Wednesday, January 26, 2011

Aspartame and Cancer in Rats vs. Humans

A friend of mine (who I swear sometimes suffers from hyperactive agency detection device) referred me here when he was telling me that aspartame (sometimes abbreviated as APM) is hazardous to human health.  Specifically, he was talking about this:

An animal study that fed 0, 4, 20, 100, 500, 2500, and 5000 mg per kilogram of body weight of aspartame to rats saw lymphoma/leukemia increase in female rats, starting from about twice the risk with 20 mg per kilogram of body weight (a person weighing 75 kilograms or 165 lbs, consuming 1500 mg aspartame, or about 8 cans of diet soda) compared with a control group that was not fed aspartame.

It's strange that he pointed me there when the rest of the article talks about how the most recent HUMAN study shows no association between aspartame consumption and cancer rates, but nevertheless, I'd like to deal with this issue.

Before I get into that, let me give a brief overview of the idea behind non-nutritive or "0 Calorie" sweeteners.  Sugar (such as sucrose or fructose -- there are many types of sugars) is perceived as sweet because it interacts with taste buds on our tongue.  These taste buds have receptors that temporarily interact with sucrose and other sugars, and when that happens our brain gets a signal that says "oooh, this tastes sweet."  Each of these sugars has a varying level of "sweetness" as perceived by the brain depending on how it interacts with these receptors.  Evolutionarily, this is an advantage in that sugars are used by our bodies for energy, so being able to detect sugar and have a pleasurable response to it makes sense.  But when we consume more Calories than we require and we become obese, this reward response can become counterproductive.  One weapon against this is to use compounds that activate our taste buds for "sweet" but without that compound being used for energy.  Instead, the compound passes through your digestive tract without being absorbed.  That way the food tastes good without making us fatter!

Animal studies are an excellent start when it comes to testing new drugs or ideas.  It allows us to test a hypothesis on a living system without harming a human being.  That being said, we can't just take every animal study at face value.  We have a lot in common with other mammals, but not everything.  Sometimes a study will show some beneficial or harmful effect, but in humans we'll observe absolutely no effect -- or even the opposite effect!  So while they're an excellent start, they are by no means conclusive, regardless of whether the results are comforting or alarming.

In the case of aspartame, there were several studies in rats that showed an increase in the incidence of cancer in rats fed a diet containing aspartame versus a control group given no aspartame.  The quote above is from one of them (you can find some of these studies at the bottom of that page).  I'll admit that I haven't read every single one of those studies.  But my focus here is on human studies anyway -- not animal studies that may or may not have any correlation to effects in humans.  As one might expect, these studies made people ask whether or not the same effect occurs in humans.  The short answer: it doesn't.  Again, from (emphasis mine):

A study of about half a million people, published in 2006, compared people who drank aspartame-containing beverages with those who did not. Results of the study showed that increasing levels of consumption were not associated with any risk of lymphomas, leukemias, or brain cancers in men or women.


Researchers examined the relationship between aspartame intake and 1,888 lymphomas or leukemias and 315 malignant brain cancers among the participants of the NIH-AARP Diet and Health Study from 1995 until 2000. Development of these cancers was not associated with estimated aspartame consumption, refuting a recent animal study with positive findings for lymphomas and leukemias and also contradicting claims regarding brain cancer risk. 

Epidemiological studies like the ones above still have their issues, of course.  If you don't control for variables like age, gender, ethnicity, environmental exposure, etc., you can artificially infalte or deflate any possible differences between the two groups.  In the case of patient-reported information, you can introduce a bias in the way patients recall information.  If a patient with leukemia remembers reading something about rats and aspartame, he might be more inclined to remember that he consumed 2000 mg/day of aspartame in diet sodas.  A healthy participant who never saw that news report, on the other hand, might never have even thought about the aspartame in the sodas he drank.  A good questionnaire would be set up so as to limit this bias, but even so, you get the idea -- a patient's recall of what he did yesterday, last week, or over the last several years is not always reliable.  This isn't a bias inserted by the researchers -- it's just an inherent flaw in how people remember things and how these studies are conducted.  But the fact that they are not perfect does NOT mean that these studies are useless!

In general, if a statistical difference cannot be found in a well-constructed epidemiological study, it is likely that there is either no effect at all, or the effect is so small that it cannot be distinguished from the background noise inherent in how the data is collected.  In this case, it is important to keep in mind the context of what's being studied.  For example, well-conducted epidemiological studies have shown no link between vaccines and autism rates.  That alone is not enough to absolve vaccines, but when you couple it with the vast amount of scientific knowledge about vaccines and the immune system, support overwhelmingly comes out on the side of vaccines being safe and effective.  These studies CANNOT prove that vaccines CANNOT cause autism, but that's simply because you cannot prove a negative -- see the Celestial Teapot argument.

In the case of aspartame, epidemiological evidence shows no link between cancer and aspartame consumption at or below currently-recommended levels.  Scientifically, there is little reason to expect otherwise.  A lot of background information on Aspartame, what it's composed of, and how it's digested and absorbed, can be found in the Introduction of this article.  It's where I got the basis for much of the information below.

