Aspartame isn't just widely consumed, it's practically universally consumed. If it was carcinogenic in humans, wouldn't there be obvious epidemiological evidence to back that up?
Basically the mechanism works because the hexagon ring slides between the base pairs and this leads to a lowest energy state due to a phenomenon call pi orbital stacking resulting in the molecule getting stuck there. The carbon chain is mostly valuable in the sense that it distances the rest of molecule from interfering with the stacking process.
Take a look at ethidium bromide or pretty much any other intercalating dna stain and you’ll see similar characteristics. It’s also extremely carcinogenic.
https://en.m.wikipedia.org/wiki/Pi-Stacking_(chemistry)
It’s analogous to getting some cloth stuck in your zipper. Sometimes you can zip and unzip easily enough but sometimes it’ll get stuck. My understanding is that really DNA replication issues tend to be the root cause of some, possibly many cancers but really that’s outside my expertise.
So I would say that it is internally consistent with my limited knowledge of biochemistry that aspartame is carcinogenic.
I would strongly caveat this with saying that these structures occur in pretty high frequency across many forms of plant and animal life. Chemists in my lab used to joke about how potatoes contain 17 or so know carcinogenic compounds so why buy organic. My point is, if you go looking for correlations with cancer in many forms of food, you will find them.
I think for most people, aspartame is not likely to be major risk factor unless you are consuming it in extreme quantities and otherwise live a very healthy life.
(I'm butchering this and mostly just having fun with it.)
Edit
He is correcting me and saying that at the moment he is technically working as a veterinary immunologist. But the point about 6-carbon thingies stands.
Ah, the joys of having young-adult offspring! I was recently surprised and delighted when the high-school history teacher that I raised brought home a bottle of the not-expensive whisky that we drink (Famous Grouse) to replace the bottle that magically empties so much faster since he started coming over for dinner now and then. He hasn't brought whiskey yet (Jameson's Port Cask) because we don't drink that up as quickly ....
Intercalation is way more complicated than just some flat pi-bonded moieties. If that's all it took, we'd see everyone getting cancer like...rats...oooohhhh, I wonder...
Maybe rodents (especially Sprague rats) are way more vulnerable to intercalation? That would explain why so many things cause cancer - weak recovery mechanisms for DNA replication errors. I need to look into this further.
Anyway... the pattern I see across known intercalators is large, multi-ring (3 or more) fused flat structures. Like PAHs.
From the purely geometric model, some of the molecules you proposed have pretty large functional groups adjacent to rings which I think may make the intercalation process less efficient. That being said, if you took those molecules and gave massive doses to rats, some may comeback as carcinogenic.
I think that your multi-ring point is fair. The multi ring structure to me suggests that the more the pi orbitals are able to delocalize their electrons the higher the binding efficiency. I have tested 1-2 molecules where non-fused rings showed some affinity but not near the potency of fused ring structures. I would also say two rings with a carbon-carbon link seem to be potent binding as well. I presume that it’s also related to delocalizing pi orbitals and extra degrees of freedom in the intercalation process but I suppose that’s just speculative.
And many more do not.
> if you took those molecules and gave massive doses to rats, some may comeback as carcinogenic.
Luckily we don't have to guess. For example, look at the hundreds of terpenoids that saturate traditional diets, many of which and are widely believed to prevent cancer. If you have any actual evidence, put it up.
> The multi ring structure to me suggests...
All this is interesting, but it has exactly nothing to do with in vivo carcinogenicity. You don't have to look far to see this is true. Healthy diets are chock full of polyphenols that exhibit significant DNA binding affinity, but lack evidence of carcinogenicity. And it's not for lack of looking.
You appear to have some specialized knowledge, but when you try to extrapolate it to a wider field where you're out of your depth, these hand-waving guesses can easily turn into fearmongering.
I recognize that what I’m engaging in is entirely wild speculation based on limited experience and data, likely very error prone and that really I’m just having fun without considering how it may impact other readers.
I understand that for many this an important issue of health and research. I did not intend to detract from these more legitimate forms of discussion.
Absolutely, geometry of electric fields is the primary factor in biochemical interactions. "The electron is where its at" as my o-chem teacher always said.
But that's exactly why aspartame is totally different than intercalators like EthBr, doxorubicin, and PAHs. That phenyl moeity has a rotational degree of freedom, and the whole peptide backbone is floppy. EthBr has a Ph but it's stabilized in-plane by the tri-ring. Intercalators typically have 300-500 daltons worth in a "planar greasy brick" regime, with very little in the way of bulky or floppy steric groups. On paper, aspartame looks pretty flat, but you gotta think about thermal molecules in solution.
E: just noticed this
> I would also say two rings with a carbon-carbon link seem to be potent binding as well.
Oh yeah, like biphenylyl, -Ph-Ph? So that's actually much more planar than a single Ph. The conjugation (any time you see carbon chains with alternating double bonds) of the pi-orbitals stabilizes the rings in-plane. Also it's rather unnatural, there's not a lot of reactions which forge a sigma bond between two aromatics like that.
