Does aspartame cause cancer? It’s complicated

Aspartame has been sweetening diet soda and other sugar-free products since the 1980s, and its safety seemed established. But that certainty changed in July last year after an arm of the World Health Organization (WHO) released the results of a controversial hazard evaluation.

The group, the International Agency for Research on Cancer (IARC), concluded that aspartame is possibly carcinogenic to humans. The conclusion was based on limited evidence of liver cancer in humans. IARC also found limited evidence of cancer in animal studies and limited mechanistic data on how carcinogenicity may occur, such as whether aspartame induces oxidative stress or chronic inflammation.

But in a joint news release by IARC and the Joint Expert Committee on Food Additives (JECFA), which is also part of the WHO, Moez Sanaa, the WHO’s head of the Standards and Scientific Advice on Food and Nutrition Unit, says that “the evidence of an association between aspartame consumption and cancer in humans is not convincing.” The committee recommended maintaining the acceptable daily intake (ADI) of 40 mg/kg body weight.

After these conflicting conclusions, regulatory agencies, the food and beverage industry, and scientists are again debating a question that was once settled: Can aspartame cause cancer?

Consumers are confused by the mixed messages, but not much else has happened in the aftermath of the WHO announcement, says Thomas Galligan, principal scientist for food additives and supplements at the Center for Science in the Public Interest (CSPI), a consumer advocacy group that is concerned about aspartame. “The US Food and Drug Administration hasn’t taken any new stance on aspartame,” he says. “And I haven’t seen any companies decide to reformulate away from aspartame.”

Instead, the food and beverage industry and the FDA are defending aspartame, saying it is safe at current permitted use levels. The FDA’s ADI for aspartame is 50 mg/kg body weight, which is slightly higher than the 40 mg/kg body weight recommended by JECFA and adopted by the European Food Safety Authority. A can of diet soda typically contains 200–300 mg of aspartame, so a 70 kg person would need to drink more than 9–14 cans per day to exceed the safe level in the European Union.

Regulators established the ADI levels in the 1980s on the basis of the toxicity of aspartame’s breakdown products in animal studies, not the risk of cancer. They maintain that aspartame lacks carcinogenic activity.

“The FDA disagrees with IARC’s conclusion that these studies support classifying aspartame as a possible carcinogen to humans,” the FDA says in a July 2023 response to the IARC evaluation. “FDA scientists reviewed the scientific information included in IARC’s review in 2021 when it was first made available and identified significant shortcomings in the studies on which IARC relied.”

Aspartame, which is about 200 times as sweet as sugar, is one of the most studied food additives, according to the FDA. In both laboratory animals and humans, enzymes in the gastrointestinal tract metabolize the intense, low-calorie sweetener into two amino acids—aspartic acid and phenylalanine—and methanol.

Scientists have published more than 100 animal and human studies on the toxicology of aspartame as well as thousands of research papers on mechanistic data like absorption, distribution, metabolism, and excretion.

Toxicologists and other attendees discussed the strengths and weaknesses of some of those studies at the Society of Toxicology annual meeting in March in Salt Lake City. An information session was chaired by Susan Borghoff, a toxicologist with the consulting firm ToxStrategies, and Sabine Francke, a senior pathologist at the FDA. The American Beverage Association paid Borghoff for her preparation time and attendance at the meeting.

The session’s overall message was clear: the totality of the scientific evidence, including animal, human epidemiological, and mechanistic data, supports aspartame’s safety in food and beverages.

That’s the same message Borghoff and colleagues drove home in a systematic review published last year (Food Chem. Toxicol. 2023, DOI: 10.1016/j.fct.2022.113549). The American Beverage Association paid for the review. The toxicologists reported a lack of evidence that the consumption of aspartame is associated with cancer in humans.

Consumer groups don’t share that opinion. The CSPI nominated aspartame to be evaluated by IARC in 2014 and again in 2019. IARC agreed to do the cancer hazard assessment in 2019 primarily because three rodent studies, all conducted by Morando Soffritti and colleagues at the European Ramazzini Foundation for Oncology and Environmental Sciences, showed that aspartame induces lymphomas, leukemias, and other cancers.

Numerous toxicologists and pathologists have questioned the results of the three studies, which were published in 2005, 2007, and 2010. Even IARC agreed that the evidence is limited because of questions about the adequacy of the study designs.

