Melamine follow-up

By revere on May 12, 2007.

The problem of melamine in the food chain continues to be discussed, so we thought we'd do a follow-up of our earlier post. The mechanism whereby melamine, or melamine plus some other factor, or something else entirely is the cause of pet deaths remains unclear. The latest theory is that a co-precipitate of melamine and cyanuric acid might be the cause of the apparent renal failure in cats and dogs who ate pet food contaminated with melamine and like compounds. Here's what I have been able to make out at this point.

To recap, melamine is a nitrogen-rich chemical added surreptitiously to animal foodstuffs to make them look higher in protein than they really are. Exactly what form the melamine is in when it is added isn't exactly clear. Melanime is polymerized with formaldehyde to make melamine resin (melamine formaldehyde, also frequently called melamine, although it is not the same). When melamine, proper, is synthesized it can produce a significant amount of wastewater:

Crystallization and washing of melamine generates a considerable amount of waste water, which is a pollutant if discharged directly into the environment. The waste water may be concentrated into a solid (1.5-5% of the weight) for easier disposal. The solid may contain approximately 70% melamine, 23% oxytriazines (ammeline, ammelide and cyanuric acid), 0.7% polycondensates (melem, melam and melon). (Wikipedia entry on melamine and SM Lahalih, M Absi-Halabi, "Recovery of solids from melamine waste effluents and their conversion to useful products", Industrial & Engineering Chemistry Research, vol.28, 500-504 (1989))

It is my impression that this solid waste by-product of melamine synthesis is what is referred to in the news stories as "melamine scrap" and is the melamine rich substance added to the Chinese wheat gluten that wound up in pet food. This scrap is mainly melamine (70%) but contains a significant amount of the oxytriazines, among them, cyanuric acid. One of the leading theories of how pets are being harmed is related to this combination of melamine and cyanuric acid. It has been known for some time that there is a strong tendency for the two to form large hydrogen-bonded complexes (melamine is green, cyanuric acid is red; from the Wikipedia entry on Melamine):

i-4199d9341e134c6feb74a1e13c9341c2-250px-M-CA_aggregate.gif

Characteristic spoke-like crystals have been reported in both contaminated wheat gluten concentrate and tissues and urine of afflicted animals. The potential connection strengthened when researchers at the University of Guelph announced they could make similar crystals by combining melamine and cyanuric acid in solutions with the acidity of animal kidneys. This suggested that these two relatively non-toxic materials when combined can interfere sufficiently with kidney function (we don't know how) to produce the pet deaths. While plausible, most of this is currently speculation.

What about human health? Melamine doesn't accumulate in the body, since it is water soluble and has a half life reported to be only three hours. That means it is mostly excreted through the kidney, so the main question would be whether there is enough there at any one time to combine with whatever else it needs to combine with (e.g., by speculation, one of the oxytriazines) to cause damage in humans. Since the concentrations in humans are likely orders of magnitude less than for pets, my speculation would be, "no." This doesn't mean that we shouldn't worry about very small amounts of chemical. I have already discussed why we are worried about small amounts when they produce damage that can be biologically amplified (see here, here and here). It means I don't think melamine contamination is one of those instances.

However it still has major public health significance because it shows how easily potentially harmful contamination can travel undetected through the food chain from distant sources.

Melamine may not be a skull and crossbones but it is certainly a red flag.

More like this

Melamine and cyanuric acid chemistry lesson

Via the Knight Science Journalism Tracker at MIT, I was directed to one of the best-written articles on melamine contamination of pet food and animal feed. David Brown at the Washington Post is the guilty party whose article appeared Monday. Brown does a terrific job of explaining how the…

Melamine and cyanuric acid revisited

This morning's post from Molecule of the Day reminds me to ask "cyanuric acid question." With the recent adulterations with melamine of Chinese milk and milk products (like White Rabbit chocolates) and foods with other milk-derived ingredients, we wonder if we will ultimately hear that a compound…

Melamine: tastes like chicken

Lots of us knew melamine as a heat resistant plastic polymer found in kitchen items, like plastic plates. Despite its reputation for heat resistance it would melt in an oven, although it doesn't catch fire. It is used in a lot of other places: floor tiles, white boards, fabrics, filters, even the…

Melamine (Fire-retardant, nephrotoxic, stain erasing fertilizer)

The pet food recall scare continues unabated; a couple weeks ago, people were pointing at aminopterin, a folic acid analogue, which was covered here. Now, people are pointing fingers at melamine as a potential contaminant. Melamine is a pretty simple compound, with a number of uses. Here, it's…

Interesting that the news media have steadfastly referred to the melamine in foodstuffs as 'contamination', while all along it has been a deliberate adulterant made from industrial waste.