The meta (1,3) oxazinium is more stable, but it still needs 3 big electron-withdrawing groups to stabilize it in the case of 2,4,6-Triphenyl-1,3-oxazine-1-ium.
https://en.m.wikipedia.org/wiki/Oxazines
https://chemdrawdirect.perkinelmer.cloud/js/sample/index.htm...
This is a myth. This is actually a good example of a plausible biological effect that doesn't apply to living organisms:
https://blogs.sciencemag.org/pipeline/archives/2016/04/18/th...
Regardless, where did you get the idea it's "practically universally" consumed?
Taking soda for example, people typically either do or don't drink diet soda, and in much of the beverage chillers I've seen "diet" is stocked in the minority (with limited regional variation). Bear in mind diet itself is fractured into aspartame and stevia and various others.
Similarly, aspartame or sorbitol or other artificial sweeteners are presented as an option for most hot drinks, alongside sugar - in my experience it's the sugar constantly being replaced on the table.
Looking at packaged foods, I can find few products containing it, and again, packaged foods are only a subsection of all foods out there.
Also there are those among us who consume predominantly (in many cases only) fresh vegetables, fruit, grains, legumes etc.
Look at India, China, Africa, and everywhere in between - this is well over half the worlds population and while many are exposed to at least a small selection of packaged foods, few can afford them, and many simply have no interest.
Just a cursory glance and very rough estimate showed 6000 metric tonnes of Nutrasweet produced in 2014. Divided into a population of 7.8 billion gives each person less than a gram per year.
Aside from the fact that like all products a chunk of that will go back to landfill unsold, there simply isn't nearly enough for it to be universally consumed.
That's the argument I'm inviting you to rebut. There are ways to rebut it! But "the data is super subtle" is on its own not a powerful argument.
As far as I'm concerned, if rats are shown to get cancer from something for which there are many alternatives, I'll steer clear of it.
- All citrus fruits (due to the limonene content)
- Mint of any kind (limonene again)
- Red meat
- Excess protein
- Coffee (acrylamide)
- Chips and fries (acrylamide)
- Bread (often contains acrylamide)
- Dried fruits and nuts (another acrylamide risk)
- Arugula, beets, cabbage, celery, cilantro, endive, fennel, lettuce, parsley, rhubarb, spinach, and any other vegetables that are high in nitrates.
Also be sure to stay away from cell phones, WiFi, and microwave ovens.
This is just a short list off the top of my head. It's a dangerous world out there. For a lab rat.
That's not to say there isn't interesting stuff in these investigations. The recent studies the effect of sweeteners on gut biomes and the resulting effects on serum chemistry are fascinating to me, and I think these studies will be productive in other ways.
That being said, this is a rodent study. Really not a good input to guide human behavior. And human cohort studies have only found associations with cancer after really long periods, like decades. Might be nothing there.
Regarding cholesterol and dietary levels to serum levels, it's curvilinear. If you have a low baseline, dietary input has a strong impact on serum output. If you are eating a standard American diet that has a relatively high baseline cholesterol level, the relationship weakens to being statistically insignificant.
And sure, you can get fat without eating fat, and you can create high fat diets that don't increase visible body fat, but those aren't healthy diets.
People worry about suspected carcinogens but they are everywhere. Overall cancer rates are at record low levels except colon cancer and skin cancer. Skin cancer is a weird one since Americans spend less time in the sun and use sunblock.
https://www.dietdoctor.com/red-meat-is-not-associated-with-h...
I take issue with this, frankly. Aspartame seems to be particularly popular in the USA (diet sodas), and less popular the further away you go.
It's used in other stuff, sure, but most products outside of the USA just use sugar or corn-syrup-based sweeteners. I don't think anyone in my circle of family or friends has had a diet soda in decades, save for exactly one individual who drinks a lot of diet drinks.
At least in Germany, it’s very similar. Most diet sodas here are aspartame sweetened.
I agree there should be an epidemiological case for a link, but alternatively maybe the link is that there is no strong link to cancer.
Everything in moderation, as they say.
0: search "aspartame intake", I can't easily cite anything right now.
Maybe there’s the evidence.
A better question is, suppose it was known that it did create a small but measurable in lifetime cancer risk, would you actually want to keep consuming it?
EDIT: Also aspartame is hardly universal - it's biggest use is in diet soda. Those of us who essentially never consume it (it's been...over 2 years for me) would almost never be exposed to it.
You're commenting on a story that suggests that even small exposures to aspartame might be dangerous. And you stopped drinking diet soda only recently. I think you might have a hard time finding an American (for instance) that hadn't consumed a substantial amount of aspartame.
Asking out of idle curiosity/surprise. I'm not afraid of aspartame, I just don't care for the taste much.
I don't really worry about aspartame cancer risk though, it doesn't seem like a big deal if it exists at all. I do buy the idea that diet sodas kill good gut bacteria and avoid them for that reason, but I don't remember a single thing about where I got that idea. It just "feels" right, and I don't mind the lack.