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Aspartame: The scares that turned out to be false Subscribe to New Scientist

THINK about what you ate and drank over the last 24 hours, and chances are you will have swallowed some aspartame. Perhaps you followed your lunch with a low-calorie yogurt, washed it down with a diet soda followed by a stick of sugar-free gum. Even if you don't have a sweet tooth, you may have eaten some aspartame. The sweetener also turns up in some processed savoury snacks as a flavour enhancer.

Aspartame, also known in Europe as E951, is the artificial sweetener people love to hate. Since it was approved for food use 25 years ago it has been linked to pretty much every health scare going, from brain tumours to insomnia and mood swings. Each time, the evidence has crumbled under closer scrutiny.

Now aspartame is under fresh attack. In 2005 a group of scientists at the European Ramazzini Foundation in Bentivoglio, near Bologna in Italy, published some new findings. When the foundation's researchers added aspartame to the diet of 1500 rats, they saw an increase in the incidence of leukaemias and lymphomas - cancers of the blood and lymphatic systems - particularly among females. Notably, cancer incidence rose even in rats fed the equivalent of half the World Health Organization's acceptable daily intake (ADI) of 40 milligrams of aspartame per kilogram of body weight.

The report caught the attention of many of the world's food watchdogs. Despite the succession of scare stories and rumours (see Table), national and international regulators universally regard aspartame as safe. Several, however, including the European Food Safety Authority (EFSA), the US Food and Drug Administration (FDA) and some equivalent national bodies, are currently scrutinizing the Ramazzini Foundation's findings to see if they stand up. None has yet come to a conclusion, but the EFSA has all but finished its "risk assessment" into the study and is due to report this week. What it decides may have far-reaching consequences for the food industry and the millions of people trying to go sugar free.

Aspartame was discovered in 1965 when chemist James Schlatter accidentally spilt some laboratory reagent on his hands. Later, when he touched a finger to his lips, he found that it had an unexpectedly sweet taste. Gram for gram, the chemical turned out to be 200 times sweeter than sucrose. Aspartame went on to become a food industry staple and is now used in more than 6000 products and consumed by 200 million people worldwide. Annual production is more than ten thousand tonnes and rising, and the global industry is worth more than $1 billion a year.

Even before it was approved for food use, aspartame attracted the attention of scientists interested in the links between diet and health. This delayed the compound's approval by the US Food and Drug Administration, but after extensive studies failed to find any link between aspartame and ill health, even in very high doses, it was licensed by the FDA for dry foods in 1981. The European Union approved the sweetener for all foods in 1994, and the FDA allowed similarly broad use in 1996. Burden of proof

The rumours continued in the mid-1990s with claims that increases in brain tumours and breast cancer could be linked to the sweetener. These were demolished when it emerged that the increased incidence in these diseases had occurred at the same time as aspartame use had been growing. If the link had been causal, there should have been a time lag between mass use and increases in cancers. Supposed links to depression, bipolar disorder, migraines, insomnia and panic attacks are still regularly touted online, but none has ever been backed up with solid scientific evidence.

Scientific experts are still struggling to understand the ramifications of the new study. That's partly because the European Foundation of Oncology and Environmental Sciences, to give the Ramazzini Foundation its full name, has performed more than 200 cancer studies in the past 35 years. Previous Ramazzini studies have led to the revamping of regulations on the plastic PVC after one of its components was found to be carcinogenic, and changes in the rules on petrol after the foundation reported that the additive MTBE caused cancer. The study also commands respect because it has been published in Environmental Health Perspectives (vol 114, p 379), a peer-reviewed journal published by the US National Institute of Environmental Health Sciences (NIEHS).

The key finding was that aspartame-fed rats suffered significantly increased levels of leukaemias and lymphomas at the sort of doses that some people might be consuming. A few of the aspartame-fed animals also developed kidney tumours. Although the numbers of kidney tumours were too small to show statistical significance, they still caught the attention of the Ramazzini Foundation's researchers because these cancers are normally very rare: in the past 20 years of research, they had only seen single figures of control animals with the disease. In this study, there were a total of 21 in the 1500 animals receiving aspartame, and none in the control group.

