A critical appraisal of the WHO reviews of aspartame


  •  Following a comprehensive safety assessment of all available evidence, the Joint FAO/WHO Expert Committee on Food Additives (JECFA), reconfirmed the safety of aspartame and re-affirmed the Acceptable Daily Intake.
  • As part of its comprehensive assessment, JECFA examined recent conclusions of the International Agency for Research on Cancer (IARC), which classified aspartame as possibly carcinogenic to humans (Group 2B), based on “limited” evidence. IARC is not a food safety authority.
  • Despite the large body of scientific evidence, which has undergone multiple regulatory reviews with agreement on a lack of association between aspartame and cancer, the IARC relied on 3 epidemiological studies as the basis of the “limited” evidence of hepatocellular carcinoma in humans – studies for which IARC reported that chance, bias, and confounding could not be ruled out – and 3 experimental animal studies as the basis for the  “limited” evidence in experimental animal data – studies which have consistently determined to be unreliable by regulatory bodies. JECFA found no convincing evidence of any concern for human health and reaffirmed the safety of aspartame.
  • Aspartame is one of the most thoroughly researched ingredients in the world.


Aspartame is safe     

On 14th July 2023, the Joint Food and Agriculture Organisation (FAO)/WHO Expert Committee on Food Additives (JECFA) re-affirmed the safety of aspartame and re-confirmed the Acceptable Daily Intake (ADI) of 40 mg/kg body weight.

Following review of an extensive evidence base, JECFA concluded that there was no convincing evidence from experimental animal or human data that aspartame has adverse effects after ingestion. JECFA also evaluated carcinogenic potential, concluding that there was “no concern for carcinogenicity in animals from oral exposure to aspartame,” and that the “evidence of an association between aspartame consumption and cancer in humans is not convincing” (JECFA 2023).

Limitations of the IARC review 

At their meeting in June 2023, a working group of the International Agency for Research on Cancer (IARC) classified aspartame as “possibly carcinogenic to humans (Group 2B)” (Riboli 2023). This classification was based on “limited” evidence in epidemiology studies, “limited” evidence in animal data, and “limited” mechanistic data. As defined in the IARC Preamble, the “limited” evidence category is used when “a causal interpretation of the positive association observed in the body of evidence on exposure to the agent and cancer is credible, but chance, bias, or confounding could not be ruled out with reasonable confidence” and is less than “sufficient evidence” (IARC 2019).

Information on the rationale for this classification is currently limited to a summary provided in the Lancet (Riboli 2023) and a joint summary of findings from IARC and JECFA (IARC and JECFA 2023).

  • Limited Evidence in Human Studies

With respect to human data, the IARC committee found that there was “inadequate” evidence for all cancer types except hepatocellular carcinoma, which was found to have “limited evidence,” based on the findings of three studies which IARC states report positive associations. However, because chance, bias, or confounding could not be ruled out with reasonable confidence in this set of studies, evidence for cancer in humans was deemed “limited” for hepatocellular carcinoma (Riboli 2023).

The three human studies cited by IARC (Jones 2022, McCullough 2022, and Stepien 2016) each assessed potential associations between non-sugar sweetened beverage consumption and cancer. Notably, none of these studies measured aspartame consumption in their study populations. Instead, they used consumption of non-sugar sweetened beverages as a proxy for consumption of aspartame – and – importantly – only collected consumption information once, at the start of each study.  That is, no additional information was collected on dietary consumption patterns throughout the duration of the follow up (which ranged from 11 to 34 years), highlighting the likelihood for misclassification bias in exposure to aspartame.

