA find

We all know that aspartame (E 951) is a sweetener authorised for use as a food additive in many countries. It is used extensively in diet soft drinks in particular. Chemically it is a dipeptide, that is the molecule is formed by the two amino acids, aspartic acid and the methyl ester of phenylalanine, binding together. In the gastro-intestinal system it is rapidly hydrolysed and fully degraded into its primary constituents of aspartic acid, phenylalanine and methanol with little or no aspartame available to be absorbed by the body. The amount of intact aspartame that enters the bloodstream has actually been reported as undetectable. Thus  potential toxic effects must be caused by any or all of these three major metabolites.

EFSA stated that it was clear from their literature review that the acute toxicity of aspartame as tested in mice, rats, rabbits and dogs was very low. Similarly, sub-acute and sub-chronic studies did not indicate any significant toxic effects in rats, mice or dogs. Neither did available data indicate a genotoxic concern for aspartame. Results from three chronic toxicity and carcinogenicity studies in rats and one in mice revealed no aspartame-related increase in any type of neoplasms at the doses tested.

There was a caveat though with debate raging about tumour findings reported by the European Ramazzini Foundation. However, EFSA and other authorities are of the view that many of the malignant neoplasms and the lymphoid dysplasias diagnosed in the studies were hyperplasias related to unknown chronic infection in the animals and not related to aspartame intake. Also hepatic and pulmonary tumour incidences reported fell within the institute’s own historical control ranges for spontaneous tumours.

There was also a problem with birth weight data from several reproductive and developmental toxicity studies performed in rabbits. However, EFSA stated that the findings were confounded both by a decrease in feed intake in the treated group and poor health of the animals.

What about human studies?

Artificially sweetened soft drinks a common source of aspartame

Artificially sweetened soft drinks a common source of aspartame

Looking at human studies, EFSA noted that there was no epidemiological evidence for possible associations of aspartame with various cancers in the human population.

A large prospective cohort study in Denmark found no consistent association between the consumption of artificially sweetened beverages in general (of which some might have been using aspartame) during pregnancy and the diagnosis of asthma or allergic rhinitis in children. Though they did find a small but significantly elevated risk of medically induced pre-term delivery in women with higher reported consumption of artificially sweetened drinks. This was countered by findings in another prospective study in Norway showing a barely discernible association between pre-term delivery and artificially sweetened soft drinks but a stronger association with consumption of sugar-sweetened soft drinks.

And the metabolites specifically

Methanol was cleared from any effects after aspartame consumption since it only contributes to a very small part of methanol exposure. Fruit and vegetables play a more important part in methanol exposure and it is also naturally produced by the body. It is only toxic at fairly high levels, such as from consumption of some home-distilled alcoholic spirits.

Neither did aspartic acid raise any human safety concerns. The body can convert aspartic acid into the neurotransmitter glutamate which, at levels very much high than can be derived from aspartame consumption, can have harmful effects on the nervous system.

Phenylalanine is the remaining potential culprit. It is known to be toxic at high intake levels, in particular to the developing foetus in women suffering from the medical condition phenylketonuria (PKU). EFSA considered that it was plausible that phenylalanine could be responsible for some or all of the adverse effects reported for aspartame in rat and rabbit developmental toxicity studies. However, phenylalanine blood levels reached after realistic dietary intake of aspartame were well below conservative estimates of the levels necessary to cause harm.

So all clear for everyone except PKU patients where total control of dietary phenylalanine intake is necessary to manage the risk from elevated phenylalanine blood levels. Fortunately, it is a requirement in many countries that products containing aspartame should indicate through labelling that they contain a source of phenylalanine to protect the small minority unable to metabolise the compound.

And the conclusion?

All-in-all EFSA considered aspartame safe at normal use levels and retained an Acceptable Daily Intake of 40 mg/kg bodyweight. Some dubious results remain but scientific studies are seldom perfect. It seems clear that all doubtful results can be explained without casting a shadow over aspartame. At least according to the EFSA evaluation.

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Aspartame (almost) cleared

The aspartame molecule

The aspartame molecule (Illustration: Wikimedia)

The artificial sweetener aspartame has been associated with some controversy from its initial approval for use in dry food in 1974 by the Food and Drug Administration in the USA. Aspartame has since been deemed safe for human consumption by over 100 regulatory agencies in their respective countries. Although there were some clear irregularities in the initial submission by G.D. Searle, this was not considered detrimental to its approval.

Because of the initial controversy, the safety of aspartame has been studied extensively since its discovery with research that includes animal studies, clinical and epidemiological research, and post-market surveillance. Aspartame is now one of the most rigorously tested food ingredients to date. Comprehensive peer-review studies, as well as independent scrutiny by governmental regulatory bodies, have analysed the published research and deemed aspartame safe for consumption at current levels. This has not silenced the critics.

