It started out as a crazy stunt — a gag to keep commuters entertained. DJs at KDND-FMSacramento had lined up 20 volunteers for a water-drinking contest. Whoever drank the most water without urinating would take a Nintendo Wii home as a prize.

Jennifer Strange was 28 and the mother of three children; she’d entered the contest to win the Wii for her kids. Several hours into the event, she started to complain about the pain in her head, and by the time it was over, her belly was protruding so badly she looked pregnant. The DJs thought it was funny. She left the station crying, the pain in her head growing worse all the time.

She was found dead that afternoon; poisoned by water.

Ms. Strange’s tragic story illustrates a peculiar fact: even water can be toxic if you drink too much. It seems odd because most of the time, we think of toxicity as clear-cut, a property some things have and others don’t. A widespread belief in popular culture has it the origins of a substance tell you how toxic it will be. If a compound is made by Nature, we assume it must be good for us. If it’s artificial or it has a long unpronounceable name, on the other hand, we assume it must be toxic, and it’s only a matter of time until scientists figure that out.

Alas, the truth is more complicated than popular culture would have you believe. Nature makes poisons more vicious than any chemists can invent. And nearly anything can be toxic if you consume too much.

Take iron, for example. It’s both an essential nutrient and a common cause of poisoning deaths in children. Usually these deaths happen when kids mistake mom’s prenatal tablets for candy; a few dozen is more than enough to seriously harm a toddler. Or think about acetaminophen, popular painkiller and frequent cause of admission at the ER. (Overdosing on Tylenol is more dangerous than most people think.)

Or take another more commonplace example: the ocean. Perhaps you’ve gone swimming at the beach at one time or another in your life. You swam in water that contained both mercury and lead, and yet you are uninjured and alive. So how did you escape unscathed?

It turns out that while both these metals are found in seawater, the concentration of each is minute — we’re talking about parts per trillion levels. Most fish and shellfish you eat accumulate trace amounts of methylmercury thanks to the seawater they call home. Some fish accumulate larger quantities of mercury, which is why the EPA recommends pregnant women avoid shark, king mackerel and swordfish, among others.

So this simple-sounding concept we call “toxic” turns out to be rather complicated — and certainly messier than the natural/synthetic, toxic chemical/wholesome product dichotomy we usually take it to be. Figuring out how much is safe can sometimes be a thorny problem, and often it gives rise to bitter controversy.

Sweeter than Sin

Aspartame or NutraSweet has long been a favorite with conspiracy theorists. Sometimes the criticism has gone mainstream. In 2007, a British supermarket chain tried to win over customers by removing aspartame and other additives from their products. Over the last few years, that sordid hive of quackery we call the Huffington Post has published multiple articles blaming aspartame for a host of ills. This part isn’t surprising, unfortunately, because the Huffington Post is infested with quacks offering dubious health advice.

Take, for example, this post by a “Dr. Mercola,” who describes aspartame as “America’s Deadliest Sweetener”. The article is almost toxic with hysterical exaggerations and distortions. Mercola claims, for example, that symptoms of aspartame toxicity mimic those of multiple sclerosis, Alzheimer’s, lupus, lymphoma, ADD, Lyme disease and 10 other disorders. He recommends you deal with your sweet cravings through psychological acupressure and leave the “biochemical warfare agent” aside. (Is this guy really a doctor? I just don’t know.) I’ll give credit where it’s due, however, and there is one point Dr. Mercola makes which is entirely true. When aspartame breaks down during digestion, it does release methanol. Let’s take a look and see how it happens.

This is aspartame. It’s made up of three simple building blocks: an amino acid called aspartate on the left, an amino acid called phenylalanine on the center/right, and a methyl ester (the CO-O-CH3 on the far right). When you put esters in water, they tend to break up but the reaction is sloooow. To make it happen in real time, you need to heat it up and/or add a catalyst that speeds up the reaction. An enzyme you have in your intestines called chymotrypsin can do the job. Omitting the catalyst & mechanism, the reaction is like this:

You can see the aspartame splits up into two fragments. The big fragment is the aspartate and the phenylalanine. Your body will handle those just the way it would handle amino acids from a bean burrito; they’re amino acids, just like the amino acids in any other protein in your food. So that part is usually fine, unless you have a genetic disorder called phenylketonuria and have to watch how much phenylalanine you consume. (Hence the warning about phenylalanine on the side of soft drink cans.)