In one study which included two US-based cohorts, artificially sweetened beverage consumption and risk of liver cancer was assessed by diabetes status (Jones 2022). The assessment of exposure to the artificially sweetened beverages was frequency of consumption per day, as opposed to amount per day. Study authors did not find any association between artificially sweetened beverage consumption and liver cancer in non-diabetic participants. In participants with diabetes (with no distinction between Type 1 and Type 2) an association was observed between increasing time per day of artificially sweetened beverages and liver cancer risk up to 12 years after the start of the study (Hazard Ratio (HR): 1.13; 95% Confidence Interval (CI): 1.02-1.25). However, no such association was found when evaluating participants twelve or more years after the start of the study (HR: 0.82; 95% CI: 0.64-1.05).  The authors stated that it is not clear why the risk did not persist with increased follow up time – something that would have been expected if a true association was present.

In another US-based study (McCullough 2022), the effect of artificially sweetened beverages on several types of cancer-related mortality were assessed. Notably, the assessment of consumption of sweetened beverages in this study occurred in 1982, one year before aspartame was approved in carbonated beverages in the United States (US FDA 2023 a). Although IARC indicates a positive association between artificially sweetened beverage consumption and cancer mortality was reported in a subgroup (Riboli 2023), no statistically significant associations were observed between artificially sweetened beverage consumption and liver cancer. In fact, when comparing the risk of liver cancer with artificially sweetened beverages the risk appears to decrease with increasing amount of consumption when compared to “never drinkers”. When considering the consumption of artificially sweetened beverages as a continuous variable, there was no association with increased liver cancer risk.

The third article referenced by IARC (Stepien et al. 2016) was conducted in a European cohort and aimed to assess the risk of intake of combined soft-drinks (sugar and artificially sweetened) and fruit and vegetable juices and the risk of liver cancer. In this analysis, a slight increase in the risk of liver cancer was observed with each additional serving of artificially sweetened beverage (HR: 1.06; 95% CI: 1.03-1.09). However, the article does not clarify what variables were accounted for in this analysis, bringing into question whether authors accounted for important potential confounders of the relationship between artificially sweetened beverage consumption and liver cancer. Without information on the variables considered for this risk estimate, this small increased risk could likely be due to residual confounding or exposure misclassification bias.

Collectively, the limitations across the studies cited by IARC are substantial, precluding the ability to assess or determine causality. These – and other- limitations led JECFA to conclude that, “[A] consistent association between aspartame consumption and a specific cancer type was not observed. All studies have limitations with respect to their assessment of exposure and, in many studies, particularly with respect to aspartame versus intense sweeteners in general. Reverse causality, chance, bias and confounding by socioeconomic or lifestyle factors, or consumption of other dietary components cannot be ruled out. Overall, the JECFA Committee concluded that the evidence of an association between aspartame consumption and cancer in humans is not convincing” (emphasis added).

These conclusions are also consistent with a recent comprehensive quantitative review of the toxicological and epidemiological evidence on a possible relation between non-sugar sweeteners (NSS), including aspartame, and cancer, which found no evidence of cancer risk associated to NSS consumption (Pavenello 2023).

  • Limited Animal Evidence

Twelve experimental animal cancer studies of aspartame were evaluated by JECFA; all but three showed negative results (JECFA 2023). These twelve studies are not all individually discussed in the Lancet summary, but the three positive studies are identified and described as “limited” evidence for cancer in experimental animals (Soffriti 2010, Soffritti 2007, Soffriti 2006). These studies report data from three lifetime cancer bioassays conducted at the Ramazzini Institute, two in Sprague-Dawley rats and one in Swiss mice, and IARC lists the specific cancer types observed in males and females. However, “because questions about adequacy of the design, conduct, interpretation, and reporting of each of the studies, the IARC considered the evidence for cancer in experimental animals to be ‘limited.’” In looking at the same studies, JECFA concluded that “the results of the Soffritti et al. studies are of uncertain relevance and therefore cannot be used for the risk assessment of aspartame,” with a specific statement regarding the limitations of the lifetime study protocols (JECFA 2023).

