Urea - Carcinogen Precursor

According to various sources across the internet, Urea, commonly found in yeast energizer or yeast nutrient is a precursor to urethane or Ethyl Carbamate.

I'm looking for facts regarding the levels necessary to be considered dangerous.

Bottles containing Urea + DAP have directions calling for '1 tsp per gallon'; though that seems to apply to wine, mead, cider.

Facts pertaining to its usage in beer would also be helpful.

Any other facts regarding the hazards of urea would be appreciated.

http://www.thebrewingnetwork.com/forum/viewtopic.php?f=&t=23065
http://home.comcast.net/~mzapx1/FAQ/Urea.pdf

https://www.homebrewtalk.com/f30/new-mead-concerned-about-dap-urea-carcinogens-forming-289949/
https://www.homebrewtalk.com/f39/ammonium-phosphate-urea-beer-95876/

Urea is a nitrogen source for yeast so I think that the urea is mostly metabolized by the yeast and would't be around or would be at very low levels by time the yeast is done fermenting. I cant find any articles beer related regarding urea conc post fermentation though but it would be interesting to see what is left.

your body makes urea

Yeah your kidneys put urea in your bladder all day long.

grr

The yeasts we use are rich in urease, the enzyme that speeds the breakdown of urea into ammonium ions and CO2. Urea wouldn't make a very good nutrient for yeast if they didn't. Other pathways producing nasty things? Perhaps but I can't imagine that much product comes out of those pathways. After all, the commercial yeast nutrients are approved for use in food products.

Can you expand on the precursor concern? Just because urea is used in a chemical process to make something else that is toxic doesn't mean it is toxic itself. If it metabolizes in the body into something toxic, that is a different story.

There was some PR stunt playing on this concept a while back but I forget what it was...maybe some sugar substitute. It was something like "product X is made from toxic chemicals but our product is synthesized from a natural product so it is safer" As long as an end product is purified and there are no traces of the precursors, it doesn't matter what it starts from.

The Wikipedia article on Ethyl Carbamate (Urethane) is quite interesting. Doesn't really answer the OP's questions but it turns out we are drinking it every time we tip a beer, wine or distilled beverage glass. Urea reacts directly with ethanol to produce it (and an ammonium ion). Whether using yeast nutrient that contains it is an appreciable source of urea (i.e. if the yeast don't convert it all) I have no idea.

ajdelange said:

The Wikipedia article on Ethyl Carbamate (Urethane) is quite interesting.

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That's enough to convince me to switch to Fermaid or DAP. That sucks, since I just bought a new bag of DAP + Urea nutrients (LD Carlson) and just added some to my mead batches . Hopefully, the staggered additions will reduce the chances of conversion. I'll try my best to keep the temps down too.

MSDS:

Toxicological Data on Ingredients: Urethane: ORAL (LD50): Acute: 1809 mg/kg [Rat]. 2500 mg/kg [Mouse].

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Meh.

Everything is toxic at the right doses. But the dose makes the poison.

As has been mentioned in this thread, urea is produced by your body. It's an extremely common metabolic byproduct found in all species on Earth, and unless you're eating gram quantities of the stuff straight, you won't have any problems with it.

It also doesn't make ethyl carbamate at any appreciable rate without heat, so you almost certainly won't get toxic (carcinogenic) doses of urethane in beer. And if you really, really don't want any urea in your beer at all - tough titties! Your yeast will make some for themselves whether you like it or not. So adding urea (at a teaspoon per five gallons) is not gonna make a difference.

By the way, all food contains carcinogens. Any cooked food contains benzo[a]pyrene. If you like a little bit of char on your hamburgers, that char is full of carcinogens. Any deep-fried food contains acrylamide, which is a neurotoxin. But again, the dose makes the poison - you can detect all these compounds on fancy instruments, but unless you're burning your burgers to a crisp and eating ten a day, the odds that you're going to get cancer from a burger are less than one in a million. Your body has lots of ways of dealing with carcinogens.

invivoSaccharomyces said:

Everything is toxic at the right doses. But the dose makes the poison.

As has been mentioned in this thread, urea is produced by your body.

It also doesn't make ethyl carbamate at any appreciable rate without heat

By the way, all food contains carcinogens.