The ultimate review?

In May, 2011, the European Food Safety Authority (EFSA) was asked by the European Commission to bring forward a full re-evaluation of the safety of aspartame, previously planned for completion by 2020. On January 8, 2013, EFSA released a draft opinion for comment. As part of the evaluation process, EFSA commissioned an external review of the available literature on aspartame. This review was published on 1 March, 2013 and provides an overview of current knowledge regarding the metabolism and toxicity of aspartame. From a database containing 5,023 references the review team identified 1,366 documents of direct or indirect relevance to the risk assessment of aspartame. After scrutiny of those documents, 358 were carried forward for detailed examination.

Review and consultations on aspartame (Photo: ALDEADLE)

Aspartame under review (Photo: ALDEADLE)

The review team noted that aspartame after ingestion is immediately split into three constituents already in the gastrointestinal system and these are consequently absorbed individually. Two of the three components (aspartate and methanol) are cleared rapidly from the body and the only component remaining in the circulation system is phenylalanine. Aspartame itself is normally not absorbed.

The effective potential toxicity of aspartame is therefore only related to the phenylalanine component.

The team reported that:

  • No significant acute or subchronic toxicity had been observed in animal models or in humans even at the highest doses of aspartame which could reasonably be administered, and early concerns that aspartame might cause neurotoxicity in neonates and infants could not be substantiated.
  • There was no evidence to indicate that aspartame is genotoxic. Reported marginally positive results occurred only sporadically and did not indicate any particular cause for concern.
  • Available chronic toxicity studies did not indicate any overt carcinogenic effect in experimental animals due to aspartame, but all the conventional studies were limited in various ways.
  • One epidemiological study addressing possible reproductive effects in humans found an increased risk of preterm delivery in women who frequently consumed either carbonated or (to a lesser extent) non-carbonated diet drinks but did not address aspartame directly and was subject to a number of confounding factors.

The review concluded that there was no consistent evidence that aspartame has adverse effects, either in healthy individuals or in potentially susceptible groups, under normal conditions of use although phenylketonurics do need to regulate their intake of aspartame for health reasons. They are supported in doing this by clear labelling of aspartame-containing products. The review team left some question marks in relation to chronic and reproductive toxicity and supported further research to conclusively exclude any such effects.

Current state of the art

EFSA’s draft opinion now states that aspartame and its metabolites “pose no toxicity concern for consumers at current levels of exposure. The current Acceptable Daily Intake (ADI) is considered to be safe for the general population and consumer exposure to aspartame is below this ADI”. The final opinion is expected to be delivered in May 2013.

If this will be the end of the controversy over the use of aspartame as a food additive is still doubtful. The remaining uncertainty over chronic and reproductive toxicity, although slight, might need to be conclusively resolved to silence all critics. Further unnecessary controversy has been ignited by the dairy industry request to sweeten flavoured milk for children with aspartame without declaring it on the label.

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Aspartame controversy

SummaryNormal use of the synthetic sweetener aspartame in diet products is considered safe by several national and international authorities, but has been questioned by public groups raising a range of concerns. The European Food Safety Authority, in a re-evaluation of the safety of aspartame to be completed by May 2013, recently requested more information on potential degradation products.

Aspartame is a low-calorie, intense sweetener which is approximately 200 times sweeter than sucrose (table sugar). It is used to sweeten a variety of foods and beverages such as drinks, desserts, sweets, chewing gum, yoghurt, energy-reduced and weight control products and as a table-top sweetener. Aspartame was first approved for use in dry goods in 1981 and for carbonated beverages in 1983 by the U.S. Food and Drug Administration. During the 1980s, aspartame was authorised for use in foods and as a table-top sweetener by several EU Member States. European legislation harmonising its use in food wa introduced in 1994.

Early controversy

Aspartame was discovered by accident in 1965, when James Schlatter, a chemist of the G.D. Searle Company was testing for an anti-ulcer drug and licked his contaminated finger to pick up a piece of paper. He noticed an intense sweet taste. The company set out to benefit from his findings and patented the substance. Early controversy over aspartame safety was due to perceived irregularities in the aspartame approval process during the 1970s and early 1980s, including allegations of conflicts of interest and claims that aspartame producer G.D. Searle had withheld and falsified safety data. Aspartame consumption has since been claimed to cause 92 different health side effects including brain tumors, preterm delivery, birth defects, diabetes, emotional disorders and chronic neurological disruptions including epilepsy/seizures. Most claims are populistic in nature without credible scientific backing, but there are also some published scientific studies providing initial support for the theories. The published reports have been reviewed several times by government authorities in different countries without any clear confirmation of their validity.

