melamine: good or evil?

I was listening to a number of news reports lately in which melamine was described as “the industrial chemical melamine”. “Industrial chemicals” are, not surprisingly, chemicals used in industry, but the implication is that “industrial” means “bad” chemicals. I’m always amused by people’s reaction to “chemicals”. We don’t want any of those artificial chemicals, you know. Just natural ones. Like, maybe, arsenic?  This week, the FDA set “safe” levels of melamine in baby formula at 1 ppm, which is one part per million or 1000 parts per billion.

Melamine, as you probably already know, was implicated first in the pet food scandal of 2007 and, more recently, in the sickening of over 47,000 babies (and the deaths of at least four) in China due to melamine contamination of powdered milk. The FDA’s action was taken after testing infant formula destined for the US.

Melamine is based on what chemists endearingly call a 1,3,5-triazine skeleton. Triazine is a cyclic ring analogous to the six-membered benzene ring; however, three of the carbon atoms are replaced by nitrogen atoms. ‘Azine’ means ring. ‘Tri’ comes from there being three nitrogen atoms, and the 1,3,5 part of the name comes from the fact that the nitrogens are located in positions 1,3 and 5 if you were counting around the ring. An amine is a functional group that contains a basic nitrogen atom (basic meaning it can accept protons) with a lone pair. Lone pair means that the two electrons aren’t doing any bonding with other atoms, just hanging out. Nitrogen has five valence electrons, which means it can make three bonds and the lone pair. In melamine, the nitrogens in the ring have a double bond with one carbon and a single bond with the other in the ring, and the NH₂ groups have three bonds (again) and one lone pair.

Here’s why melamine is an “industrial chemical”. Its primary use is to make melamine resin, which is a thermosetting plastic (meaning that once you make it into a shape, you can’t just melt it down and make it into something else). Melamine is found in dry erase boards, cheap kitchen cabinets, flame retardants and glues. Melamine also is used to make concrete take longer to set – it reduces how much water you use in mixing the cement, but gives the mixture fluidity the same way water would.

If melamine excels in these uses, why, you ask, would anyone mix melamine with anything animals (or people) would ingest?

It’s because of all those nitrogen atoms. Proteins are combinations of amino acids. The amino acids are arranged in a linear chain. (The connections between the amino acids are linear, but the proteins fold and unfold, so it’s not like they are one long linear molecule.) Amino acids are defined by having an amine group (like a nitrogen with two hydrogens) and a carboxyl group (CO₂H ) Amino acids are held together by peptide bonds between carboxyl and amine groups. A peptide bond is a bond formed when the carboxyl group of one amino acid reacts with the amino group of a second amino acid and produces a molecule of water as a byproduct.

Proteins participate in virtually every process within a cell. They catalyze the biochemical reactions that are your metabolism and they also have structural functions in creating the scaffolding for things like muscle. They also are integral to immune response.

There are about 20 amino acids involved in proteins. Microorganisms and plants can synthesize all the amino acids they need. Surprisingly, we can’t. Essential amino acids are the ones we can’t synthesize on our own and consequently have to get from food. Although one can argue how evolution could have failed to give us this skill (c’mon, plants can do it, for heavens’ sake!), without it we have the need for cooking. I argue that is a very good thing.

The proteins are broken down by acids and hydrolysis (the digestive process) in your stomach. If you don’t get enough protein from food, your body starts breaking down the proteins that are found in your muscles to get the amino acids.

When foods are tested for protein content, they don’t go in and figure out which proteins are there. They measure how much nitrogen is present in the food being tested. Take a look at the diagram of the amino acid: The higher the nitrogen content, the more amino acids.  If you were trying to cut corners on your product, you might look for cheaper sources of protein.

Or, you might look for a molecule that has a lot of nitrogen in it, so that tests would make it look like your product has more protein than it actually has.