One of the conclusions that the Ramazzini Foundation highlighted is that tumours, including three of the kidney cancer cases, were seen at doses equivalent to 20 milligrams per kilogram of body weight, or half the acceptable daily intake laid down by the World Health Organization. That is 1/50 of the lowest dose tested in any of the studies conducted when aspartame was being scrutinised for official approval, and is the equivalent of around 3 litres of diet soda per day for an average adult. Unlike many other studies purporting to show the dangers of aspartame, the finding can't be dismissed on the grounds that animals are being fed more than any human will ever consume. "This is in a different league," says Michael Jacobson, executive director of the Center for Science in the Public Interest (CSPI) a New York-based consumer group. People can drink 3 litres of soda a day, he says. "Many teenage boys do." Conflicting results

The study remains highly controversial, however, not least because many people find it hard to understand how aspartame could be harmful. Aspartame is a dipeptide, a pair of amino acids joined together. Amino acids are the basic building blocks of proteins, and the two that make up aspartame - aspartic acid and phenylalanine - are nothing unusual. Normally, the gut digests peptides into their component amino acids and metabolises the products just as it does your breakfast eggs.

Morando Soffritti, the Ramazzini Foundation's scientific director, hypothesises that the danger arises because the compound is slightly more complex than a simple dipeptide: it is two amino acids with an extra group called a methyl ester tagged onto the phenylalanine portion. In the gut, this extra segment becomes methanol, which a prior Ramazzini study found to cause lymphomas and leukaemias when added to rats' drinking water in fairly small doses. Aspartame's foes have long voiced concern over the methanol factor. But Lyn Nabors of the Calorie Control Council, a US-based body representing low-calorie food and drink manufacturers, doesn't buy it. We get a lot more methanol from alcoholic and even non-alcoholic drinks, so, Nabors argues, methanol in the diet is not a problem. "Six ounces of tomato juice has six times more methanol than six ounces of diet soda," she says.

Jacobson is also cautious - although for a different reason. If aspartame is carcinogenic at such low doses, he wonders, why haven't we been seeing an epidemic of leukaemias and lymphomas over the past 25 years? He is not the only one to ask this question. Prompted by the Ramazzini findings, a team of epidemiologists at the US National Cancer Institute (NCI) has scoured diet-and-cancer data from more than half a million 50 to 69-year-old men and women. The conclusion, announced last month at a meeting of the American Association for Cancer Research in Washington DC, was that there was no correlation between aspartame consumption and leukaemias, lymphomas or, for that matter, brain tumours. The result, Jacobson says, "significantly allays" concerns raised by the Ramazzini study.

So why the difference between the two studies? The explanation could lie in the unusual protocol used by the Italian group. While most toxicology studies are terminated after two years, the Ramazzini Foundation's policy is to test compounds over the entire lifespan of the animals. Limiting a rat study to two years, says Soffritti, is like studying humans only to age 55. Cancer is largely a disease of old age: in fact, he says, 80 per cent of cancer diagnoses in people are made in the last one-third of life. Jacobson notes that the NCI study also omitted elderly people by focusing entirely on those in their 50s and 60s. Another difference is that while most studies use, at most, a few hundred rats, the Ramazzini team's aspartame study used far more, a minimum of 100 per dose group.

If lifespan studies are such a good idea, why doesn't everyone do them? Often it's simply a matter of cost: a two-year study costs less than waiting until the last rat dies, after three years or more. Government studies are often carried out by contract labs, which need a specified time frame. The Ramazzini Foundation uses its own labs, making it easier for it to design studies to outlast the longest-lived rats.

Lifespan studies present methodological problems, too. Continuing to study animals as they grow very old raises tricky questions about how much of any observed effect is caused by a compound and how much is due to normal ageing. To Nabors, this is reason enough to discount the study. No major regulatory agency in the US or Europe uses lifetime studies, she points out, and disregarding the conventional wisdom merely generates "background noise that just confuses the real outcome", she says.