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Agreed. However, if you can easily reduce the amount of exposure you have to carcinogens (I'm talking chronic, not acute exposure...I'm not afraid of toxicity, I'm concerned about developing cancer), then why not do so? How difficult is it to switch from my current DAP + urea to an all-DAP or otherwise formulated nutrient? Why not try our best to store our beverages at lower temps to reduce the conversion to urethane?

I believe in the concept of triage. There's no evidence that doses of urea as small as what we're talking about could ever result in even the tiniest noticeable elevation in cancer risk, even if you drink 10 homebrews a day. There are a thousand small adjustments you could make to your lifestyle that would do far more to protect you from cancer. Why worry about this one thing?

Shakybones said:

Why not try our best to store our beverages at lower temps to reduce the conversion to urethane?

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Well you should do this for the good of your beer anyway.

invivoSaccharomyces said:

I believe in the concept of triage. There's no evidence that doses of urea as small as what we're talking about could ever result in even the tiniest noticeable elevation in cancer risk, even if you drink 10 homebrews a day. There are a thousand small adjustments you could make to your lifestyle that would do far more to protect you from cancer. Why worry about this one thing?

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Okay, don't worry. But why sit next to the smoking man when you can just as easily sit in the clean air?

Looking out for potential risks and avoiding them as you see fit is applaudable.

Arrheinous said:

Looking out for potential risks and avoiding them as you see fit is applaudable.

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Within reason. But in general, it's not a good idea to go looking at the basic chemistry of substances and then extrapolating on ways they might impact your health. That's how crackpot theories and urban legends are born and propagated. It's why the Daily Mail Oncological Ontology Project exists, which started as a joke to catalog all such crackpot theories based on flimsy evidence that have appeared in that tabloid (sadly, it is no longer updated).

Human biology is complicated. It takes rigorous, controlled trials to know what effects things have on our health. Unless actual medical experts have advice one way or another on a substance, it's probably not a good idea for a layperson to make too many inferences.

invivoSaccharomyces said:

Within reason. But in general, it's not a good idea to go looking at the basic chemistry of substances and then extrapolating on ways they might impact your health. That's how crackpot theories and urban legends are born and propagated. It's why the Daily Mail Oncological Ontology Project exists, which started as a joke to catalog all such crackpot theories based on flimsy evidence that have appeared in that tabloid (sadly, it is no longer updated).

Human biology is complicated. It takes rigorous, controlled trials to know what effects things have on our health. Unless actual medical experts have advice one way or another on a substance, it's probably not a good idea for a layperson to make too many inferences.

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This type of stuff has been showing up so much recently (not just in HBT) that I figured I'd humor someone for once.

Forming urea derivatives isn't anything I would expect to happen in the very mild conditions of a fermenter. I've tried to do reactions on urea before for different things but it wasn't reactive enough for my purposes.

Urea's actually used to produce my favorite compound - melamine. Melamine was figured to cause an outbreak of milk poisonings due to crooks trying to adulterate milk with nitrogen-rich melamine and sell it off at higher prices as higher protein milk. Whatever was added to cheat the system contained what researches now think is a combination of melamine and a similar compound that together form dangerous kidney stone-like crystals.

People have been spooked by melamine showing up in the milk supply since then. But resins of melamine and formaldehyde are used in cookware like bowls and utensils and it's used in food contact surfaces for machinery that processes foods. It's endemic when you really look at it and it hasn't caused any of the personal damage attributed to the isolated milk cases. Melamine's actually pretty inert, low hazard while being a good flame retardant and possessing very neat properties.

Now I could cause trouble and go around saying that dioxane looks awfully similar to two ethanol molecules combined...

And now that I've gone back a re-read OP's post: a 'source on the internet' doesn't qualify anything in itself. These references just look like people feeding into a cycle of conjecture, a snake eating it's own tail. At least someone put the effort to format a PDF and host it on a Comcast site. The homebrewing community probably won't get into the New England Journal of Medicine but I haven't heard of an article on urea/carbamate danger in Zymurgy either.

90% of everything crap, especially online sources. Look at Youtube. This is my source saying that the world experiences four days within a single day. Because I have a link it must be true.

Arrheinous said:

Forming urea derivatives isn't anything I would expect to happen in the very mild conditions of a fermenter.

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Thank you for your informed perspective on this subject. However, the US FDA has published warnings about Ethyl carbamate in fermented beverages. Also, the Ethyl carbamate preventative action manual was published by UC Davis professors of viticulture and enology (one of whom I was fortunate enough to have taken a class under:rockin. It seems unlikely that they would go so far as to have BATF prohibit the use of urea as a fermentation supplement (pg. 5) if there was no cause for concern.

