In March 2015, the World Health Organization’s International Agency for Research on Cancer (IARC) designated glyphosate, the active ingredient in Roundup, as “probably carcinogenic to humans” (Group 2A). Within months, the first lawsuits were filed seeking to hold glyphosate patent holder Monsanto responsible for injuries in people exposed to glyphosate.

Glyphosate was one of the most popular herbicides at the time, making it easy for opportunistic lawyers to find people with high exposure, and nearly every filed complaint referenced the IARC decision naming it as probably carcinogenic to humans.

In what would turn out to be a riskier business decision than they thought, Bayer acquired Monsanto in 2018 while initial glyphosate cases were already pending. By the end of 2019, juries in two trials awarded plaintiffs $289 million and $80 million in cases where they alleged glyphosate caused their cancers. Damages in those cases were reduced on appeal to $21 million and $25 million, respectively. In 2020, Bayer settled the majority of the glyphosate litigation for $10 billion.

Fast forward to 2022—IARC announced that it would issue a carcinogenicity determination on another chemical with broad exposure: aspartame, one of the most commonly used non-nutritive sweeteners.

Like glyphosate, aspartame has a history of controversy that began not long after the FDA approved it as a food additive. Concerns about its health effects have lingered, at least in some circles, since the 1970s, and the scientific investigations showing aspartame’s safety for human consumption have done little to alleviate them. Perhaps some of the suspicion stems from the fact Monsanto owned the original manufacturer of aspartame from 1985 to 2000. (Editor’s Note: Monsanto acquired Searle, the maker of NutraSweet, in 1985; PE firm J.W. Childs bought NutraSweet in 2000, according to online reports.)

When IARC announced that it would evaluate aspartame’s carcinogenicity, alarm bells rang at Praedicat that it could be a repeat of the glyphosate situation. Both chemicals had a history of controversy and scientific literatures that could be read to suggest there were important health risks from them but could also be read to suggest there was little risk if used as directed.

Could IARC conclude aspartame was Group 2A/”probably carcinogenic to humans” despite scientific evidence suggesting the risk to any individual was, at most, small?

If IARC did decide on a Group 2A classification for aspartame, would it lead to an onslaught of lawsuits just as their glyphosate determination did?

Thankfully for all involved, IARC seems to have taken note of the consequences of its glyphosate decision. Aside from the immense cost imposed on Monsanto/Bayer, IARC was heavily scrutinized and was even vilified in many circles for its decision on glyphosate. Some claimed IARC had an anti-business agenda, while others derided IARC’s determinations as meaningless in practice because they fail to consider real-world risk. It’s fair to guess that IARC thought carefully about how to conduct this evaluation and the potential fallout of its determination.

The process IARC followed for releasing its aspartame evaluation appears to have, at least for now, significantly reduced the likelihood of mass litigation claiming aspartame consumption causes cancer. The main change the agency made with aspartame compared to glyphosate is that it coordinated with the WHO agency responsible for regulating food additives: The Joint Expert Committee on Food Additives, or JECFA.

To understand the interplay between IARC and JECFA it is helpful to review the regulatory process governing food additives. Generally, food regulators review the scientific evidence amassed about the safety of a food additive and then determine what a safe daily intake would be after applying a factor of safety. Depending on the intended use of the additive, the regulator may then propose limits on how much of the additive can be used in certain foods. JECFA had previously assessed the safety of aspartame and had concluded that a safe daily intake was 40-50 mg of aspartame per kilogram of body weight per day. That equates to at least 15 cans of artificially sweetened beverages for the average adult.

IARC realized that its review of aspartame’s carcinogenicity and finding that aspartame belonged in Group 2B could have led the public to distrust the published acceptable intake limits. In a smart piece of public relations, it coordinated with JECFA’s pending re-evaluation of aspartame’s acceptable intake limits so that they could release their findings together.

In July 2023, their findings and joint statement were released. IARC announced that aspartame is “possibly” carcinogenic—Group 2B—while JECFA reaffirmed its prior assessment that a 40 mg/kg acceptable daily intake is safe. Despite using the exact same literature base, IARC and JECFA arrived at their conclusions using different methods.

IARC reviewed 1,300 studies for its aspartame analysis this past June. It ended up focusing primarily on three recently published human epidemiology studies that examined whether artificially sweetened beverage intake led to increased cancer incidence, explicitly deeming consumption of artificially sweetened beverages a good proxy for exposure to aspartame. These studies concluded that there was an association between artificially sweetened beverage intake and liver or pancreatic cancers.

IARC also assessed the reliability of the studies and determined that chance, bias or confounding could not be ruled out as an explanation for the association. That led the agency to conclude that there was “limited” evidence for a causal relationship between aspartame and cancer in human studies. IARC similarly ascertained there is “limited” evidence from both animal and in vitro studies to support an association between aspartame and cancer.

IARC’s scoring system then required it to rate aspartame as “possibly carcinogenic to humans.” IARC confidentially shared this determination with JECFA before the latter held its meeting in early July.

JECFA’s analysis, on the other hand, focused on studies directly investigating aspartame’s biological effects because it found sufficient literature to complete the assessment. For its analysis, JECFA relied heavily on the fact that aspartame does not enter the bloodstream itself. Instead, it fully hydrolyzes in the gastrointestinal tract into its primary metabolites: methanol and the amino acids phenylalanine and aspartic acid. These three substances are common constituents of food and are regularly released by the hydrolysis of many foods. JECFA noted that blood levels of aspartame’s metabolites do not increase after ingestion of aspartame at the current ADI (acceptable daily intake). The committee also declared that the evidence from human and animal studies finding that aspartame is harmful was “not convincing.” Finally, JECFA examined in vitro and in vivo genotoxicity studies, finding that aspartame is not genotoxic (damaging to DNA).

In the end, JECFA opted to retain its current intake limits for aspartame.

It’s worth noting that both IARC and JECFA focused on the evidence that aspartame could be carcinogenic in their evaluations. Neither of them addressed the existing bodies of scientific literature that suggest artificially sweetened beverages could be linked to other kinds of bodily injury. Some epidemiological studies have shown that increased artificially sweetened beverage consumption is correlated with cardiovascular disease and endocrine system dysfunction, giving those harm hypotheses a stronger scientific consensus than that of aspartame’s (or artificially sweetened beverage as a proxy) ability to cause cancer.

We also note that IARC’s determination that aspartame should be in Group 2B is consistent with Praedicat’s view of the scientific literature consensus.

The coordination between IARC and JECFA helped ensure that despite IARC’s finding of “possible” carcinogenicity, one level lower than its classification of glyphosate, the public is unlikely to react with the level of concern it had with its Group 2A designation of glyphosate—despite the Monsanto connection. Of course, this doesn’t deter creative plaintiffs’ lawyers from perhaps trying to find a way to turn IARC’s finding into litigation. But if they do, they will have a less convincing argument than the glyphosate lawyers.