Melamine has a lot of nitrogen in it, so you would get quite a boost from adding very small quantities of it. But isn’t melamine toxic?  Not necessarily. At least, as far as we knew a few months ago. Melamine has been added to cattle feed for some time as a ‘non-protein source of nitrogen’, although it’s not a very good one. If you’re selling milk, you take a look at the scientific literature and realize that if you dilute the milk with water and add a little melamine, the tests will show that you have the same protein content (milk is only 3-3.5% protein) and you’ve saved your company some money. To boot, adding melamine also makes the milkfat content appear higher.

There was, prior to the two episodes mentioned above, very little information in the literature about melamine toxicity. In fact, melamine by itself in small quantities, is not toxic to people or animals. That’s one of the reasons it took the people investigating this a long time to figure it out.

The key in the pet food scandal was the observation that the stricken pets had high nitrogen levels in the blood and some very distinctive round greenish-brown kidney stones. The babies who were stricken in China also had these very unusual kidney stones.

Although melamine by itself is nontoxic, if you combine it with cyanuric acid, it forms melamine cyanurate. Melamine cyanurate is soluble in high-acid environments (like the stomach), but when the pH changes, it precipitates. The pH of the kidneys is around 5 and that’s enough to cause the precipitate of greenish brown melamine cyanurate kidney stones. Kidney stones disrupt the renal cells and the kidneys malfunction, which is what led to the deaths and sicknesses.

It turns out that similar cat-and-dog death outbreak in Asia in 2004 was, in retrospect, likely to have been caused by the same effect. Some drugs that are fine by themselves, but combine them, and they have really bad side effects.

In the pet food case, the issue was melamine in wheat and rice gluten products. It turns out a number of companies had been using melamine as a binder in fish and livestock feed. Animals and babies tend to get their nutrition from single sources (pet food and formula respectively), and their weight is low, so melamine cyanurate poisoning is much more significant in small animals and babies than in adults. In order for the danger to propagate to adult humans, they'd have to eat a prohibitively large amount of meat that had in turn eaten the melamine, so there really isn’t any danger to humans.

Melamine was detected using mass spectroscopy. You vaporize whatever you’re analyzing, ionize it, and then run it through a set of magnetic and electric fields that allow you to determine its mass. The particular technique is called DART (direct analysis in real time). Normally, mass spec is done in a vacuum. That necessitates a lot of pain-in-the-butt sample prep (and expense), which usually precludes the technique being used for routine assays. However, a number of people have been making great inroads in finding ways to do the vaporization and ionization in ambient environments, which opens up a whole range of applications from verifying the purity of pharmaceuticals to art history.

In the interest of equal treatment, I should point out that melamine has some potentially redeeming characteristics. In fact, what got me going on the topic was a seminar by Eric Simanek, a chemist from Texas A&M. Simanek's group is using melamine-based dendrimers as drug carriers for chemotherapy.  The idea is the EPR effect which, for biomedical types, is very different than for physics types. 

EPR for biomedical types is enhanced permeation/retention, which basically says that certain sizes of molecules will accumulate in tumor tissue much more than they do in normal tissues. The drugs used in chemotherapy tend to be fairly small; however, if you attach them to Simanek's dendrimers, which are much larger, they hope that the combined dendrimer/drug combination will be more efficacious in attacking cancer tumors.

So remember, chemicals don’t kill people. People who don’t understand chemicals kill people. People who understand chemicals kill cancer.

Comments

[Lab Lemming]

The people who used melamine to disguise their dilutions understood the chemicals involved perfectly well. And they killed people. So I reckon it is people willing to poison total strangers for a cheap buck who kill people.

Where does the cyanuric acid come from?

[Lee Kottner]

I used to have this "chemicals" argument with one of my natural foods freak friends (hoo boy, say that fast five times!), who insisted on taking only "natural" vitamins. It's not the vitamins that are "natural," it's the binders. The chemical formulae of the vitamins are all the same, regardless. "But chemicals are bad!" she'd insist. "I'm not taking chemicals when I take vitamins."

And what can you say at that point? *Sigh* I wonder if those natural binders were melamine?