Of course, the government and the universities do silly things all the time, so...

My opinion is less than full informed since I don't do any biology and enzymes have a habit of producing things a chemist couldn't do except under relatively extreme conditions. Go Nature.

That data's from 1995 so I did some searching into quantification of ethyl carbamate (EC) within recent scientific literature.

This paper is on a study of several Hungarian wines. They found that EC was present in concentrations of 4.9 to 39.9 micrograms/L in 33 wine samples.

One microgram/L is equal to 1.3×10^-7 ounces/gallon.

The average content was 17.7 ug/L + 52%. Three wine samples exceeded the 30 ug/L maximum for Czech/Canadian regulations. Arguably, one of the 'failed' samples was within experimental error of being below the limit. Two were commercial wines and one was domestic. They couldn't attribute the levels of EC to any specific style of wine.



Now if you look at this report by the European Food Safety Authority:

"For almost 93% of the beer samples, 42% of the wine samples, but fewer than 15% of the spirit samples, the results were below the limit of detection. Median levels of ethyl carbamate in alcoholic beverages of up to 5 µg/L for beer and wine, 21 µg/L for spirits other than fruit brandy and 260 µg/L for fruit brandy were calculated. From these data, a dietary exposure of 17 ng/kg per day was estimated from food for an average 60 kg person who does not consume alcohol, whereas this would increase up to 65 ng/kg for consumers of a variety of different alcoholic beverages. The highest exposure to ethyl carbamate can be expected for persons exclusively consuming fruit brandy with exposure at a 95th percentile consumption level of 558 ng/kg per day."

As of 2007, the US regulation is on 15 ug/L on wines and 60 ug/L on fortified wines. Elsewhere, distilled spirits are set at 150 ug/L, sake 200 ug/L, and fruit brandy 400 ug/L.

WHO as of 2006 in that report, says that the levels of EC in wine can range from 4 - 10 ug/L. In beer, you're looking at undetectable levels to up to 1 ug/L on average.



Now if you look at that, any food product resulting from fermentation - breads, yogurt, soy sauce, even vinegar according to similar reports - contain somewhat measurable levels of EC. And in a few instances the average of those exceeds what you'd find in beer.

This has to be coupled with information of whether EC at these levels is harmful before anyone decides to give up alcohol for life.

And that research has been done! [Free Paper]

Key points:

1) The legal limit of ethyl carbamate in Canada, .15mg/L, is based on data that shows that intake of 0.3ug/kg per day will likely cause cancer at a rate of less than one in a million.

2) Beers sampled for EC content had an average of .005mg/L. The top 5% of beers had .006mg/L. This means that the EC content of beer is not highly variable. Your beer will almost certainly have just as much EC as the next guy's.

3) The BMDL value (the lowest dose at which you have 95% confidence that you will not increase your risk by more than 10%) for EC is 0.3mg/kg per day. That is, if you weigh 80kg, you have to drink 4,800 liters of beer every day for the rest of your life in order to have a 10% chance of getting cancer as a result.

4) If you drink one beer per day for your whole life, your risk of developing cancer from it is 1/460,000. If you increase that to ten beers per day, your risk is still lower than 1/40,000.

5) Ethanol and acetaldehyde are orders of magnitude more likely to cause cancer than EC in any type of beverage, but particularly in beer.

invivoSaccharomyces said:

And that research has been done!

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To quote your source: "According to our risk assessment, EC poses a significant cancer risk for the alcohol-drinking population in Brazil, in addition to that of alcohol alone."

How does that square with your calculations?

Oh, my bad, they were looking at spirits with much higher levels.

So are your figures taking into account that the sampled beers were likely produced without the use of urea nutrients (due to the BATF ban and the fact that beer doesn't require additional nutrients)? I wonder what the EC levels would be in a glass of mead produced using urea nutrients at the recommended rate (1 tsp per gal on my bag).

Oh, and thank you also for contributing your insights to this discussion!

The difference is very likely close to none. Yeast don't convert the urea to ethyl carbamate, they metabolize it to ammonium and carbon dioxide. The reason you add it is because the yeast use the ammonium in the synthesis of amino acids.

Yeast can very efficiently and effectively use urea, and can use it as their sole source of nitrogen.

