Issue: March 2006

Gimme Some Sugar: Artificial Sweetener Linked to Cancer . . . Again

by Elisheva Coleman

Glazed Donuts

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Sugar May Be In Again. A new study has reopened the artificial sweetener debate by showing a link in lab rats between ingesting aspartame and developing cancer.

When saccharin, the first artificial sweetener, appeared on grocery shelves in 1900, it appeared to be a miracle food—sweet like sugar, without packing a single calorie. Other sweet chemicals were discovered later in the 20th century, and now diet food manufacturers can choose from an array of cheerily named products like Sweet n' Low (saccharin), NutraSweet (aspartame) and Splenda (sucralose). Almost from the moment they arrived, however, many people, including some scientists, have suspected that these guilt-free sweeteners were too good to be true. First saccharine, and then aspartame, was accused of causing cancer. [See Saccharin Linked to Human Cancer, June 16, 1977]. By 1981 a number of studies seemed to have cleared both chemicals, but a core group of moms and scientists still harbored suspicions that aspartame was carcinogenic. Now a study, the largest ever conducted, has reopened the debate with a vengeance, showing strong evidence that in lab rats, there is a link between ingesting aspartame and developing cancer.

Thoroughly Tested

The new study was conducted by the European Ramazzini Foundation of Oncology and Environmental Sciences, a nonprofit organization that specializes in testing substances for cancer-causing properties. It is shaking the medical and food-additive communities, which had essentially considered the aspartame issue to be settled. Before the Food and Drug Administration (FDA) approved the sweetener in 1981, it reviewed four separate studies of aspartame and cancer. [See FDA Approves New Sugar Substitute, July 15, 1981]. Three of the studies were negative, while the fourth showed a mild increase in brain cancer in rats that were fed aspartame. That study, the FDA concluded after examining the underlying data, was flawed, and in fact did not demonstrate any cancer link. Since aspartame won FDA approval, hundreds of other studies have been conducted, most looking for links between aspartame and neurological symptoms. (A few physicians had accused aspartame of causing behavioral and other neurological problems.) All these studies came back negative. The FDA calls aspartame "one of the most thoroughly tested and studied food additives the agency has ever approved."

Two Amino Acids, One Sweet Taste

Sugar Substitute (Splenda) Desserts with 'No-Calorie' Sugar

Left: Mario Tama/Getty Images; Right: Sebastian d'Souza/AFP/Getty Images

Almost from the moment they arrived many people, including some scientists, have suspected that these guilt-free sweeteners were too good to be true. LEFT: Packets of the popular sucralose-based sugar substitute, Splenda. RIGHT: Tempting desserts made from a 'no-calorie' sugar substitute, Zero.

Aspartame is a relatively simple compound, made of two amino acids, aspartic acid and phenylalanine, bound together. Inside the body, it breaks down into three smaller compounds—the two amino acids, and methanol, a type of alcohol that is poisonous in large doses. All three of these chemicals are present in natural foods as well as in aspartame; aspartic acid and phenylalanine are components of protein, while citrus and tomato juices contain modest amounts of methanol.

Aspartame packs a powerful flavor punch; gram for gram, it is more than 200 times sweeter than sugar. A powdery white solid, the chemical dissolves easily in water and is stable at high temperatures, qualities that make it a versatile food additive. Marketed under the brand names Equal and NutraSweet, aspartame is used in hundreds of products, including diet sodas, chewing gum and sugar-free yogurt, and is consumed by an estimated 350 million people across the globe. As a calorie-free replacement for sugar (the components of aspartame are not metabolized and never leave the digestive tract, so it does not contribute to energy intake), aspartame is a boon to dieters and diabetics.

Rats of Ramazzini

Morando Soffritti, the scientific director of the Ramazzini cancer foundation, felt that the cancer studies on which the FDA and European regulators based their approval of aspartame were flawed. Because so many people, including children and pregnant women (both of whom are especially vulnerable to carcinogens), are exposed to the sweetener, he felt obligated to conduct a more definitive trial. Three of the four cancer studies, Soffritti observed, were conducted by G.D. Searle, the company that makes aspartame, which had an obvious interest in a positive outcome. In terms of design, Soffritti saw two major deficiencies in the earlier studies: they did not, in his opinion, test enough animals, and the animals were not allowed to live long enough.

Designed with those problems in mind, the Ramazzini study enlisted 1,800 rats, more than twice the number used in any other aspartame cancer probe. The rats were divided into seven groups, each of which received a different concentration of aspartame in its drinking water. Dosage started at 0 parts per million (ppm) for the control group, and then ranged from 80 to 100,000 ppm. The lowest dose, 80 ppm, is roughly equivalent to a human intake of 275 mg, while 100,000 ppm translates to a whopping 340,000 mg. For comparison, the FDA sets the acceptable daily intake (ADI) for aspartame at 50 mg/kg body weight, which computes to 3,400 mg for a 150-pound person.