Aspartame is broken down by your digestive system into 2 amino acids (phenlyalanine and aspartic acid) and methanol.  The amino acids are the same things you'd get from any other protein meal, so there's no worry there (unless you have phenylketonuria, a disease in which your body can't metabolize phenylalanine).  The methanol part might sound a little scary, but let's consider how much methanol that actually is.  A can of diet soda typically contains 50-200 mg of aspartame -- let's say 200 mg for the worst-case scenario.  Using some good old-fashioned stoichiometry, that would be converted to ~22 mg (or .028  mL) of methanol.  Methanol toxicity typically begins after ingestion of approximately 6-10 mL of pure methanol.  eMedicine (behind a pay wall, sorry) said it was 6 mL, but I've seen 10+ mL elsewhere.  This can vary depending on individual pharmacokinetic factors, how it's ingested, and other factors that I won't get into.  Nevertheless, unless you can drink 200+ cans of diet soda in less time than it takes your body to excrete the methanol, you'd have one hell of a time trying to get methanol poisoning from aspartame.  If I didn't have 3 exams in one day next Monday, I'd spend some time calculating at what rate you would need to drink Diet Coke in order to reach those toxic levels.  Maybe later!

But if aspartame is broken down into amino acids (same as protein used for energy), how and/or why is it used as a 0 calorie sweetener?   Remember, the idea behind most non-nutritive sweeteners is that they are NOT broken down and absorbed by the body, so producing amino acids that can be used for energy seems rather antithetical to aspartame's purpose.  The difference with aspartame is that because it's perceived by your brain as SIGNIFICANTLY sweeter than sucrose or fructose (~200x sweeter than sucrose), very little aspartame needs to be used to sweeten the food/beverage.  If you compare the amount of aspartame in a can of Diet Coke with the amount of sugar in regular Coke, you get 125mg aspartame versus 39g sugar -- that's 0.3% of the amount of sweetener in Coke!  The Coca-Cola website doesn't list the amount of aspartame used (I came upon the 125mg figure after Googling but the original source link was dead), but in general diet and zero Calorie sodas contain 50-200mg of aspartame.  With so much less sweetener being used (by 2-3 orders of magnitude!), the Calories from aspartame are negligible.  Though technically, this is why aspartame would be a "low Calorie" sweetener and not truly a "0 Calorie" sweetener.

One of the studies that I read in particular was this one by Morando Soffritti et al.  In it, the authors make a rather compelling case for aspartame's effects in mice.  The statistical significance of some of their results are iffy in my opinion (when you only have ~60 mice in each group, your statistical power is somewhat limited).  I'd like to see some data with more mice, as I don't always like the idea of statistical regression models in biological systems.  But that's a personal opinion and I'll admit to not having studied those statistical models, so I'll just leave that as a personal issue.

Nevertheless, onto the study's conclusions, which I think sum up my argument very well (emphasis mine):

Given that APM is completely metabolized in the gastrointestinal tract to phenylalanine, aspartic acid, and methanol, it may be concluded that the observed carcinogenic effects were caused not by APM itself but rather by its metabolites. In particular, it cannot be disregarded that the conversion of APM methanol into formaldehyde in the liver may result in a generation of formaldehyde adducts [Trocho et al., 1998], which could explain the plausibility of hepatocarcinogenic effects of APM in male mice. The fact that females did not develop a significantly increased incidence of liver tumors may be explained by the gender resistance, as already reported.

The authors suspect that the effects of APM are due to the metabolism of its methanol byproducts.  I don't know at what levels methanol can become toxic to mice, but we do know that the amount of methanol we get from APM is less than what we consume in our daily lives from fruit juice (another excellent article).  That article also deals with the idea of aspartame becoming dangerous if beverages containing APM are stored at warmer temperatures where APM might release methanol, which is something I've heard before.  Because APM is digested and absorbed anyway, the methanol it would release is no different than what you'd absorb anyway (remember, it's still less than what you get from fruit juice), so that's not a hazard either.  Considering the scientific data surrounding APM, it is quite unlikely that its ingestion at currently-recommended levels is hazardous to humans.  The epidemiological data support this idea as well.

A more reasonable argument might deal with how to educate people about eating healthier and exercising more often, rather than just using aspartame to avoid 200 Calories per day from drinking soda.  It's extremely unlikely that these artificial sweeteners cause cancer in humans, but they may or may not actually be helpful in losing weight in the first place!  The short answer: Drinking diet soda containing aspartame won't give you cancer, but don't expect it to help you lose weight without additional changes in diet and exercise!

As usual, no one can guarantee that aspartame doesn't cause cancer.  The rat data can be worrying (and reasonably so, at first), but we have to remember that animal data does not always have parity with actual effects in humans.  In this case, we had some data in rats that suggested aspartame might be dangerous, but the data in humans shows that there was no detectable increased risk.  And considering everything we know about aspartame, it's unlikely from a scientific standpoint that aspartame would be dangerous to humans.  In this case, the animal data cannot be extrapolated to humans!

If you prefer to stay away from aspartame anyway, that's perfectly acceptable.  That precaution isn't necessary at all, but it's not as though avoiding aspartame is harmful by any means.  But please remember that just because various beverage companies use aspartame as a sweetener does NOT mean that they're poisoning their customers or giving them cancer!

This is something I could talk about at length for quite some time and there is a TON of information out there.  Check out some of the research papers I linked, and if you have anything else you'd like me to address, let me know in the comments!

*Note:  I posted this earlier on Saturday, 01/22/2011, but realized that I failed to explain how aspartame can be broken down into amino acids and yet provide zero Calories.  I added that explanation along with some general information about non-nutritive sweeteners and aspartame.

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