I grew up in Appalachia where dirt roads were oiled every spring to keep the dust down. Now and then there would be backpage newspaper reports of somebody being fined for using 'contaminated' oil. Nobody ever went to prison for this practice of dumping hazardous industrial waste on country roads, and the papers never reported it for what it was. The racket was run by mobsters who made deals with industry and county governments.

My experience leads me to suspect that somebody with a lot of industrial waste was looking for ways to maximize profits. There should be no assumption of innocent mistakes.

Roy: I think you are exactly correct, and the us of "contamination," as in "accidental" is incorrect (I plead guilty). The use of contaminated oil for dust suppression, however, basicialy was "contamination." The usual culprit was dioxin, which was an accidental and unwanted by-product of heating to produce a condensation reaction from furans. The oil was deliberately spread on roads but the presence of dioxin was usually not recognized, unlike the melamine example.

One can also view Depleted Uranium as a way to get rid of radwaste. Instead of letting minute amounts of discarded waste leach into the environment where it might kill someone, we put it in armor piercing munitions for the purpose of killing someone. Go figure.

Melamine has revealed a surprising problem: many so-called wild salmon are raised in fish farms called hatcheries for up to a year or more, before being released into the ocean for a grow-out period and capture by fishermen.

How prevalent is this problem? In some areas, 80% or more of the "wild" salmon were actually raised in hatcheries.

Lacking disclosure of this problem, you can't manage your own health by choosing wisely. For more, see blogfish May 9, May 10, and May 11, including figures on % hatchery fish in wild populations by area and salmon species.

This kind of thing is standard procedure in creative capitalism. Perhaps the most outlandish success in this regard is the disposal of fluoride waste by incorporating it into toothpaste and then drinking water all over the world. Even people who should know better actually think this procedure contributes somehow to 'dental health'. You gotta hand it to them. An ingenous way of getting the public to dispose of a very poisonous substance by washing it down each individual drain--and getting paid for it!

I heard Donald Rumsfeld was behind this marvellous idea, but I am unable to confirm that.

Ron: Fluoridation started when Rummy was in kneepants. It is not a plot to dispose of fluroide. If it were, it would be easier to deal with. I blogged about it early on, here:

http://effectmeasure.blogspot.com/2004/12/not-tooth-fairy.html

I don't know about Rummy, but fluoride is poisonous, it screws your kidneys, your brain and is linked to bone cancer in small boys. It also wrecks your teeth. The NRC report last year, amazingly, lays it out clearly, stating unequivocally that the EPA accepted 'safe' levels in water must be lowered to protect health. In fact, there are a number of scientific papers over the past year or so that document clear health threats represented by currently accepted levels of F. So your statement in the previous blog that there is no 'smoking gun' needs to be revised.

This from the fluoride action network:

"The National Research Councils long-awaited review of fluoride, released in March of 2006, was a watershed moment in the fluoride debate. The 500 page review, which took 12 scientists over three years to produce, describes in great detail why EPAs purportedly safe drinking water standard (4 ppm) needs to be reduced in order to protect human health (1). The report documents myriad potential hazards from fluoride exposure, including damage to the bones, brain, and various glands of the endocrine system. According to Dr. Bob Carton, a former risk-assessment scientist at EPA, this report should be the centerpiece of every discussion on fluoridation. It changes everything.

Link to report: http://www.fluoridealert.org/health/epa/nrc/index.html

The point is, there was never any real evidence that this practice was safe, let alone that it contributes anything to health of any kind. But it means big money on both sides, avoiding disposal costs and selling the waste. I don't see how you can say it is not a plot to dispose of fluoride. What else is it then?

What Revere posts above confirms what I said about melamine and that the chemical has to have been deliberately mixed in with the feed. In other words to do this they had to do it for a monetary reason. They had to have known that it would artificially raise the protein indications of the gluten. That makes it a cognizant act and if any human death is attributable to this then someone is going to get hung or shot (take your pick) in China in very short order.

Their laws work very differently than hours. The burden of proof is on you to prove you are innocent. Hard to do when you are in prison. Worse for the ChiComs is that we are arguing about the content of melamine in human food supplies.... They are worried about loss of face. Big item there and suddenly, the WTO is on their asses too.

