The Case of the Toxic Chemical Substitutions

What's the connection between China and milk, heparin, toys, pet food and cough syrup?

For those of us in the industrial problem-solving business, a sinister new problem is just beginning to come into focus. It has always been present as a remote possibility, but recently the number of incidences has increased rapidly. Welcome to the world of toxic chemical substitution. Lets call it TCS for short. TCS is the deliberate substitution of one chemical for another in a consumer product, with no regard for its toxicity to humans or animals.

Milk Products & Pet Foods

There have been many examples of TCS in the news recently. Milk ingredients from China have been identified as the source of melamine poisoning implicated in the illness of tens of thousands of Chinese infants and the deaths of four. So far melamine has been found in infant formula, a milk-based dessert, an instant coffee product, a cake and candies.

Another well known case involving melamine occurred with wheat germ. In this case many cats and dogs died after ingesting name brand pet foods which contained wheat germ from China. The toxic compound was found to be melamine, shown in the Figure below.

This chemical was added to fool a test for protein. In the food test world, a general test for nitrogen is used to determine the protein content of wheat products. You will notice in the picture that melamine contains lots of nitrogen, represented by the “N”s in the diagram. In fact, each melamine molecule contains 6 nitrogen atoms. It is about as many nitrogen atoms as you can pack into a small molecule. In this case, melamine would raise the apparent protein content of the product. This would allow the seller to sell product that was failing on the protein content. We're not sure. The key point here is that melamine is toxic. It was deliberately added to enhance the "value" of the wheat germ and milk ingredients.

Cough Syrup

In Panama, 94 people died after ingesting cough syrup containing 15% diethylene glycol, or DEG, a common component of anti-freeze. It is known to be toxic to humans.

How did it come to be in the syrup? As far as we know, someone in a factory in China, substituted diethylene glycol for what should have been there, glycerol (also known as glycerin). Why would someone do that? The reasons are partly explained by examining the structures shown in the Figure below.

As you can see from the diagram, these two chemicals are very similar. Both contain at least two "OH" groups, one on either end. Each bend in the line joining the “OH” groups represents a carbon atom. DEG contains 4 carbon atoms, while glycerol contains three. Chemically the molecules are both thick syrupy liquids. They are both sweet to the taste, and give the characteristic "legs" that wine drinkers value in a good glass of wine. In a thick sweet syrup like cough medicine, they would be virtually indistinguishable.

The over-riding feature of diethylene glycol, though, is that it is cheap compared to food grade glycerol. To illustrate, diethylene glycol can be purchased from a typical North American supplier for about $23/kilogram. The price for food grade glycerin is about $110/Kg, or nearly 5 times the price. Large bulk purchasers can probably get a better price, but the ratio of the two prices should be accurate. A large manufacturer could therefore cut their raw material costs by about 80% by substituting diethylene glycol for food grade glycerin.

Toys

In another well-publicized example, the date rape drug precursor, 1,4-butanediol, was found in a popular toy called "Aqua Dots", reportedly manufactured in China. These small beads can be assembled into myriad shapes, and then sprayed with water to set the glue. The chemical that is supposed to be present is 1,5-pentanediol; generally regarded as safe. As you can see from the chemical structures in the Figure below, these two chemicals are again very similar. Both contain "OH" groups on either end. This is the "Di-ol" feature, meaning that there are two OH groups per molecule. As before, each bend in the line joining the diols represents a carbon atom. The only difference between the two molecules is that one contains four carbons and the other contains five.

Why would such a subtle difference cause one to be toxic and the other not? The explanation is that the butanediol, can easily be converted into the "Date Rape" drug gamma-hydroxy butyric acid in the body. This molecule exerts its effect by fitting perfectly into a neuroreceptor in the brain. In large doses, it induces unconsciousness and death. The striking thing about the issue with 1,4-butanediol in the toys is the dose. Several children in the U.S. and Australia fell into coma after ingesting "Aqua Dots". The doses required to induce coma in adults would be in the range of 2-4 grams. A smaller dose would be required in children, perhaps 1 gram, but we are still talking a large dose here. This was clearly not simply a trace amount of 1,4-butanediol in impure 1,5-pentanediol. The suspect beads must have contained high levels of nearly pure 1,4-butanediol.

Again, someone made a chemical substitution here. Why? 1,4-Butanediol would be expected to have the same desired chemical properties as the pentanediol, but, again, it is cheaper. 1,4-Butanediol can be purchased from a local supplier for about $15/Kg, while the 1,5-pentanediol costs about $112/Kg. A large purchaser of these materials could reduce their raw material costs by more than 85% by substituting the butanediol for the pentanediol. The fact that the substitute is a deadly chemical, banned in Canada, was apparently of no concern to whoever made the decision.

