Aspartame and cancer: Why you really shouldn’t worry about this

The World Health Organization's cancer agency released an anticipated assessment late last week, finding that the common artificial sweetener aspartame "possibly" has the ability to cause cancer—specifically, a type of liver cancer called hepatocellular carcinoma.

The assessment, leaked to Reuters in June, was poised to set off alarms. But, a closer look at the designation itself, the safety evaluation of the current daily recommended limited, and the data underpinning the assessment should comfort anyone worried about their cancer risk and considering ditching their favorite diet drink or snack.

Low-confidence designation

The concern is all based on a designation from the WHO's cancer agency—the International Agency for Research on Cancer (IARC)—labeling aspartame a Group 2B agent, which is considered "possibly carcinogenic to humans." Group 2B is one of four possible classifications, which span "carcinogenic" (Group 1),  "probably" carcinogenic (Group 2A), "possibly" carcinogenic (Group 2B), and "not classifiable" (Group 3). This is the first time the IARC has evaluated aspartame—it's not an update to a previous assessment.

The Group 2B designation is low-confidence by definition, based on "limited evidence." It's intended to spur more research more than anything. The 322 other agents with a 2B designation include Ginkgo biloba extract, Aloe vera whole leaf extract, and radio-frequency electromagnetic waves. And, importantly, the IARC assessment and designation do not address the exposure level at which a 2B agent would potentially begin to pose their possible cancer risk. For food additives, there's a separate committee for that—the Joint Expert Committee on Food Additives (JECFA) for the WHO and the Food and Agriculture Organization (FAO).

JECFA did a separate evaluation of aspartame recently, its third evaluation for the popular diet sweetener. It released its conclusion jointly with the IARC assessment last week. In contrast to the cancer agency, JECFA found no convincing link between aspartame and any type of cancer, including hepatocellular carcinoma. "[A] consistent association between aspartame consumption and a specific cancer type was not observed," the committee concluded its assessment report.

Overall, JECFA concluded once again that it is safe to consume aspartame at the committee's previously established daily limit, called the acceptable daily intake (ADI), set at 0–40 mg/kg body weight. And most people probably stay within this fairly easily. As an example, the committee noted that, with a can of diet soda containing between 200 and 300 mg of aspartame, an adult weighing 70 kg (about 154 pounds) would need to consume between 9–14 cans of soda per day to exceed the ADI, assuming no other intake from other aspartame-containing foods, such as sugar-free gums, Jell-O, or syrup.

Limited evidence

Though the two groups came to seemingly different conclusions, they based their assessments on the same body of data—which, again, is limited.

There are some animal studies linking aspartame to cancers, but both groups concluded that the data is questionable. Following three mouse and rat studies from one research group linking aspartame to cancer, the IARC concluded it had "concerns over the study design, interpretation and reporting of data." JECFA looked at 12 studies, noting that the three studies the IARC mentioned were the only ones that claimed to find a cancer link. The committee was more specific in its criticism of the three studies, noting that they lacked controls, adjustments for litters effects, and background levels of cancers. Overall, JECFA concluded the studies were of "uncertain relevance" and did not establish a connection between aspartame and cancer.

JECFA also took aim at the mechanism by which aspartame might spur cancers—noting that, essentially, there isn't one so far. The committee reviewed recent lab studies suggesting that aspartame may cause oxidative stress in cells, which can be a cancer trigger. But JECFA noted that toxicity studies of aspartame have failed to turn up hallmarks of prolonged oxidative stress, knocking back the suggestion.

The committee further noted that, when consumed, aspartame quickly breaks down in the gastrointestinal tract into three common metabolites: phenylalanine, aspartic acid, and methanol. These metabolites are not specific to aspartame and are released from commonly consumed foods. Moreover, oral aspartame studies have found that plasma concentrations of those common metabolites do not increase above normal levels after aspartame consumption.

But, the crux of the discrepancy between JECFA's and IARC's take on aspartame come down to just three large cancer studies in humans. The IARC summarized them as showing a "positive association"  between aspartame and risk of liver cancer. JECFA summarized them as being "not convincing."