Using more animals affects the way results can be interpreted—in scientific trials, there is always a strong distinction between results that are "statistically significant" and results that are not. Statistics is a branch of mathematics that evaluates how greatly sets of data differ from one another. It seeks to distinguish between results that could be due to chance, and those that demonstrate a genuine link between an experimental condition and a given result. (In the Ramazzini trial, for example, the experimental condition is aspartame ingestion, and the result is cancer.) When a study uses a large number of animals, each individual has a smaller effect on the data totals, which minimizes the effects of chance and makes it easier to distinguish statistically significant results. Previous studies had seen small increases in cancer rates among rats fed aspartame, but the differences were too small to pass the bar of statistical significance. Soffritti suspected that when many more rats were tested, those small differences would be magnified enough to make the statistically significant cut.

The other major difference between Soffritti's study and earlier ones was the rats' lifespan. Normal protocol in rat cancer studies is to kill animals when they reach a predetermined age and check their bodies for cancerous growths; in all four prior aspartame studies, rats were sacrificed at 110 weeks of age (that is, just past the age of two). In Soffritti's study, on the other hand, the rats were allowed to live until they died naturally, and were then dissected in search of cancers. The longest-lived rats made it to 159 weeks, nearly a year longer than the lifespan of rats previously studied.

The logic behind this controversial decision, which has prompted much of the criticism leveled at the Ramazzini study, was that since cancer hits predominantly in old age, a cancer study ought to look at elderly lab rats. "Cancer is a disease of the third part of life," Soffritti explained to the New York Times. "So if you truncate the experiments at 110 weeks and the rats are supposed to live until 150 or 160 weeks, it means you avoid the development of cancer at the time when cancer would be starting to arise." While this argument is compelling, other researchers contend that allowing rats to reach old age and die naturally, rather than killing them while they are still relatively healthy, results in tissues that are poorly preserved and harder to screen for cancerous irregularities. To minimize damage to tissue between death and dissection, Soffritti's team patrolled the rat cages three times a day looking for dead animals, and stuck deceased rats in the freezer until they could be screened.

Identifying cancers in the lab animals was a painstaking process. While earlier aspartame studies concentrated on brain tissue (the studies did examine other tissues as well, but did not specify all the tissue types they tested), Soffritti's team meticulously examined a long list of organs, searching for malignancies. These included skin, brain, mammary glands, liver, kidneys, stomach, intestines, bones and blood.

Disturbing Results

Rats fed aspartame, Ramazzini researchers found, contracted more cancerous tumors than those in the control group. For some types of cancer, the increase was statistically significant among rats receiving just 400 ppm, the equivalent for a human of 20 mg/kg body weight, or about 8 Diet Cokes a day. That's less than half the FDA's safe daily intake guideline of 50 mg/kg body weight. The most common types of cancer were lymphoma and leukemia (blood cancers), with several types of solid tumors also occurring at significant rates. Several female rats fed aspartame experienced tumors of the kidney and ureter (tube leading from the kidney to the bladder), a fact which was particularly alarming because under normal conditions, kidney tumors are extremely rare in the rat strain used for the study. Since they observed a variety of cancer types at statistically significant rates, the researchers concluded that "aspartame is a multipotential carcinogenic compound," in other words, a substance that causes cancer in multiple ways. Interestingly, there was no difference in survival among the groups of rats—those receiving the heaviest doses of aspartame lived just as long as members of the control group, but were much more likely to have cancer somewhere in their bodies when they died.

What Makes It Toxic?

Despite statistically compelling evidence that aspartame is a carcinogen, the Ramazzini team still cannot explain how aspartame causes cancer. One theory, which Soffritti supports, is that methanol, a byproduct of aspartame metabolism, is the culprit. Inside mammalian bodies, methanol is converted to formaldehyde, a chemical that has been linked to cancer before. Specifically, formaldehyde has been connected to lymphoma and leukemia, the two cancers observed most heavily in the aspartame-treated rats. Critics argue that methanol is found in many common, natural foods, and therefore cannot be responsible for aspartame's carcinogenic effects; Soffritti in turn responds that the human body may be equipped to handle a certain amount of methanol, but the extra shot of it from aspartame pushes methanol levels into dangerous territory.

Even if the methanol-formaldehyde theory is right, Soffritti believes that other factors are also at work. Formaldehyde has not been linked to solid tumors, so the researchers guess that one of aspartame's other components—aspartic acid or phenylalanine, must also be toxic under certain conditions. They do not have a fully developed theory for how these amino acids cause cancer, but in their paper, they pointed to high rates of calcification (build-ups of calcium and calcium-based minerals) in kidney cells of rats ingesting high doses of aspartame. In a separate study, also at the Ramazzini center, a different aspartic acid-containing chemical was linked to calcification in rat kidney cells. Somehow, they suspect, aspartic acid causes calcification, which in turn increases the likelihood of tumors.