At one point in time, the amino acids were also controversial. Some critics were concerned about the phenylalanine(Phe), for example, because they thought it might temporarily change the ratio of Phe to certain other amino acids in your bloodstream, mess with brain Phe concentrations and indirectly alter serotonin and dopamine levels. Lab tests with mice & rats have found that up to ridiculously high doses of aspartame, you didn’t get any significant changes in serotonin or dopamine levels at all [1]. Pace Dr. Mercola, at the doses found in diet sodas and coffee drinks, there is no reason whatsoever to believe these amino acids (which are, after all, present in far larger quantities in most food you eat) will be harmful.

But the other product of this reaction is a little more interesting, because it’s methanol — the same chemical you find in denatured alcohol. There’s an enzyme in your liver called alcohol dehydrogenase that helps you metabolize the ethanol in wine and beer. Unfortunately, methanol is similar enough to ethanol that alcohol dehydrogenase can take methanol and convert it to formaldehyde. Another enzyme takes formaldehyde and converts it to formic acid in turn. These end products are what actually make methanol poisonous.

But so wait a minute. Let’s get this straight. We drink Diet Coke (at least I do). We know it has aspartame, and digestion of aspartame produces a little methanol. So why aren’t we all dead? This is the interesting part. Unless you are consuming a very large amount of aspartame, the quantities of methanol involved aren’t large enough for concentrations in your bloodstream to reach dangerous levels, and your body will break it down. If you have about 555 milligrams per liter of aspartame in a flavored beverage, that equates to about 55 milligrams of methanol per liter of soda, give or take[2]. You can actually get more methanol by drinking fruit juice[2]. Likewise, the methanol from 500 mg of aspartame is about equivalent to the methanol from 8 ounces of vegetable juice, and there’s even more methanol in gin. Dr. Mercola doesn’t think about this kind of thing, because fruit & vegetable juice are “natural”, and Dr. Mercola is under the illusion that “natural” = good.

Could aspartame be toxic if you were to eat large quantities? Certainly. But that’s no surprise, because nearly anything can be toxic if you take too much. True, some things are more toxic than other things; take hydrofluoric acid, for example. (Or better yet: don’t take it.) But asking whether aspartame is “toxic” is not meaningful. The question we should ask is “how toxic” and “what are the effects of long-term exposure”, in other words, can it cause cumulative damage to your system with repeated exposure over a long period of time. Aspartame has been exhaustively studied and there is ample evidence the doses you have in soft drinks are not a concern. It’s also worth remembering that packets of sweetener like Equal are actually part aspartame and part “fillers” like glucose (the food industry calls it dextrose, but glucose by any other name will taste as sweet.)

Note: Aspartame can also cyclize to form a DKP, but the same is true of dipeptides from other food sources, so there is nothing unusual about this or any reason to suppose it would be dangerous — Dr. Mercola to the contrary.

Sausage-Poison

Another interesting food-additive controversy involves a salt called sodium nitrite, a common preservative in cured meats like bacon and hot dogs. If you read the ingredient list on, say, salami the next time you’re at the supermarket, you’ll probably notice sodium nitrite at the tail end of the list.

Nitrite first became controversial back in the 1970s, when farmers in Norway noticed that animals fed herring meal preserved with large quantities of sodium nitrite seemed unusually prone to liver disorders.

How was this happening? Scientists realized the nitrite was reacting with molecules in the herring meal to form nitrosamines. (The Rs in this picture just represent any ol’ side chain — they’re basically just placeholders.)

This reaction happens much more rapidly at high temperature, and of course we heat cured meats like bacon to high temperatures when we cook them. Nitrosamines have been detected in meats like bacon and smoked fish, and many of them are thought to be carcinogenic.

All of this might sound a little crazy, but don’t panic — there’s more to this story than meets the eye. First of all, the amount of nitrite added to cured meats is very low, below 200 ppm or 1 pound sodium nitrite to 5,000 pounds meat. The FDA tightly regulates this process, and manufacturers typically incorporate other additives like ascorbic acid (Vitamin C), which drastically reduces nitrosamine formation, so the amount of nitrosamines you have in these meats is quite small. Moreover, humans are exposed to nitrite from other sources anyway. You have bacteria in your mouth that reduce a little of the nitrates in your food to make nitrites, and under the highly acidic conditions in your stomach, the nitrite can react with amines in your food to form nitrosamines in trace quantities. So the nitrosamines in certain cured meats or beer do add to your level of exposure — just by a very small amount.