But John Bucher, deputy director of environmental toxicology at NIEHS, argues that there are statistical techniques that can account for changes due to ageing alone. Further doubts

Another criticism of the study surrounds the issue of "historical controls", the technique of using the sum total of a lab's experience with control groups from all the experiments it has ever conducted. On the face of it, using historical controls adds weight to the Ramazzini Foundation's discovery of kidney tumours, as they reveal just how rare such cancers normally are. Conversely, it tends to undercut the findings regarding lymphomas and leukaemia because lymphoma and leukaemia rates for the control group in the aspartame tests were lower than the average for the more than 4500 control group animals used over the last two decades.

Historically, Ramazzini's lab has seen about a 13 per cent rate of leukaemias and lymphomas in its control groups of female rats, but for the aspartame experiments the rate was only 8.7 per cent. Compared with that, the 20.0 per cent cancer rate in the 20 mg/kg dose group looks like a substantial increase, but if the 8.7 per cent was simply a random fluctuation, much of the apparent effect of aspartame may not be real. "I would guess that there's a 50:50 chance you are dealing with a low control group here," Bucher says.

Independent toxicologist F. Jay Murray, who has reviewed other toxicology studies for both industry and government clients, points out that low rates of cancer in the experiment's dedicated control group may not be a blip. "It's also possible that the background rate of cancer is really lower for some reason," he says, like a shift in the formulation of the animals' feed or improvements in the lab's air quality. Genetic drift in their bloodline might have made them less susceptible to these types of tumours.

For critics of the study, the strongest doubts are raised by the fact that the Ramazzini Foundation appears to be restricting access to the mountain of data created by this study with its unusual lifetime protocol. When traditional rat studies are terminated, most of the animals are still alive and can be sacrificed under controlled conditions. In lifetime studies, animals may die and start decomposing before lab technicians discover them. It's desirable to catch animals shortly after they die. "What you want to know is what condition the animals were in when they were necropsied," says Murray.

Diagnosis of certain types of tumours is notoriously complicated, and Nabors challenges the Ramazzini researchers to give photos of its microscope slides to regulatory agencies so they can determine whether growths catalogued as tumours were what they say they were. Prior to publication of their work in Environmental Health Perspectives, the Ramazzini team sent scans of about 70 of the 34,000 microscope slides to the US for review by scientists at the NIEHS's National Toxicology Program. There were, apparently, some disagreements between the American pathologists and their Italian counterparts. Bucher says they were not substantial, but Nabors puts a different spin on it. "We assume those slides were the best, or they wouldn't have brought them," she says.

The Ramazzini Foundation's dealings with regulatory agencies have added further fuel to the fire. Regulatory agencies often subject toxicological studies to an especially rigorous review, in which reviewers go through the raw data. "My experience," Murray says, "is that scientists who have a good study are usually eager to have other scientists peer review their work." The Ramazzini Foundation, however, refuses to play ball.

Kathryn Knowles, a spokeswoman for the foundation, rejects any suggestion that it is unwilling to let others double-check its work, citing the National Toxicology Program's review as evidence of its openness. "But we do not think it is appropriate for slides to be reviewed on data that has already been published. It's 34,000 slides and eight years of work. Dr Soffritti is not open to a third party reading a small subset of slides and issuing an opinion on the study." Instead, the foundation challenges others to repeat the study.

Jacobson predicts that this is exactly what will happen, but it will be many years before we have an answer. "A year to plan, three years to conduct, then another year to analyse," he says. "What is that, 2011?"

Soffritti declines to say whether the regulatory agencies should tighten restrictions on aspartame use. "We produce data; they produce opinion," he says. Murray describes the new findings as interesting and potentially important, but reminds consumers that "aspartame has a rich history of allegations that turned out to be false". Perhaps this one will be the same.

Update, 5 May 2006

The European Food Safety Authority announced the results of its risk assessment at a press conference in Rome, Italy, on Friday 5 May. It concluded that there was nothing in the Ramazzini Foundation study to suggest that aspartame is a human carcinogen, and no need to carry out any further risk assessment. The acceptable daily intake remains unchanged at 40 milligrams per kilogram of body weight. Close this window Printed on Mon May 08 19:23:55 BST 2006