Strong Dissent

Though Soffritti and his colleagues feel that their research shows definitively that aspartame is a carcinogen, they have not convinced the entire scientific community to accept their conclusion. Far from it—though the FDA and the European Food Safety Authority have promised to take another look at aspartame, both are waiting to review all the raw data before they announce any policy decisions. For the time being, the FDA is standing by its assurance that aspartame is safe, and has not recommended that people avoid it.

Manufacturers of aspartame are, predictably, up in arms. They point first and foremost to the huge body of earlier research that all concluded that aspartame was safe, arguing that one study should not debunk decades' worth of data. "Aspartame has a record of 25 years of safe use," said a spokesman for Ajinmoto, Inc., Japan's largest aspartame producer. The companies have taken aim especially at the study's practice of allowing the rats to die naturally, rather than killing them at a prescribed time. Lyn Nabors, executive vice president of the Calorie Control Council, a nonprofit association representing low-calorie food manufacturers, explained to the New York Times that developing cancers is a natural part of the aging process. In very old rats, "It's difficult to determine if the cancers you find are due to something else. Just as in humans, the rat's body slows down later in life, and the aging process causes all kinds of things." Of course, the problem with this argument is that separating the effects of old age from the effects of aspartame is precisely the function of a control group. Rats in the control group also died naturally of old age, and yet had less cancer than rats that ate aspartame. A more serious objection to the Ramazzini practice claims that when animals die of old age, their tissue tends to have deteriorated. Cells look different simply because they are older, and this makes it harder to pick out cancer cells from healthy cells. Soffritti's team may, these critics allege, have identified some samples as cancerous, when in fact they were just showing signs of old age.

Several scientists who have no association with the aspartame industry have criticized Soffritti for failing to get a second opinion on most of his cancer specimens. Combing through whole bodies for cancer cells can be tricky under any circumstances, and so many experts believe that results should be checked by more than one group; the fact that the Ramazzini researchers were dealing with aged tissue just complicates things further. Jose Russo, a cancer researcher at the Fox Chase Center in Philadelphia, told the New York Times that "People need to see every tumor," and another expert, James Swenberg of the University of North Carolina at Chapel Hill, agreed that Soffritti had not gotten enough of his samples verified by outsiders.

Everything in Moderation

Even if the Ramazzini results are totally reliable, no one is claiming that one Diet Coke a day will kill you. John Bucher, a toxicologist with the National Toxicology Program in North Carolina, told Science News that because it was so large and thorough, the study has "a fair amount of power." Even so, the correlation it found between aspartame and cancer was "not overly strong.It's not like what one would get with a frank, strong carcinogen." To the extent that aspartame does cause cancer, it does so only at very large doses, and even then, the risk of cancer is only slightly heightened.

Though there have not been any major studies of cancer rates and aspartame consumption in humans, what little research has been done has not shown any increase in cancer in people who ingested even large amounts of the sweetener. One study looked at cancer rates among diabetics, who tend to use a lot of aspartame in place of sugar, and found that they have experienced no rise in cancer since aspartame came on the market. The Ramazzini study may prompt more extensive epidemiological studies of aspartame in humans, which could help government agencies figure out how to deal with the product. After all, by replacing sugar in people's diets, aspartame provides important health benefits, especially at a time when rates of obesity and diabetes are reaching new heights. The FDA—and consumers—must weigh the pros of aspartame against the cons.

For regular people trying to make healthy decisions, all this controversy can be confusing. The best way to handle the study's conclusions is probably to follow the maxim "everything in moderation"—that is, one Diet Coke a day is OK, but 10 may not be such a good idea.


Harder, Ben. "Not So Sweet: Cancers in Rats That Consumed Aspartame." Science News, February 18, 2006, page 101.

Lawrence, Felicity. "Sweetener Manufacturer Disputes Validity of New Health Research." The Guardian, (September 30, 2005) [accessed February 27, 2006]: food/ Story/ 0,,1581639, 00.html.

Soffritti, Morando et al. "First Experimental Demonstration of the Multipotential Carcinogenic Effects of Aspartame." Environmental Health Perspectives, March 2006, page 379. Available on-line at: members/ 2005/ 8711/ 8711.pdf.

Warner, Melanie. "The Lowdown on Sweet?" New York Times, (February 12, 2006) [accessed February 24, 2006]: 2006/ 02/12/ business/ yourmoney/ 12sweet.html?ex= 1141448400&en= 5a1ef352196921f6& ei=5070.


aspartame, aspartic acid, phenylalanine, methanol, artificial sweetener, carcinogen, Morando Soffritti, cancer, rats

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