Ron: I am not pro-fluoride and think it shouldn't be in water. But you aren't quite right about it. I know the IOM report well as two of my colleagues were on it and wrote the most important sections. It is not a smoking gun, by either of their interpretations, nor is the cancer data as black and white as you portraÂ¥ it (far from it). The problem with fluoridation as I see it is that it increases natural fluroide intake to levels that may be close to or exceed harmful levels for some people. You might want to look at the actual IOM Report, not what advocates on one side or other say is in it. The motor behind fluroide is not the waste industry, it is (unfortunately) the medical and dental professions (my people) who are not current with fluoride research, what little of it there is. Moreover, they have an inflated notion of its benefits, today and historically (although these are not part of the IOM report). But we will never deal adequately with it if you are not accurate in discussing it.

So I guess nobody's up to take a look-see at dead folk to find out if this stuff has accumulated in humans. Seems to me that would be the quickest and most definitive way to find out if the amount we're exposed to has biological significance to us. Rather like dunking the Morton-Thiokol space-shuttle o-rings into ice-water to illustrate that they become stiff and shatter when cold--a pretty direct illustration yea or nay.

I read somewhere that veterinarians were finding macroscopic blockage of the ureters in pets killed by the toxin, which would make its mechanism of toxicity pretty clear--mechanical obstruction of the kidney tubules. Don't have a link offhand, if I find it again I'll link you. If that's the case then it might first show up as glomerular or tubular deposits.

While the melamine is water soluble, the crystals themselves cannot be water soluble. Otherwise the process wouldn't be useful in getting the melamine out of the waste-water. Will have to see if I can get that engineering article later. The nearest decent academic library where I have access to journals is an hour's drive away.

Um, peer-request to other repliers, can we stay on the melamine topic and not get diverted too long onto other past instances of unsafe contaminations?

Politically I don't think 'contamination' leans either way in terms of 'deliberate' or 'accidental'. I think people are avoiding 'poisoning' as an alternative because the toxicity in this situation is unclear.

And I still think the easiest way to see if there's been toxicity to humans is to look at human kidneys that are accessible for other reasons (eg: recent autopsy specimens not saved in formaldehyde, which dissolves the crystals). It can't be *that* expensive to take a look, can it?

Lisa: According to some sources there is quite a bit of cell necrosis in the kidneys, unlikely to be caused by mechanical blockage. Thus the suspicion that something else is going on. If you are going to look at melamine in the kidney, what will you look for? It isn't in fat? The only possibility would be to see the crystals and I think at the levels humans are exposed this is pretty unlikely. How would you design this? Certainly not a cross sectional study. The only possibility would be a case control study of renal failure, but then the exposure prevalence would likely be too rare for any adequate power. So this doesn't sound amenable to post mortem study, to me. Of course I also think it's unlikely we are being harmed by melamine, but my technical concerns are unrelated to that except to the extent that I wouldn't spend tens of millions doing this.

Just a conjectural look at the kidney failure in animals..,

Crystals in the urine (in nephrons and ureters) could cause a variety of kidney problems. In this case though, a of a very atypical cause.

Chief among the symptoms are basic blockage and inflamation. (Crystals of melamine-Cyanuric acid complex are sharp little buggers.) Another symptom would be blood or serum protein in the urine. As the nephrons become inflamed and blocked kidney shutdown and hematologic complications are inevitable. Death would probably be attributable to glomerulonephritis leading to necrosis of the kidney.

I would a treatment options might include modification of the blood and urine Ph to disolve out the amine complex crystals. This may or may not be a viable treatment depending on the Ph necessary to dissolve the crystals..,

However, from what I've read of nephritis the prognosis in the disease is not good. Nephron damage is not very reversible..,

Maybe the mechanism is similar to ethylene glycol.

I don't think it would cost millions of dollars to do this. If you can't easily detect it by microscopy, it occurs to me that the formalyn that dissolves the crystals--the medium in which samples are likely to be preserved unless you otherwise specify--should contain melamine that was dissolved from the tissue. In which case all you need to do is run the formalyn through a gas chromatograph and see if you can discern a spectrum from melamine in the mix. There shouldn't be too many small organic molecules floating in the formalyn to confuse the data, most of the biological stuff would be big molecules, plus urea and a few ions.

As for experimental design for a preliminary survey, how about the following--

Identify a region where a large number of possibly contaminated chickens or pork was sold. Test all available samples from people who died within a particular time window. What you're looking for is evidence of melamine accumulation in the general population. If you get any positives at all then you need to do a wider study. If you get no positives, continue until you have enough negatives to prove that there's 95% probability that accumulated melamine occurs in less than 1 out of a target number of the general population.

For a control you might test kidney samples that have been stored for whatever purpose from more than 4 years ago, or you might use samples from an area where contamination seems less likely, or from individuals who were reported to be vegetarians in life, since meat is the suspect culprit in this. On the other end you could deliberately add melamine to a 'clean' sample to act as your 'positive' control for your assay.