The three studies do not follow the FDA’s good laboratory practices that have been in place since 1979, the FDA’s Francke said at the Society of Toxicology meeting.

One of the biggest criticisms about the studies is that their duration was over the lifetime of the test animals rather than the typical 2-year cancer bioassay for rats.

Animals lose their innate immunity as they age and become more susceptible to disease, including infections, Francke said. The high incidence of inflammatory lesions in the rats in the three studies indicates underlying infections, she added. In older animals, it is harder for pathologists to differentiate between effects related to aspartame and background changes, such as loss of immunity or inflammation, she said.

Francke noted that nine other relevant animal studies, including four with 2-year bioassays that adhere to the FDA’s quality standards, showed no cancer effects from the consumption of aspartame.

Criticism of the studies by Soffritti and colleagues has been “discussed ad nauseam in the literature,” Galligan says. But the CSPI argues that the research is valid. “There are a lot of positive signals in those studies that are not easily dismissed as just being the result of faulty design or execution of the studies,” he says.

Galligan also says lifetime bioassays are superior to 2-year studies. “Two years in the lifespan of a rat is basically middle age. But many cancers in humans occur much later in life,” he says.

A minority of the IARC working group considered the evidence for cancer in experimental animals to be sufficient, which would have supported classifying aspartame as a probable human carcinogen, or group 2A. But the majority of the group considered the evidence limited.

IARC’s decision to classify aspartame as a possible carcinogen, or group 2B, was ultimately driven by three epidemiological studies that provided limited evidence linking artificially sweetened beverages with liver cancer in humans.

The studies examined data from large cohorts. One of them, published in 2014, used data from the European Prospective Investigation into Cancer and Nutrition cohort of 477,206 participants from 10 European countries who were followed for 11.4 years (Eur. J. Nutr. DOI: 10.1007/s00394-014-0818-5). The researchers found that artificially sweetened soft drinks increased the risk of liver cancer by 6% per serving. They found no association between sugar- sweetened soft drinks and liver cancer.

The second study, published in 2022, used data from two US cohorts pooled together, which included 553,874 participants (Cancer Epidemiol. DOI: 10.1016/j.canep.2022.102201). The researchers found no association between drinking artificially sweetened beverages and liver cancer for people without diabetes. But they did find a significant association for people with diabetes during the first 12 years of follow-up.

In the third study, also published in 2022, researchers used data from 934,777 participants enrolled in a US cancer prevention study (Cancer Epidemiol., Biomarkers Prev., DOI: 10.1158/1055-9965.EPI-22-0392). They reported a positive association between artificially sweetened beverages and cancers correlated with higher weight, including liver cancer, but that association disappeared after controlling for body mass index (BMI). They also found an increased risk of pancreatic cancer that did not disappear after controlling for BMI.

Review articles, largely written by toxicologists funded by the beverage industry, criticize the studies for using artificially sweetened beverages as a proxy for aspartame. They point to inconsistent and weak positive associations across studies that could be due to confounding variables such as metabolic syndrome, hepatitis, and conditions that predispose people to gaining weight.

IARC acknowledges in a summary of its results that “chance, bias or confounding could not be ruled out as an explanation for the positive findings.” But the agency considered the evidence limited rather than inadequate. That distinction is key to its decision to classify aspartame as a possible carcinogen, or group 2B. If IARC had considered the evidence inadequate, as regulators and industry say it should have, aspartame would have been considered “not classifiable as to its carcinogenicity to humans,” or group 3.

Explaining to the public what a group 2B classification means is quite challenging, Borghoff said during a panel discussion at the Society of Toxicology meeting. For people who drink and eat food containing aspartame, seeing the words “possibly carcinogenic” is really concerning, she said.

It is unclear whether people who consumed aspartame regularly before the IARC classification will now opt for something else when they get a sweet tooth. The food and beverage industry is spending millions of dollars to convince them that aspartame is safe. Consumer groups encourage people to drink unsweetened beverages, especially water.

“But if your only options are between a diet beverage and a sugar-sweetened beverage, we do recommend the diet beverage,” Galligan says. “That’s because the health risks of sugar-sweetened beverage consumption far outweigh the risks posed by aspartame.”