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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4 thoughts on “Aspartame deemed safe after a mammoth effort

  1. Dear Stefan,

    I just Googled my way to your terrific blog. It’s great to see a resource that ties together the findings of the world’s major regulatory agencies — and in clear, plain language! Nicely done.

    As a former employee of EFSA, I wonder what you think of the charges that the members of the Expert Panel were often too closely tied to industry to render an impartial verdict. There is concern in some quarters that studies which found possible harm from aspartame were generally found unreliable, while studies that confirmed its safety were generally deemed reliable. In other words, the Panel was likely to treat positives as false positives and negatives as true negatives.

    I am inclined to believe that regulators around the world, including in my home of the United States, are careful people committed to the science. But I may be biased — or have blinders on.

    What’s your opinion?

    • Thank you bunsen68 for your kind comments. I might also be biased in relation to the impartiality of the scientists working for EFSA since I have worked closely with many of them in working groups and Panels. However, it is my firm opinion that the process is completely fair. There is peer pressure among the scientists to be fully impartial irrespective of background. The working group draft is peer reviewed by the 21 scientists on the respective panel and they take responsibility for the final output. And EFSA staff that most often are also well qualified scientists oversee the process. I believe that the recent criticism is unfounded.

      You also should remember that the process of reviewing the safety of an already approved substance is very different from reviewing a new substance. For a new substance you need to prove that it is safe but for an already approved substance it is the opposite. You have to consider reports claiming it is not safe. And unfortunately not all scientific publications use the right rigour for the evaluation. Toxicologists would like a response linked to the dosage of the substance. If all dose levels give the same response there might be an underlying problem in the methodology.

      Having said all that we are all human and carry our biases. But I am pretty happy that the EFSA process is as good as it can get. The wetting process for the scientists to be involved is already very cumbersome.

      • Thanks for your thoughtful response, and for your clear explanation of pre- versus post-approval assessments. I’m happy to hear that you think the recent criticisms are unfounded.

        The way I’ve come to see it, regulators are Bayesians: If what they know about a chemical — say, a sweetner — indicates (e.g.) that it is not genotoxic; shows no previous carcinogenic potential; and is either eliminated (as with Ace-K) or fully metabolized by known pathways (as with aspartame), any assertion that the substance is harmful amounts to an extraordinary claim. And extraordinary claims require extraordinary evidence — including (at minimum) unambiguous dose-reponse curves.

        Regulators are Bayesians and perform risk assessments informed by their evidence-based priors. The public — and some advocacy organizations — privilege the precautionary principle: If there is any hint of danger, no matter how slight, the substance should be banned to protect public health.

        These different approaches lead many members of the public to distrust regulators. Do you think it might be productive if regulators talked more openly in Bayesian terms? Would that help the public to understand their methods, or create more confusion?

  2. So true and never will the two meet. The problem as you well know is that alternatives may well be more dangerous but not yet tested at the same level. Nothing is completely without risk (a platitude I know but still true). I like very much your Bayesian idea. In some respect the MoE approach used for some compounds is a start. There is also an attempt to quantify uncertainty at the end of most EFSA opinions (not using Bayesian calculations but rather joint expert opinion). I found the uncertainty descriptions the most difficult to comprehend in the EFSA opinions and not very useful. A new method to illustrate uncertainty and probability would be a big step forward. But you might need more accurate data for this to be possible.

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