The point at this point wouldn't be to determine the biological effect of the melamine, merely whether it is ever *present* in detectable quantities. There is value in proving that it is not present in the population at large.

Dumb question dep't:

I've heard some speculation that ethylene glycol (antifreeze) can produce the same symptoms, and that it is also a suspect contaminant in this case. Anyone know anything about that, or have good reason to rule it in or out?

Lisa the GP: we may know about the contaminated feed being feed to chickens and pigs, but from early reports it sounded like they weren't sure it hadn't entered the human food supply directly, since the gluten was "food grade", not "feed grade". So there is a possibility of direct consumption by humans.

Not necessarily a likely possibility, but perhaps enough to muddy the import of the data, if it showed up in the samples from vegetarians.

A better control, although one that might restrict the sample size too much, could be tissues from people who were both vegetarians and celiacs. (People with celiac disease must avoid wheat gluten in even minute amounts.)

caia, I'm not in a position to do the experiment or influence anyone to do so, looks like revere's not following these reply threads, so its a moot point.

If you're taking advantage of folk who happened to die in the timeframe of interest I don' think you're going to find a convenient celiac vegetarian who also happened to die in the time of interest for you to get the sample.

The experiment in general is a doable non-pricey thing but nobody's going to do it. :sigh:

Lisa the GP. As I said before, I completely agree.

If past history is any example, this issue will be swept under the rug and disappear shortly...

...but this is not the end of the story...this is not the end of the beginning of the story...

...we either do your study on what may be subclinical conditions now, or we do the study on clinical conditions later...like an influenza pandemic, it is inevitable given a mastery of chemical manipulation combined with an utter disregard for the consequences.

Hi,

1)In the pet food recall, the FDA redacted an ingredient they were testing for- they didn't want to disclose it. The 5th ingredient. If they found it, would they tell us? If they found it would it be a "silent recall"?

2)Does anybody know of a lab that could do testing on the pet foods for adulterations that isn't receiving funds (like UC Davis & AVMA) from the pet food industry?

3)Does anybody know a toxicologist that is able & willing to take a look at food samples where acetaminophen was found by one lab(in unrecalled products)? The FDA and ASPCA calls it unfounded. However, we know they did not even test the same lot that *did* test positive for acetaminophen. One lab, who doesn't even test for acetaminophen, but does test for pet food companies called it a hoax. UC Davis said there wasn't any in it *before* they even received the sample for testing...sigh. We're also being told that it is impossible to test for trace amounts of acetaminophen- True/not true?

Thanks for any help you all can provide.

I hope this topic doesn't get forgotten.

The recent DVM:
DVMs seeing fewer cases; online survey, long-range government probe continue
James M Lewis. DVM. Cleveland: Jun 2007. Vol.38, Iss. 6; pg. 24, 2 pgs

"But Dr. Barbara E. Powers, professor of surgical pathology at the University of Colorado College of Veterinary Medicine's Department of Microbiology, Immunology and Pathology, tells DVM Newsmagazine that, while renal blockage may play a part, "it's more than that. There's something more going on. Otherwise there wouldn't be so much necrosis (cell death) and inflammation.""

"We've [AAVLD] had an excellent (survey) response so far," Powers says, but she urges practitioners "to make sure you have very good evidence before submitting a case. We're not just looking for cases of renal failure. That can come from many causes. We need more specific evidence."

Ann: If there is something new I'll post on it. The quote you give from Powers is old, made at the time of the above posts, so doesn't represent a new view.

Thanks Revere. I've got a sick cat and anything to help figure out what to do that would hopefully solve it would be great. She got ill Jan 17th. Yes, the foods were eventually recalled. Yes, I've been to the vet monthly, muliple times in a month. 2 Vets and 2 more consultants. My least favorite answer "Gosh. I have no idea what is wrong with your poor kitty" So, it's trial & error. Her bloodwork is better, but her MCHC has dropped from 36.1 to 29. She's 1yr 4mths old now. Prednisone is the last thing being tried and it seems to have helped a little.

There are some survivors from this and it's pretty rough going for us.

I didn't know that June article was old, sorry.

Back to the comments made by Ron and Revere, on fluoride and fluoridation. Revere I agree completely that possible benefits of putting fluoride in water are massively overstated by promotional agencies. But I dont agree the agenda is entirely driven by public health dentistry.
The definitive history of the water fluoridation project is Christopher Bryson's "The Fluoride Deception" (2004). Marvelously researched and documented it clearly shows that heavy industrial cartels with fluoride pollution problems provided all the money and the initiative for the original (and often bogus) fluoridation research. They used influence in high places to get the program accepted and finally supported by official dentistry and medicine.
Perhaps it is now maintained by a public health dental lobby at WHO, CDC and elsewhere, but these disciplines were coopted into it by a massive organized effort by PR experts employed by ALCOA and other industrial conglomerates in the early days. God knows if they still have such a finger in it now. Colgate of course still funds most of the dental schools that do fluoride research, and heaven help the funding of any researcher who dares publish anything detrimental to the fuzzy, friendly image created for fluoride over many decades.