Although this is not mentioned in the IARC summary, the Ramazzini Institute studies have been routinely dismissed as unreliable by regulatory agencies, including by the European Food Safety Authority (EFSA), which conducted one of the most comprehensive safety reviews ever undertaken on aspartame (EFSA 2013) and also in the peer reviewed literature (Borghoff 2023, Elmore 2023, EFSA 2013, FDA 2023 b, FSANZ 2022). The Ramazzini Institute studies were not conducted under good laboratory practice (GLP) or using standard cancer bioassay guidelines and did not meet industry standards for tissue fixation or study duration. In addition, animals were necropsied at natural death and not the standard 104-week timepoint. The lack of animal health surveillance monitoring and potential for a pathogen-induced chronic inflammatory reaction may have played a role in observed tumor responses, greatly limiting potential interpretation of observed lesions (Elmore 2023).

  • Limited Mechanistic Evidence

The IARC summary reports “mechanistic evidence for aspartame was ‘limited’ for the key characteristics of carcinogens,” calling out studies showing oxidative stress and chronic inflammation in particular (specific study citations were not provided) (Riboli 2023). IARC notes that while some studies showed positive genotoxicity findings, the studies had design, data analysis, or interpretation limitations. JECFA also concluded that there was no concern of genotoxicity (JECFA 2023).

JECFA also reviewed recently published studies investigating possible mechanisms that may be relevant to the induction of cancer, such as oxidative stress and noted that “studies that reported changes in markers of oxidative stress had limitations in their design” and concluded that there was no concern of genotoxicity and a “lack of plausible mechanism by which oral exposure could induce cancer” (JECFA 2023). Overall, when considering the available mechanistic evidence, the data do not support a biological plausible pathway to carcinogenicity (Borghoff 2023; JECFA 2023).

Aspartame is one of the most thoroughly researched ingredients in the world

Aspartame is one of the most thoroughly researched ingredients in history, reviewed by over 90 food safety agencies across the globe, including the European Food Safety Authority (EFSA) and the US Food and Drug Administration (FDA). JECFA conclusions are consistent with findings of those agencies, confirming that aspartame is safe.

Low/no calorie sweeteners provide consumers with choice

 Aspartame, like all other low/no calorie sweeteners, when used as part of a balanced diet, aspartame provides consumers with choice to reduce sugar intake, a critical public health objective.

Low/no calorie sweeteners play an important role in providing consumers with choice of sweet-tasting options with low or no calories. As part of a balanced diet, low/no calorie sweeteners can be a useful tool to reduce sugar and calorie intake, as well as to manage blood glucose levels (Diabetes UK 2018) and reduce the risk of dental caries (EFSA 2011).

Borghoff, S.J., Cohen, S.S., Jiang, X., Lea, I.A., Klaren, W.D., Chappell, G.A., Britt, J.K., Rivera, B.N., Choski, N.Y. and Wikoff, D.S. 2022. Updated systematic assessment of human, animal and mechanistic evidence demonstrates lack of human carcinogenicity with consumption of aspartame. Food and Chemical Toxicology, p.113549.

Diabetes UK. 2018. The use of low or no calorie sweeteners. Position Statement (Updated December 2018). Available at: https://www.diabetes.org.uk/professionals/position-statements-reports/food-nutrition-lifestyle/use-of-low-or-no-calorie-sweetners

EFSA. 2013. Scientific Opinion on the re-evaluation of aspartame (E 951) as a food additive.https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2013.3496

EFSA. 2011. Scientific opinion on the substantiation of health claims related to intense sweeteners. EFSA 2011 Journal 9(6): 2229, and 9(4): 2076

Elmore, S.A., J.E. Rehg, T.R. Schoeb, J.I. Everitt, B. Bolon. 2023. Pathologists’ perspective on the study design, analysis, and interpretation of proliferative lesions in lifetime and prenatal rodent carcinogenicity bioassays of aspartame. Food and Chemical Toxicology. 171: 113504 ISSN 0278-6915, https://doi.org/10.1016/j.fct.2022.113504

FSANZ 2022. Website information on Aspartame (Updated in May 2022). Available at: https://www.foodstandards.gov.au/consumer/additives/aspartame/Pages/default.aspx

Goodman J E, Boon D N, Jack M M, Perspectives on recent reviews of aspartame cancer epidemiology, Global Epidemiology, Volume 6, 2023, 100117, https://doi.org/10.1016/j.gloepi.2023.100117

IARC. 2019. IARC Monographs on the Identification of Carcinogenic Hazards to Humans: Preamble. Lyon, France. Amended January 2019.