More info: http://biochemie.web.med.uni-muenchen.de/Yeast_Biol/03 Yeast Metabolism.pdf

I understand that the yeast don't convert urea to ethyl carbamate. That happens in reaction with ethanol, as thoroughly discussed previously.

Obviously, the yeast can use the urea as a nitrogen source, that's why I bought the bag to add to my mead. How efficient and effective they are is of some consequence, but only as far as they remain active until all the urea is exhausted.

Based on my limited knowledge of chemistry, I would think that at the point when the yeast go dormant from exhausting their energy source or from reaching their ethanol threshold, any remaining urea in solution is likely to be converted over time into ethyl carbamate (time depending on temperature), due to their exposure to ethanol - now at a fairly high concentration.

Unless I am mistaken in my assumption, isn't it at least fair to say that care should be taken to limit urea addition to what can be converted by yeast into ammonium and carbonate? This rate would depend on the yeast and amount of fermentable sugar present.

All this makes my head hurt a bit. Seems simpler to just buy pure DAP next time.

But DAP contains ammonia - 2 in fact and 2NH3 + CO2 + 3ATP --> urea + water + 3ADP. How do you know that reaction won't take place?

ajdelange said:

But DAP contains ammonia - 2 in fact and 2NH3 + CO2 + 3ATP --> urea + water + 3ADP. How do you know that reaction won't take place?

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Because its been going on for billion years in every species capable of breaking down proteins?

You all are reading too much into this.

That suggests that it will take place.

The comment was made tongue in cheek to suggest that using DAP may not be an effective means of relieving the poster's phobia.

I think the world was a better place when we were fat, dumb and happier and drank beer and whiskey without worrying that we should do it in the basement because of potential meteor strike.

Shakybones said:

To quote your source: "According to our risk assessment, EC poses a significant cancer risk for the alcohol-drinking population in Brazil, in addition to that of alcohol alone."

How does that square with your calculations?

Oh, my bad, they were looking at spirits with much higher levels.

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Does ethyl carbamate come over through the distillation process or is it picked up in barrel ageing.

DaleHair said:

Does ethyl carbamate come over through the distillation process or is it picked up in barrel ageing.

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I'm not sure what the source of urea would be in distilled products. Good question. Maybe it's present in what they add back to the alcohol to bring it back down to drinkable levels.

ajdelange said:

But DAP contains ammonia - 2 in fact and 2NH3 + CO2 + 3ATP --> urea + water + 3ADP. How do you know that reaction won't take place?

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Good point. I realize that you're poking fun at me. Understand that I am going to drink the mead anyway. I'm not that crazy. I will, however, try to limit the amount of nutrient that I use in the future to only what is necessary to keep the buggers going. Couldn't hurt.

Shakybones said:

I'm not sure what the source of urea would be in distilled products. Good question. Maybe it's present in what they add back to the alcohol to bring it back down to drinkable levels.

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I'm certainly not sure either but apparently one concern is in the use of urea based fertilizers in the field. As has been observed, all living things that contain/metabolize protein (and by extension anything that contains nucelotides - DNA, RNA, ATP...) is going to produce some urea. As the reaction between ethanol and urea is accelerated by heat I think it is reasonable to suppose that the distillation process is responsible, at least in part, for the formation of urethane.

The method I've been using is to add the DAP-Urea to the last 10 mins. of the boil along with the Servomyces/Wyeast Nutrient. That may or may not be a wise thing to do according this thread.

The purpose of adding to the boil would be to help dissolve the nutrient in the wort. Will the DAP-Urea dissolve in chilled wort just as well? (If it dissolves in wine must then it should dissolve in wort?)

ShootsNRoots said:

The method I've been using is to add the DAP-Urea to the last 10 mins. of the boil along with the Servomyces/Wyeast Nutrient. That may or may not be a wise thing to do according this thread.

The purpose of adding to the boil would be to help dissolve the nutrient in the wort. Will the DAP-Urea dissolve in chilled wort just as well? (If it dissolves in wine must then it should dissolve in wort?)

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It probably doesn't matter. The urea will dissolve just fine at fermentation temperature. There is no danger in adding it at boil, since the problem with conversion to ethyl carbamate is due to the presence of ethanol. No ethanol in boiling wort, so no problem.

Here's my educated guess, as someone who studies microbes for a living:

It doesn't matter what form of N you add to your wort as yeast nutrient.

