Silencing the alarm on aspartame and cancer - Peter Attia, MD

Last month, the International Agency for Research on Cancer (IARC) – a branch of the World Health Organization – announced it had designated aspartame, the common low-calorie sweetener used in diet beverages such as Diet Coke and Diet Dr. Pepper, as “possibly carcinogenic to humans.” The bitter news was met with swift criticism and disagreement from the sweetener industry and the U.S. Food and Drug Administration (FDA), the latter noting that they had “identified significant shortcomings in the studies on which IARC relied.” Who’s right? Should we avoid the ubiquitous sweetener, or brush off the IARC’s announcement as a false alarm?

What does the announcement mean?

The IARC’s ruling has swept through mainstream media, where the mere inclusion of “aspartame” and “carcinogen” in the same headline is likely to spread alarm among consumers. But even taking the announcement at face value, we have little reason for heightened concern.

In reviewing chemical compounds and other exposures suspected of having carcinogenic effects, the IARC evaluates the strength of existing scientific evidence and then classifies the agent in question as “carcinogenic to humans,” “probably carcinogenic to humans,” “possibly carcinogenic to humans,” or “not classifiable as to its carcinogenicity.” On this scale, aspartame was placed in the second-to-lowest tier of “possibly carcinogenic,” which, according to the IARC, was determined based on a combination of limited mechanistic evidence, limited evidence from animal studies, and limited evidence from human data (particularly with respect to liver cancer). In other words, the IARC’s concluded that a causal link between aspartame and cancer has not been clearly established from existing literature but is sufficiently plausible to justify further investigation.

Digging deeper into the IARC’s evaluation system further weakens the power of this already underwhelming ruling. The classifications listed above are based solely on the strength of evidence for any causal association; they do not take into account the level of risk or the doses at which a carcinogenic effect may exist, so a substance could technically be classified as a carcinogen even if it increases risk by a small fraction of a percent and only at doses well above any normal human intake. Additionally, note that there is no category for “unlikely to be carcinogenic” – the options are limited to “carcinogenic” (with varying levels of certainty) or “no comment.” Indeed, many have pointed out that these limitations tend to result in widespread misinterpretation of IARC classifications and undue panic among the public (one of my favorite critiques likened the IARC designation of “carcinogenic” to the answer “42” from Douglas Adams’ The Hitchhiker’s Guide to the Galaxy).

Understanding the shortcomings of the IARC’s criteria helps us to appreciate the limits of their carcinogen designations in general. However, to determine what this means for the carcinogenic potential of aspartame specifically, we need to take a closer look at the primary research in the context of these shortcomings.

The Source of Suspicion

Perhaps the most influential body of literature driving the perception of aspartame as a possible carcinogen was a series of studies conducted in rodents in the early 2000s by the Ramazzini Institute. But since their publication, these studies have been the subject of considerable debate and criticism. Other scientists and organizations, including the European Food Safety Authority, have repeatedly called out the Ramazzini Institute for poor quality control and animal care practices, noting that pathogenic exposure and infection may have compromised study results. Yet even if we ignore any concerns regarding overall animal health and welfare, examination of the study details makes it clear that the Institute’s results have minimal relevance to human aspartame consumption.

Many of their studies in rats and mice involved aspartame doses exceeding the FDA’s acceptable daily intake (ADI) for humans of 50 mg/kg of body weight, even when accounting for metabolic scaling. This ADI in itself represents a level of intake that greatly surpasses that of the average human; for a person weighing 175 lbs, 50 mg/kg of body weight corresponds to about twenty 12-oz cans of diet soda every day. (Cue the bathroom breaks.) So even when the Institute studied doses within the ADI limit, they failed to approximate normal human consumption.

Moreover, in most of the Ramazzini Institute studies, animals were initially treated with aspartame while still in utero, and daily treatments continued throughout their entire lifespan. Aspartame consumed by women during pregnancy can indeed reach the human fetus, but high-dose aspartame exposure every day from mid-gestation until death is hardly a typical human experience. Further, this experimental design raises the possibility that any apparent carcinogenicity is secondary to other impacts on key stages of early development. (Of note, the Institute’s publications reported survival rates as a function of time and not the age at which animals first developed tumors, but based on the available data, survival rates among animals on aspartame were either equivalent to those unexposed to aspartame or otherwise fell within normal time ranges for laboratory mice. The particular timelines varied somewhat across studies, but on the whole, animals were not dying prematurely.)

Evidence from Humans

In addition to animal studies, the IARC notes that limited evidence from humans also suggests a possible link between aspartame and cancer. As you may have guessed, this “evidence” comes from that seemingly inexhaustible fountain of bad science known as nutritional epidemiology.

I’ve expressed my frustration with nutritional epidemiology on numerous occasions in the past and have noted that most data from this field can only provide evidence of a correlation, which is often mistaken for causation. Research on aspartame and cancer has certainly been no exception. As an example, let’s consider a 2012 study reporting a modest increase in risk of lymphoma and leukemia associated with aspartame consumption. It’s possible that this association is due to any number of confounding variables overlooked by the investigators – for instance, family history of these cancers. Given the widely-known links between sugar consumption and cancer risk, individuals with a family history of cancer may be more likely than others to opt for artificially-sweetened foods and beverages as a means of cutting down sugar intake. Alternatively, soda consumption of any kind – “diet” or otherwise – may be less common among the most health-conscious individuals in a given population, so those who avoid aspartame-sweetened beverages may also be engaging in other health-promoting behaviors such as exercise and avoidance of smoking and alcohol consumption.

Yet even if we ignore these problems and choose to trust epidemiology results, the preponderance of evidence points to no association between aspartame and cancer. In a 2019 review of 14 case-control and prospective cohort studies, authors Haighton et al. concluded that, among the studies meeting their quality standards, there existed little to no evidence that aspartame consumption correlated with increased cancer risk. A 2022 analysis focused specifically on liver cancer – the form noted by the IARC – found an association only in the subset of participants with diabetes, but no correlation was observed in non-diabetic participants. (Of note, this analysis assessed risk for artificially-sweetened beverages rather than aspartame specifically; however, because aspartame is included as at least one of the sweetener compounds in most major diet drinks, these data can to some extent serve as a proxy for data on aspartame itself.)

A False Alarm

Millions of people opt for aspartame-sweetened beverages and foods as a means of reducing sugar intake and promoting metabolic health. But humans have a long history of finding that solutions to one health problem wind up causing another, and the IARC’s recent designation of aspartame as a possible carcinogen has raised concerns that the sweetener might be the latest example of this pattern. Fortunately, evidence suggests that the alarm seems unwarranted in this case.

Does aspartame cause cancer? There’s a small chance that the answer is yes – but probably only if you consume 50 Diet Cokes every day from birth until death – and even then, we don’t have any evidence that this cancer would lead to premature death. At consumption levels equivalent to the ADIs set by the FDA and other organizations – let alone at lower, more typical intake levels – we have no more reason to suspect aspartame as a carcinogenic threat than we have for suspecting carcinogenicity from chewing with your mouth open or wearing flip-flops in wintertime. 

Still, carcinogenicity is only one of the many ways in which a compound or exposure may impact overall health. The fact that the sweetener doesn’t cause cancer doesn’t necessarily mean that we ought to be using it in place of sugar wherever possible. 

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