IARC and JECFA. 2023. International Agency for Research on Cancer and Joint FAO/WHO Expert Committee on Food Additives. Summary of findings of the evaluation of aspartame at the International Agency for Research on Cancer (IARC) Monographs Programme’s 134th Meeting, 6–13 June 2023 and The JOINT FAO/WHO EXPERT COMMITTEE ON FOOD ADDITIVES (JECFA) 96th meeting, 27 June–6 July 2023. Accessed on July 14, 2023. Available at https://www.iarc.who.int/featured-news/aspartame-hazard-and-risk-assessment-results-released

JECFA. 2023. Joint FAO/WHO Expert Committee on Food Additives. Ninety-sixth meeting (Safety evaluation of certain food additives) 27 June-6 July 2023. Summary and Conclusions. Accessed on July 14, 2023. Available at https://www.who.int/publications/m/item/ninety-sixth-meeting-joint-fao-who-expert-committee-on-food-additives-(jecfa)

Jones GS, Graubard BI, Ramirez Y, et al. 2022. Sweetened beverage consumption and risk of liver cancer by diabetes status: a pooled analysis. Cancer Epidemiol 79: 102201. https://www.sciencedirect.com/science/article/abs/pii/S1877782122001060?via%3Dihub

McCullough ML, Hodge RA, Campbell PT, et al. 2022. Sugar- and artificially-sweetened beverages and cancer mortality in a large U.S. prospective cohort. Cancer Epidemiol Biomarkers Prev 31: 1907–18. https://aacrjournals.org/cebp/article-abstract/31/10/1907/709398/Sugar-and-Artificially-Sweetened-Beverages-and?redirectedFrom=fulltext

Pavenello et al. Non-sugar sweeteners and cancer: Toxicological and epidemiological evidence;  Regulatory Toxicology and Pharmacology. Volume 139, March 2023, 105369 https://doi.org/10.1016/j.yrtph.2023.105369

Riboli, E., F. Beland, D. Lachenmeier, et al. 2023. International Agency for Research on Cancer (IARC): Carcinogenicity of aspartame, methyleugenol, and isoeugenol. Lancet Oncol 2023. Published online July 13, 2023. DOI 10.1016/S1470-2045(23)00341-8. Accessed on July 14, 2023. Available at https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(23)00341-8.pdf

Soffritti M, Belpoggi F, Manservigi M, et al. 2010. Aspartame administered in feed, beginning prenatally through life span, induces cancers of the liver and lung in male Swiss mice. Am J Ind Med 53: 1197–206.

Soffritti M, Belpoggi F, Tibaldi E, et al. 2007. Life-span exposure to low doses of aspartame beginning during prenatal life increases cancer effects in rats. Environ Health Perspect 115: 1293–97.

Soffritti M, Belpoggi F, Degli Esposti D, et al. 2006. First experimental demonstration of the multipotential carcinogenic effects of aspartame administered in the feed to Sprague-Dawley rats. Environ Health Perspect 114: 379–85.

Stepien M, Duarte-Salles T, Fedirko V, et al. 2016. Consumption of soft drinks and juices and risk of liver and biliary tract cancers in a European cohort. Eur J Nutr 55: 7–20.https://link.springer.com/article/10.1007/s00394-014-0818-5

US FDA. 2023. Aspartame and Other Sweeteners in Food. https://www.fda.gov/food/food-additives-petitions/aspartame-and-other-sweeteners-food

US FDA. 2023. Timeline of Selected FDA Activities and Significant Events Addressing Aspartame (Updated in May 2023) https://www.fda.gov/food/food-additives-petitions/timeline-selected-fda-activities-and-significant-events-addressing-aspartame