During the aerobic phase of rapid multiplication, the yeast are going to consume every molecule of assimilable nitrogen (including urea) for incorporation into protein and other N-containing biomolecules. This is because N is the strongly limiting nutrient (c.f. Liebig's Law of the Minimum) in a system that is replete with assimilable carbon and energy (sugars). Note that almost all of the urea will be consumed in the aerobic phase, before the yeast makes any EtOH.

It is only after the beer has attenuated and there are very few fermentable sugars left that the yeast start to catabolize en masse their proteins for energy, outstripping new protein synthesis. The decomposition of arginine, a common constituent of all proteins, produces urea, and this is the urea that reacts with EtOH to form urethane, and this only happens at the end of the fermentation. (Of course, proteins are constantly being broken down and reassembled in the cell, contributing a small background production of urea, but the cell would quickly reassimilate this N in situations where N was still a strongly limiting nutrient.)

Put simply: No matter what form of N you put in your wort, the yeast will eat it all up in the beginning, and then spit it back out as urea in the end, so don't worry about which additives you're using.

Edit: Now, limiting the AMOUNT of N you're adding will likely have an effect on how much urea you're getting out at the end, even if the form of N addition doesn't matter. But if you reduce N addition, you're going to reduce the yeast growth and fermentation activity, so I couldn't recommend that.

Thanks, Marinosr!

I guess we've all gotta die of something.

So you'd expect less urethane in a brew where the yeast dropped out from the high ethanol concentration but still had remaining fermentables than you would from one where they dropped out from lack of available fermentables, right?

That's a plausible hypothesis. I still think you'd see moderate levels of urea in beers where yeast dropped out due to high alcohol in high gravity beers, though. My thinking is that, as alcohol concentrations increase, protein catabolism (which is going on all the time in active yeast cells) will outstrip protein synthesis (as making proteins is energetically expensive and the metabolism of the yeast is severly stunted by the unfavorable environmental conditions), resulting in an excess of urea. It's not so much what is limiting protein synthesis in the yeast, be it a lack of a resource (energy supplied by sugars) or unfavorable environmental conditions (high EtOH concentrations), so much as simply the fact that more proteins are being broken down than synthesized. That's just my hunch though.

As a pack a day smoker Im not worried about adding a teaspoon or two of urea/DAP in my cider/Mead batches. Your way more likely to get cancer from some weird mold in your walls or even pollution compared to something as common as urea which we consume and make in our bodies.

Shakybones said:

Based on my limited knowledge of chemistry, I would think that at the point when the yeast go dormant from exhausting their energy source or from reaching their ethanol threshold, any remaining urea in solution is likely to be converted over time into ethyl carbamate (time depending on temperature), due to their exposure to ethanol - now at a fairly high concentration.

Unless I am mistaken in my assumption, isn't it at least fair to say that care should be taken to limit urea addition to what can be converted by yeast into ammonium and carbonate? This rate would depend on the yeast and amount of fermentable sugar present.

All this makes my head hurt a bit. Seems simpler to just buy pure DAP next time.

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This is a completely valid concern. You also have to consider that people don't follow directions and quite possibly could use too much urea and may have unpredictable amounts left. Yeast absobtion rates for urea IN YOUR vessle is a wild card as well. If you over dose with urea and have struggling yeast...I would imagine you COULD end up with higher than average levels and byproducts of urea. Temps are prob a wild card as well that will set homebrew aside from average numbers.

Keep in mind...ammonia is a carcinogen as well so pick your battles cafrefully. You don't want to jump over to a different N source thinking everythingn is fine and dandy. Maybe having left over ammonia is more of a threat than urea converting to something toxic.

Here is another random thought. Many brewers are using metal tubing off the shelf for DIY wort chillers. It is very common for metals to fail testing for toxic compounds like lead for example. Even if you are using a food grade certified metal like copper, it was most likey certified for leaching toxins ONLY from the inside of the tube AND not at hot temps. Coatings may be applied to inner surfaces to prevent leaching where outter surfaces are not if the tubing isnt intended to be submerged. Exposing the outside of tubing to hot wort could be a pretty bad practice but only testing would tell us what is going on.

In short, it is completley valid to be concerned about stuff like this. Unless there is a study specifically testing conditions home brewers are using...numbers are to be taken with a grain of salt. The only for sure thing you can do is eliminate the possible exposure by taking something out of your process.

Always keep in mind that there could be more home brewing practices that are a bigger problem so think about what has a larger impact.