Three central human studies

The first is a study initially published in 2014 and led by researchers at the IARC. It followed a cohort of nearly 480,000 people in 10 European countries for over 11 years, looking for a link between soft drink consumption (both sugar-sweetened and artificially sweetened) and a few specific types of cancer, including hepatocellular carcinoma. Lumping together sugar and artificially sweetened drinks, the study found that having six or more cans per week linked to an increased risk of liver cancer, but not the other types of cancers evaluated. But, a subgroup analysis involving just 101 cases found that each can of artificially sweetened soda increased the risk of liver cancer by 6 percent. A subgroup analysis of the sugar-sweetened soft drinks did not find such a dose-dependent association in risk.

Although not all artificially sweetened soft drinks are sweetened with aspartame, the IARC considered them a proxy for aspartame exposure.

The second study, published last August by researchers at the National Cancer Institute in the US, looked at the risk of liver cancer from all types of sweetened beverages in people with and without diabetes. It pooled data from two large diet and cancer trial cohorts, providing data on over 550,000 people. The study found a link between artificial sweeteners and liver cancer, but only in people with diabetes.

For the 500,000 or so people in the analysis who did not have diabetes, there was no association between liver cancer and consumption of sweetened beverages generally. However, those without diabetes who reported drinking sugar-sweetened sodas did have a higher risk of liver cancers. For people with diabetes, there was an increased risk of liver cancer in those who drank sweetened beverages generally, artificially sweetened beverages, any type of soda, and artificially sweetened soda specifically. Again, artificially sweetened beverages and sodas were considered a proxy for aspartame exposure by the IARC. And in this study, the risk of liver cancer linked to aspartame was only seen in those with diabetes

The third sudy was published last October by researchers at the American Cancer Society. It found an even narrower link between proxy aspartame exposure and liver cancer risk. The study looked at death certificate data from a pool of nearly 1.2 million US adults, looking at associations between sweetened beverage consumption and 20 individual cancer types. The study included over 135,000 deaths from cancer between 1982 and 2016.

The topline results were that people who drank two or more sugar-sweetened beverages a day were at a higher risk of obesity-related cancers—but the association disappeared when the researchers adjusted for BMI. For artificially sweetened beverages, there was a similar initial link to obesity-related cancers. It also evaporated upon adjusting for BMI, except that an increased risk of pancreatic cancer remained.

But, the IARC indicated this study bolstered a potential link between aspartame and liver cancers because of a small subgroup analysis that was mentioned in a single sentence in the text, but was otherwise buried in the supplemental data. The study found that among just men who also never smoked, drinking two or more artificially sweetened beverages per day was linked to an increased risk of liver cancer, as well as melanoma.

The study authors note the people in their study who drank artificially sweetened beverages were also heavier than those reporting drinking sugar-sweetened drinks, suggesting confounding by BMI. Higher BMIs and diabetes are known risk factors for some cancers, including pancreatic cancer. There have been some animal studies linking artificial sweeteners (aspartame, but also sucralose and saccharine) to gut microbiota changes that could lead to glucose intolerance, which could lead to diabetes. But the link between artificial sweeteners and the development of diabetes has not been solidified in human studies.

Disagreement

Overall, JECFA found the three study's slim and differing subgroup links to liver cancer unconvincing. And they noted that the studies all had problems. As the committee put it, the studies:

[H]ave 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 Committee concluded that the evidence of an association between aspartame consumption and cancer in humans is not convincing.

JECFA is not alone. On the same day that the IARC and JECFA evaluations came out, the US Food and Drug Administration released its own statement, saying bluntly, "The FDA disagrees with IARC’s conclusion that these studies support classifying aspartame as a possible carcinogen to humans." The agency said it does not have safety concerns about aspartame and noted that Health Canada and the European Food Safety Authority have also found aspartame to be safe.

Lastly, in an effort to clear the air about the IARC's designation, the FDA noted that "Aspartame being labeled by IARC as 'possibly carcinogenic to humans' does not mean that aspartame is actually linked to cancer."

Experts at WHO, meanwhile, called for more research on aspartame following the 2B designation. "The assessments of aspartame have indicated that, while safety is not a major concern at the doses which are commonly used, potential effects have been described that need to be investigated by more and better studies," Francesco Branca, director of the WHO's Department of Nutrition and Food Safety said in a statement.