But how much added risk do nitrosamines in meats confer? It’s difficult to say, because we’re talking about daily exposure levels estimated to be on the order of tenths of a microgram, and it’s not easy to evaluate the cancer risk associated with those kinds of doses. We could try to play it safe and stop adding sodium nitrite to cured meats, but that would actually be very dangerous. In fact, it might even be a good way to expose ourselves to one of the deadliest poisons on Earth.

Protein Data Bank, 3BTA, Botulinum toxin type A.

Remember how I said everything is toxic, but some things are more toxic than others? Well, this one falls into the latter category, make no mistake about it. It’s a protein called botulinum toxin but you probably know it as Botox. The lethal dose by injection in mice is measured in nanograms — billionths of a gram. You don’t get much more toxic than that.

Botulinum toxin is produced by a soil bacterium called Clostridium botulinum which only grows in the absence of oxygen. When times are tough, C. botulinum can form heat-resistant spores that remain dormant until the bacterium reaches the right kind of environment; at that point it can reawaken and resume its growth. Food poisoning caused by C. botulinum is called botulism. The protein toxin these bacteria make is harmless to its authors; it’s only dangerous to creatures like you and I with nervous systems that use acetylcholine as a neurotransmitter.

Medical science first recognized botulism as a separate disease back in the late eighteenth and early nineteenth century, when a series of “sausage-poisoning” deaths shocked small towns and villages in Southwest Germany. Some doctors thought prussic acid (aka hydrogen cyanide) was the culprit; others blamed housewives for cooking sausages improperly. A German doctor named Kerner correctly guessed another poison was at fault and tried to isolate it without success. Based on his experiments, he became convinced the toxin was biological in origin and that it developed in sausages under oxygen-poor conditions. In an astonishing flash of insight, he wondered whether it might have therapeutic applications.

At the time Kerner worked on botulism in the 1820s, the existence of disease-causing bacteria remained as yet unknown. It wasn’t until 30 years after Kerner’s death that C. botulinum was finally identified. Today we know far more about C. botulinum than doctors in Kerner’s day — which is precisely why we use sodium nitrite when curing meat. Sodium nitrite is a remarkably effective inhibitor of C. botulinum growth. We don’t really want random outbreaks of botulism like the kind we knew back in the 19th century.

And it’s ironic we should come to mention botulinum toxin because this protein itself is an amazing example of just how complicated this concept of toxicity can be. Here is an unbelievably potent neurotoxin, for a mammal one of the most potent poisons on Earth, and what do we do with it? We inject tiny traces of it into celebrity foreheads to keep them wrinkle-free.

Kerner might not be too surprised. After all, he guessed his “sausage-poison” might have therapeutic applications, although Hollywood starlets probably wasn’t what he had in mind. Paracelsus probably wouldn’t be surprised either. The 16th-century physician and alchemist made an observation that toxicologists still quote today:

For everything is a poison, and nothing is without poison. Only the dose permits a thing not to be poisonous.

And what do you know: where water and Botox are concerned, it’s entirely true.

[1] European Commission Health & Consumer Protection Directorate-General: Opinion of the Scientific Committee on Food: Update on the Safety of Aspartame.

[2] Lewis D. Stegink. “The aspartame story: a model for the clinical testing of a food additive.” The American Journal of Clinical Nutrition. July 1987: 46(1) 204-215.

[3] Jeffrey Kraut and Ira Kurtz. “Toxic Alcohol Ingestions: Clinical Features Diagnosis and Management.” Clinical Journal of the American Society of Nephrology. November 2007: 3(1) 208-225.

[4] Frank J. Erbguth. “Historical notes on botulism, C. botulinum, botulinum toxin, and the idea of the therapeutic use of the toxin.” Movement Disorders. March 2004: 19(S8) S2-S6.

[5] FDA, “Bad Bug Book: Clostridium Botulinum”.

Magnuson, B., Burdock, G., Doull, J., Kroes, R., Marsh, G., Pariza, M., Spencer, P., Waddell, W., Walker, R., & Williams, G. (2007). Aspartame: A Safety Evaluation Based on Current Use Levels, Regulations, and Toxicological and Epidemiological Studies Critical Reviews in Toxicology, 37 (8), 629-727 DOI: 10.1080/10408440701516184