[Diandra Leslie-Pelecky]

Lee, I have to disagree that the "people who did this understood their chemicals perfectly well". If you did a literature search on melamine prior to the pet food incident, it would not have shown that melamine, at low doses, was toxic to humans or other mammals. They 'understood' their chemicals at the same level the makers of fen-phen did - and that was FDA approved before they realized the long-term lethality of the combination. I don't believe that anyone intended to do something they thought would result in anyone's death or injury. It all, however, goes to the basic principle of people trying get something for nothing. Don't worry about good nutrition and exercise, just take a pill. Don't try to produce a high quality product, just make something cheap because more people will buy it.

[shaun]

I enjoy your blog tremendously, but your tiptoe-through-the-tulips approach to melamine did not, pardon the pun, digest well.

Melamine was added to pet food and baby formula for one reason only: Chemical trickery, not to make these products better or, heaven forbid, safer.

That does not translate neatly into consumer fraud or manslaughter, but this is one instance where your famously sharp mind could have suggested that you play more of an advocacy role and not merely that of an all-knowing professor.

[Wade Walker]

Great article on melamine! I wish the media reports I've been listening to ever since the pet food scare had gone into even half as much detail. It's nice to know the why of something as well as the what. I guess that's why I read blogs by people who know stuff :)

Obligatory nitpick (this is the Internet, after all): I always thought the "az" of "azine" was from "azote", the old name for nitrogen. But I'm not a chemist -- are there other rings without nitrogen that start with "az"?

[ZZMike]

"When foods are tested for protein content, they don’t go in and figure out which proteins are there"

That seems to be the root cause of the problem. The Chinese knew the tests looked for nitrogen, so they gave us nitrogen. (Good thing they didn't think of the CN group.)

It's probably a lot easier to test for N than for proteins and amino acids, but if you're trying to find out if X is present, you'd be better off testing for X.

[Dave]

Isn't one of the purposes of the FDA's GRAS list to prevent problems such as this?

http://www.cfsan.fda.gov/~dms/grasguid.html#Q1

Of course, the FDA doesn't have any legislative authority in China (unless the item is being imported into the US).

Dave

[milkshake]

Cyanuric acid is a melamine metabolite, and it forms very insoluble salt with melamine which precipitates in kidneys - you feed humans or an animals enough melamine for long enough time, eventually they will develop the kidney stones.

There is a political dimension to this fiasco - in the last decade the Chinese commie government has been promoting development of dairy industry as a way to improve the nutrition of the diet. There is emphasis on the protein content because there was previous a scandal when milk for cheap baby formula was watered down to a point the babies were dying of malnutrition - the formula was all starch and no milk.

Add this to the fact that the country had no dairy tradition to speak of, and the government is extremely secretive and critique-averse, and the local party officials universally corrupt. The melamine adulteration was a common practice, like cutting olive oil in Italy or improving wine taste with antifreeze in Austria - this racket has been going on for years and everybody knew about it; eventually someone pushed it too hard.

A similar, even more serious problem was with unsafely adulterated heparin made in China, which got imported and repackaged by a US company - dozens of patients died here as a result.

There is a large number of examples of seriously dangerous adulteration in the last few years and I would advise against buying food, herbs or medicines made in China. Unfortunately sometimes one cannot recognize the country of origin - like with the heparine or a fake Colgate toothpaste that contained a huge amount antifreeze.

[Wilson]

One point to note. Diandra source on how many children are sick (over 47,000) was from mid-September. In the meantime, the number has grown to over 300,000.

See http://www.cbc.ca/health/story/2008/12/02/china-babies.html

[Mike]

One note on choosing to consume 'natural chemicals' only. A more level-headed interpretation of 'natural chemicals' would be those chemicals that humans have naturally consumed without negative consequences (actually, with positive consequences) for large segments of human history (those chemicals should also be consumed in their natural states). I see that as a long term research project with results that I trust more than the engineered studies done today.