It has been shown that even at very high doses of aspartame (over 200 mg/kg), no aspartame as such is found circulating in the body due to its rapid breakdown. Hypotheses of adverse health effects have thus focused on the three metabolites aspartic acid, methanol and phenylalanine, which are formed through hydrolysis of aspartame in the small intestine. However, aspartame is far from a unique source of the three metabolites. Aspartic acid (aspartate) is one of the most common amino acids in the typical diet and in a fairly high consumer of aspartame, it still provides only between 1-2 % of the daily intake of aspartic acid. Equally, the amount of methanol formed from aspartame is less than that found in fruit juices and citrus fruits, and there are other dietary sources for methanol such as fermented beverages. Phenylalanine is one of the essential amino acids and is required for normal growth and maintenance of life. Common foods such as milk, meat, and fruit provide far greater amounts of this metabolite than aspartame.

Adverse health effects

There has been some speculation that aspartic acid, 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, and studies of metabolism suggests it is not possible to ingest enough aspartic acid and glutamate through food and drink to levels that would be expected to be toxic.

On the other hand, there is clear proof that people with the rare genetic disorder called phenylketonuria (that is tested for in many countries at birth) should keep phenylalanine levels in the diet low. In affected persons, usual levels of phenylalanine in the diet can cause problems with brain development, leading to progressive mental retardation, brain damage, and seizures.  Other concerns about the safety of phenylalanine from aspartame largely centers around 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, 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.

The methanol produced by the metabolism of aspartame is absorbed and quickly converted into formaldehyde and then completely converted to formic acid, which, due to its long half life, is considered the primary mechanism of toxicity in methanol poisoning. With regards to formaldehyde, it is rapidly converted in the body, and the amounts of formaldehyde from the metabolism of aspartame is 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 is no increased blood levels of methanol or formic acid, and ingesting aspartame at the 90th percentile of intake would produce 25 times less methanol than would be considered toxic.

Cancer

Concern about possible carcinogenic properties of aspartame was originally raised and popularised in the mainstream media in the 1970s and again in 1996 by suggesting that aspartame may be related to brain tumours. Independent agencies reanalysing multiple studies based on such claims could not confirm any credible association between aspartame and brain cancer.

Later the European Ramazzini Foundation of Oncology and Environmental Sciences (ERF) released  study results in 2007 and 2010 which claimed that aspartame could increase some malignancies in rats, concluding that aspartame is a potential carcinogen at normal dietary doses. These conclusions were contradicted by other carcinogenicity studies which found no significant danger. After reviewing the foundation’s claims, independent experts have discounted the study results. Reported flaws were numerous and included comparing cancer rates of older aspartame-consuming rats to younger control rats; a diet leading to possible nutritional deficiencies; lack of animal randomisation; overcrowding and a high incidence of possibly carcinogenic infections; and misdiagnosing of hyperplasias as malignancies.

Reviews of numerous carcinogenicity studies in animals, epidemiologic studies in humans, as well as in vitro genotoxicity studies have found no significant evidence that aspartame causes cancer in animals, damages the genome, or causes cancer in humans at doses currently used.

Neurological and psychiatric symptoms

Numerous allegations have been made in popular media purporting neurotoxic effects of aspartame leading to neurological or psychiatric symptoms such as seizures, headaches, and mood changes. Reviews of the biochemistry of aspartame have found no evidence that the doses consumed would plausibly lead to neurotoxic effects. Comprehensive reviews have not found any evidence for aspartame as a cause for these symptoms, although one review did provide a theoretical biochemical background of neurotoxicity and suggested further testing.

A review of the pediatric literature did not show any significant findings for safety concerns with regards to neuropsychiatric conditions such as panic attacks, mood changes, hallucinations or with ADHD or seizures.

Headaches are the most common symptom reported by consumers as associated with aspartame consumption. While there are some indications that aspartame might be 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”, other studies have failed to prove such links.

The current state of play

Although aspartame and its metabolites have been studied in a wide range of populations including infants, children, adolescents, and healthy adults, even at very high doses, without identifying any safety concerns in healthy adults and children there are still some lingering doubts. However, equally to the proof of safety needed for authorisation of an additive for use in food, to withdraw such an approval requires some verified safety concerns. That is not yet the case for aspartame.

The good thing is that concerned consumers can identify food containing aspartame by looking at the ingredients lists on product labels. Like all food additives, aspartame has been assigned an “E-number” following authorisation. Its presence in foods can be indicated either by name (i.e. “aspartame”) or by its number E 951.

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