Sanity check please?

http://scienceblogs.com/angrytoxicologist/2008/07/science_the_enemy_of_…

Is this guy saying exactly what he's saying?
I need an anger checkup from a toxicologist here.

http://www.google.com/hostednews/ap/article/ALeqM5j7SAbhJj3By_isZUoRAgT…

Crikey, Dave... You've done all the synopsis gruntwork for the rest of us -- ta, mate:*) I surmise you are referring to the FDA's director of food safety when you write, "Is this guy saying exactly what he's saying?" (see excerpt below)

Yes, Dave! I do believe Dr. Stephen Sundlof is attempting to indemnify the FDA by saying to the consumer, "Caveat emptor, quia ignorare non debuit quod jus alienum emit ("Let a purchaser beware, for he ought not to be ignorant of the nature of the property which he is buying from another party."). In other words, Mom and Dad have been informed these two catalyzing chemicals are in the marketplace, so -- without actually uttering it -- don't mix-blend different brands of baby formula containing melamine and cyanuric acid or you might poison and/or murder the children!

Re: ScienceBlogs.com -- "Science: the enemy of public health" Posted on: July 28, 2008, by angrytoxicologist

Reader posting excerpt by: Hank Roberts, November 30, 2008...

Let me read that [AP news excerpt] again:

"... melamine in the infant formula of one major U.S. manufacturer and cyanuric acid, a chemical relative, in the formula of a second major maker."
...
"... Sundlof, the FDA's director of food safety, said Friday the agency was confident in the 1 part per million level for either of the chemicals alone ...."

Do you feel the need of a "but" after this?

How about after reading about the interactions [eeeek-a-renal-failured-mouse]... maybe now?

Like, keep your infant on only ONE brand, don't change brands, and hope nothing else changes, because the two chemicals interact, and we know this from experience as well as lab work and theory?

Like, but why release this on the Saturday of a long holiday weekend?

Hank, I must apologize for calling you "Dave" -- at least I didn't call you "Dude":*)

More here, including some diagrams of how the three compounds (melamine, cyanuric acid, and chlorine) form crystals. Mentions elsewhere of complicated layered crystals.

http://bayblab.blogspot.com/2008/10/melamine-or-wtf-china.html

"... Cyanuric Acid Cyanuric acid is a chemical used to stabilize chlorine in outdoor pools and as a precursor to chlorine compounds used to disinfect water. It can also be found as a non-protein nitrogen source in animal feed and, similar to melamine, used to fake out protein assays. Cyanuric acid can be synthesized by hydrolysis of melamine and is also a known metabolite (in bacteria). Like melamine, cyanuric acid has low toxicity on its own - people swallow pool water all the time - but the two in combination can have serious effects.

Cyanuric acid and melamine readily form hydrogen bonds, making an insoluble crystal lattice. In fact, the analytical test for cyanuric acid is precipitation with melamine. When this reaction occurs in the body, can lead to kidney stones and renal damage...."

Hmmmm. Makes me wonder, what other common chemicals in the food system might interact with melamine?

Maybe this? I dunno .... just one of many.

Synthesis and Crystal Structure of a Complex of Melamine with Benzoic Acid

Xiu-Iian ZHANG
Department of Chemistry, Guangdong Institute of Education, Guangzhou 510310, P. R. China
Available online 13 November 2008.

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B82XH-4TX6FMX-…

Oh, shit.

It wasn't announced, it was pried out of them using FOIA:

http://www.sfgate.com/cgi-bin/blogs/sfmoms/detail?&entry_id=33110

"... Under the Freedom of Information Act, the Associated Press learned of the undisclosed tests, which showed that the FDA had detected melamine in a sample of one popular formula and the presence of cyanuric acid, a chemical relative of melamine, in the formula of a second manufacturer.

"The levels that we are detecting are extremely low," Stephen Sundlof, director of the FDA's Center for Food Safety and Applied Nutrition, told the Associated Press, adding that parents should not stop giving their tots formula (though they may want to check with their pediatricians).
--------

And dammit, I guessed right about the interaction, I think, when I wrote earlier that I thought this meant:
> Like, keep your infant on only ONE brand,
> don't change brands...because the two chemicals interact

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