November 29, 2017 — Recent publications in scientific journals claim to review the evidence of aspartame but do not provide a comprehensive perspective of the findings from hundreds of studies. Council spokesperson and toxicologist Bernadene Magnuson, PhD provides her opinion of the review “Revisiting the safety of aspartame” below.
Overall Summary:
Central to the safety assessment of aspartame are the facts that aspartame is completely digested to 2 common amino acids and methanol prior to absorption into the body, and that the amounts of these metabolites obtained from aspartame-sweetened foods and beverages are much lower than the amounts of amino acids obtained from protein-containing foods and of methanol obtained from fruits and vegetables and other sources (EFSA, 2013). These key and well-recognized points are ignored. In contrast, false and misleading statements on aspartame metabolism are presented.
This is not a “review of the safety studies conducted on aspartame”, as it purposely does not include pivotal safety studies conducted in animals and humans, including lifetime animal studies, which were required for approval of aspartame and published during 1970 to 2000. This review includes only recent (2000-2016) studies, but also does not include the recent extensive revaluation of aspartame safety by EFSA (2013) or any reference to epidemiological studies demonstrating safety (eg. Marinovich et al., 2013).
There is no critical evaluation or consideration of validity of experimental design of the studies that were discussed. Considerable emphasis is placed on in vitro studies conducted by adding aspartame directly to cells and organs, and studies using direct injection of aspartame into the animal body, which are of little to no clinical relevance since aspartame is completely digested prior to absorption. The inappropriateness of the experimental designs of the cited animal studies is discussed below.
It is a great disappointment and concern that such an inaccurate paper would be published in Nutrition Reviews.
Specific points and inaccurate statements:
Perhaps the most obvious error in this paper is in Table 1, stating that 100 ml aspartame-sweetened beverage contains about 2 g of amino acids, which is completely false and impossible considering the aspartame-sweetened drink contains less than 100 mg aspartame! Table 1 incorrectly shows the aspartame-sweetened beverage provides ~10X more amino acids than milk, although the correct information is actually later stated in the text; unfortunately the error in Table 1 is more impactful and noticeable.
The first of the false statements in the introduction, alleging that aspartame has an effect on drug action, cites not an actual study, but an anti-aspartame activist website. The authors state that “metabolites amino acids and proteins” act through a variety of mechanisms. As aspartame is a dipeptide, it is not possible for “proteins” to be a metabolite, illustrating the inaccurate and confusing statements made in this paper. No studies are cited to support these purported mechanisms on drug metabolism, which is not a surprise as none exist.
Another statement illustrating poor understanding and misinformation of aspartame metabolism is as follows: “Upon ingestion, aspartame is metabolized ….into 3 amino acid isolates, phenylalanine (50%), aspartic acid (40%), and methanol (10%).” Methanol is not an amino acid!
The authors misrepresent data on the effect of aspartame on blood methanol levels, which was discussed and assessed in detail in the EFSA 2013 report. These authors cite a paper that actually did not even measure blood methanol, while ignoring earlier critical studies on levels of metabolites in humans and children administered aspartame.
The authors’ statement that “Absorption and toxicokinetic data that compare the effects of aspartame in humans and animals at the same dosages are not available” misrepresents the literature. This may be true for studies restricted to 2000-2016, but the review in 2007 (Magnuson et al, that was cited by these authors) describes extensive studies conducted on absorption and metabolism of aspartame in rodents, pigs, primates and humans. Here is a summary statement from that review:
Studies demonstrating the metabolism of aspartame to aspartate, phenylalanine, and methanol in humans, including healthy infants, children, adolescents, and adults, were conducted by Stegink et al. (1981a, 1983a, 1983b, 1984, 1987) and Ranney et al. (1976). No aspartame or aspartylphenylalanine was detected in the blood of humans administered a single oral bolus dose of 200 mg/kg bw or repeated oral doses of 10 mg/kg bw/h for 8 h, demonstrating that similar to rats, rabbits, dogs, and monkeys (Ranney and Oppermann, 1979), aspartame in humans is completely and rapidly hydrolyzed as a dietary dipeptide.
Many of the studies included in this review were also reviewed and critically evaluated by the EFSA 2013 expert committee for relevance to the safety assessment of aspartame. Due to either deficiencies in experimental design, lack of evidence of an adverse effect, and/or lack of biological relevance of in vitro studies with high concentrations of aspartame added directly to cells or tissues, these studies were described as having no to minimal relevance for human risk assessment (EFSA, 2013). Here is an example of the discussion from EFSA of several such studies cited in this paper
Abhilash et al., (2011, 2013) treated male Wistar rats with aspartame in water by gavage, daily for 6 months. They found slight increases (1.50, 1.84, 1.11 and 4.03-fold increase, respectively) in serum liver enzyme (ALAT, ASAT, ALP and γGT) levels in animals exposed to 1000 mg/kg bw/day. The Panel considered these increases as relatively low and likely to be within the normal historical range seen in many laboratories. Therefore, they were not considered to be of biological relevance. Furthermore, the Panel considered the focal infiltration of the liver by inflammatory cells, which is generally also present in the liver of control animals, as normal background pathology. Moreover, these effects were not reported in the chronic toxicity and carcinogenicity studies in both rats and mice, which were performed with much higher doses (up to 8000 mg/kg bw/day).
Most of the studies in animals included in this review were conducted by the authors (Choudary and coworkers) and by another group (Ashok and coworkers) who are from the same institution, University of Madras. Although not described in this review, all of these studies utilize folate-deficient rats as the animal test model. To achieve this state, rats are fed a folate-deficient diet for up to 45 days and treated with a chemotherapeutic drug (methotrexate) prior to administration of aspartame. This is an inappropriate animal model for safety assessments, has questionable relevance to humans, and is likely why these papers were published in rather obscure journals. Furthermore, these experiments lack the key elements of a toxicology study, including use of more than one dose to demonstrate dose-response, and evidence of that observed changes in enzyme and protein levels are not simply adaptive changes but actual adverse effects linked to evidence of altered function or morphology. The conclusions of these studies are also in stark contrast to the overwhelming database of safety studies recently reviewed by EFSA (2013) showing no adverse effects at much higher doses of aspartame for longer periods of exposure.
Figure 3 is also misleading and inaccurate, purporting that somehow aspartame acts on the gastrointestinal tract (GIT) microflora, then is broken down and absorbed as the 3 metabolites and lead to oxidative stress. This does not make any sense, as aspartame is digested completely by digestive enzymes and metabolites absorbed in the small intestine, so aspartame does not even reach microflora in the gut. Furthermore, the allegations of effects on oxidative stress are primarily based on the authors’ own research using the inappropriate animal model described above.
There are many other examples of inappropriate statements, but further discussion of this contorted weave of misinformation gives it undue attention. Unfortunately, it is has been published in Nutrition Reviews, giving it unwarranted credibility, and representing a failure of the peer review and editorial process.
References:
European Food Safety Authority. Scientific Opinion on the re-evaluation of aspartame (E 951) as a food additive. EFSA J. 2013;11:3496.
Magnuson BA, Burdock GA, Doull J, et al. Aspartame: a safety evaluation basedon current use levels, regulations, and toxicological and epidemiological studies. CRC Crit Rev Toxicol. 2007;37:629–727.
Marinovich M, Galli CL, Bosetti C, Gallus S, La Vecchia C. Aspartame, low-calorie sweeteners and disease: regulatory safety and epidemiological issues. Food Chem Toxicol. 2013 Oct;60:109-15.
