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Paracelsus' poison

Drinking Cola will not give you Cancer

You would have to drink every single bottle in these two shelves, a day, every day, to exceed the safety threshold for 4-methylimidazole. Ian Musgrave

I used to have in my lab a small jar of substance with this warning on the label:

“Known to the State of California to cause cancer, handle with eye protection, gloves and respiratory apparatus”

The identity of this heinous substance? Washed sea sand.

Keep this in mind as I discuss the latest brouhaha over the presence of the cancer preventative chemical 4-methylimidazole in commercial soft drinks.

Wait, what? Did you just say cancer-preventative?

Yes, I did. I’ll get to that shortly.

You, shortly? Ha!

Ahem, moving along. At the heart of this disturbance of our consumption of carbonated beverages is the seemingly innocent substance caramel.

What, caramel? Like in the sweetie?

Yes, caramel. Caramel is basically burnt sugar. How you “burn” the sugar makes a lot of difference to the consistency, colour and flavour of the resulting material. You may be interested to know there are four different classes of caramel, depending on exactly how we “burn” the sugar.

4-methylimidazole. Ian Musgrave via PubChem

As part of the oxidation process in “burning” the sugar, a whole range of weird and wonderful chemicals are produced. These produce the distinctive colours and tastes of everything from the brown crust on bread to dark beers. We even add caramels to food and beverages deliberately.

For example certain famous international carbonated beverages have caramel added to them to give their characteristic dark colours. They use type IV caramel, and this is where the latest panic comes in, because type IV caramel contains 4-methylimidazole, “known to the State of California to cause cancer”.

You are going to do that “dose makes the poison” thing again, aren’t you?

We don’t actually use test tubes anymore. Ian Musgrave

Sort of, bear with me. In order to determine if a substance is carcinogenic, we can look at it in a number of ways. We can look for epidemiological evidence that the substance causes cancer, but there is no epidemiological evidence for caramel. We can do “test tube experiments” to see if the substance will damage DNA, and we can feed it to animals for a long time.

When the ability of 4-methylimidazole to damage DNA was looked at in multiple different assays, it didn’t. When rats were fed high doses of 4-methylimidazole for two years (basically their entire lifespan), there was a modest increase in one kind of leukaemia at the highest dose in female rats, but not male rats. In mice fed high doses of 4-methylimidazole for two years, at the highest dose both male and female mice developed a certain kind of lung cancer, and at the second highest dose only females developed this cancer (you can see the full assessment here).

But you said “cancer preventative”

Yes. In the rats, as well as a modest increase in leukaemia at the highest dose, there were strong, significant falls in mammary and uterine cancer in female mice, adrenal medullary cancer in male mice and pituitary gland cancer in male and female mice. You can the data buried in the links here as well.

The falls in all these cancers were bigger and more significant, and occurred at lower doses than the single increase in leukaemia. For example mammary tumors fell by 50% and uterine tumors by 72% in the 4-methylimidazole treated groups. This is a real effect and not due to something like the rats losing weight or dying early.

Why is this preventative effect never mentioned?

Maybe people want to be as cautious as possible when putting stuff in our food, and concentrate on the worst effects.

The exposure limits have been set in reference to the International Agency for Research into Cancer which has a No Observed Adverse Effect Level (NOAEL) of 80 mg 4-methylimidazole consumed per kilogramme of body weight per day. Exposure limits are usually set 100 fold lower than the NOAEL to give a good margin of error. This is 0.8 milligramme per kilo body weight per day.

Enough with the acronyms! What does this mean for the cola drinker?

You would have to drink every single bottle in these two shelves, a day, every day, to exceed the safety threshold for 4-methylimidazole (yes, I’ve used this image twice to emphasise the amount you need to consume) Ian Musgrave

Well, it depends on how much 4-methylimidazole is in your favourite Famous International Carbonated Beverage. The amount varies a bit from around 4 µgrams per 360 ml in California to 145 µgrams per 360 ml in the UK to 267 µgrams per 360 ml in Brazil.

Exactly how much is in Australian colas is unclear, I couldn’t find any data. So let’s use the highest concentration found to be safe (267 µgrams per 360 ml). It’s likely we are more like the UK in concentration though.

In order to reach the exposure limit (0.8 mg/kg/day) a 70 Kg person would have to drink 124 bottles containing 600 millilitres of cola a day, every day for decades. Again, this is for cola with the highest levels of 4-methylimidazole. If you are drinking this much cola then you have far, far bigger problems than cancer.

And remember this exposure limit is 100 times smaller than the no effect dose. You may see various other estimates around (ranging from 300 cans to 37,000 cans), these are calculated for 360 ml cans and either the exposure limit (300 cans) or the NOAEL (37,000 cans) with lower levels of 4-methylimidazole.

Yikes! So what’s the big hoo haa about then?

It’s the “known to the State of California to cause cancer” thing again. California sets its exposure standards in a completely different way to other regulatory bodies. It assumes that there is no safe level of any carcinogen and that the response to a carcinogen is linear (both highly dubious assumptions in this case), and then uses the data from the male mouse study to create a response trend line.

Now, as the male mice actually had only one dose where there was a significant increase in cancer, drawing such a trend line is rather dubious at best. As well, the entire validity of the lung cancer finding in the mice is questionable.

Not factoring in the rat data (especially the protective effects) and the test tube data is also problematic.

Despite all these problems they came up with an exposure limit of 29 µgram a day.

That’s a bit low!

You bet, it’s over a million fold lower than the NOAEL.

Some dark beers have this much 4-methylimidazole per litre. In California any food that has over 29 µgram of 4-methylimidazole in it has to have a clear label saying it has a known carcinogen in it. This is despite the International Agency for Research into Cancer listing 4-methylimidazole as Group 2B “possibly carcinogenic to humans”.

Rather than make labels for California and different labels for rest of the USA Coca Cola has reformulated its caramel, while PepsiCo has been a bit slower.

Hence the somewhat histrionic headlines. But then, “Potentially cancer preventing chemical diluted out to insanely minute levels” isn’t a headline, is it.

So we can keep drinking colas then.

Yes, the most important issue is to have a healthy, balanced diet and keep consumption of excess calories from whatever source down. And remember “Known to the State of California to cause cancer” does not mean something actually causes cancer in humans.

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