Heparin

The most recent case at the time of writing is the contamination of heparin, (an injectable anticoagulant also used as a coating for medical devices) with oversulphated chondroitin sulphate (a chemically-modified version of the ingredient used in the treatment of osteoarthritis). They are both glycosaminoglycans, polymers containing variably sulphated saccharide chains, but according to USFDA data, the oversulphated chondroitin sulphate has been linked to serious adverse events and death (131 deaths between January 2007 and April 2008, with a sharp increase in the last 6 months!). Its conspicuous absence from the product label is cause for concern.

Normally chondroitin sulphate contains fewer sulphate groups than heparin. But in this case, the chondroitin that was used was chemically enhanced (see Figure above) to contain more sulphate groups and thus fool the regulatory tests and potency assays. It is worth noting that chondroitin sulphate is widely available and is relatively inexpensive.

Why?

In each of these four cases, someone made the decision to substitute one chemical for another. Their decision must have been based solely on price and chemical similarity. The potential harm to consumers was clearly of little concern.

It is almost inconceivable that these substitutions were accidental. There are simply too many examples with the same characteristics. Real, accidental substitution, such as might be caused by a factory worker grabbing the wrong container or connecting the wrong pipe or tank, would almost certainly lead to the introduction of chemically-unrelated toxins, at least every once in a while. Consider the odds of a worker adding the wrong chemical, by accident, that fulfils the same purpose as the intended chemical, and is coincidentally, way cheaper. It simply wouldn't happen that often.

Connection

What is the connection with China? These substitutions all occurred with products made in China. The response of the Chinese regulatory authorities has been, to say the least, predictable. The Chinese government has admitted the error in the case of the cough syrup that killed 90 or more people in South America but they balked at the USFDA restriction placed on Chinese toothpaste, which requires a diethylene glycol-free product. This occurred after the USFDA found 3-4% diethylene glycol in a range of Chinese toothpastes. The Chinese regulatory agency apparently claimed that diethylene glycol up to 16.5% is acceptable in toothpaste. The USFDA says not!

The Chinese dairy industry is blaming "the illegal acts of some irresponsible milk collection centers and raw milk dealers". The pet food guys admitted to adding the chemical to boost the apparent protein content. The question is, since they knew enough chemistry to find a nitrogen-laden molecule that would fool the test, how could they have not known about the toxic side effects?

Nobody is commenting on the source of 1,4-butanediol but it is a good bet that it was substituted because of the low cost. Again, is it possible that the chemist who knew enough to substitute one for the other didn't know the lethal nature of the chemical? Possible, but not likely. In North America you can't buy 1,4-butanediol without being alerted to the fact that it is a regulated substance. In Canada, purchasers must sign government-mandated forms before suppliers will ship it. In Asia, perhaps it is different, but I doubt that anyone in the chemical supply business wouldn't have heard the rumours concerning its relationship to the “Date Rape” drug, gamma-hydroxy butyrate (GHB).

In the case of the heparin contaminated with oversulphated chondroitin sulphate, it turns out that the drug company knew the manufacturing plant had never been inspected by the USFDA, but went to market with their heparin before auditing the facility. The USFDA is now looking into whether the contamination was deliberate or accidental, and has found many Good Manufacturing Practices (GMP) violations at the manufacturing facility. It is most likely either a contamination left over from production of another product or intentionally added to crude heparin in order to reduce costs while still passing regulatory tests.

Given these facts, it is clear that firms selling consumer products will have to become much more vigilant when it comes to verifying the safety of their products. Consumer products firms that rely on the testimonials of their suppliers do so at their peril. In North America, manufacturers, importers, chemists and government agencies will now need to be much more alert to the possibility that relatively innocuous products may contain dangerous chemical substitutes, chosen with cunning and little regard for human safety. Only a carefully thought out review of the possible contaminants in each product followed by in-depth testing and inspection will be sufficient to protect consumers if this trend continues. The USFDA has implemented a screening process requiring identity tests for all imported heparin. As for manufacturing audits, USFDA spokesperson claims it would cost $225 million per year to inspect every foreign pharmaceutical manufacturing facility.

How can ISI help?

Investigative Science Incorporated (ISI) is a team of chemists, biologists and analysts that has been helping industry solve complex technical problems since 1991. Toxic chemical substitution certainly qualifies as a complex problem, but it is not unsolvable. Using our unique combination of technical expertise, problem solving strategy and chemical analysis, our scientists can assist your firm to protect itself against the fallout from chemical substitutions in offshore products or raw materials.

Don't be caught with your pants down on this issue! Don't get stuck facing an expensive product recall. Don't assume that these are all random accidents that will be picked up by your QA system. Call ISI today. For more information on ISI's consulting services, check out our chemistry and biology and pharmaceutical consulting pages.