Identification and quantification of diethylene glycol in pharmaceuticals implicated in poisoning epidemics: an historical laboratory perspective.

Over the last several decades, mass poisonings of diethylene glycol (DEG), usually ingested as an unintended component of pharmaceutical preparations, have occurred. In order to promptly halt the rise in deaths due to ingestion of these pharmaceuticals, laboratory analysis has often been employed to identify and quantify the etiologic agent after the medications have been tentatively implicated. Over the past 15 years, the Centers for Disease Control and Prevention has been involved in identifying DEG in implicated pharmaceutical products during three poisoning epidemics that occurred in Nigeria (1990), Haiti (1995), and, most recently, in Panama (2006). In each case, the timeliness of the identification was paramount in reducing the mortality involved in these mass poisonings. Using state-of-the-art analytical technology, we were able to provide initial identification of DEG within 24 h of receiving samples for each epidemic, allowing a timely public health response. However, over the past 15 years, the analytical instrumentation available and the laboratory responses undertaken have changed. In addition, the type of information and the degree of confirmation of results requested during each epidemic varied based upon the number of individuals involved and the political tenor involved with the outbreak. We describe our historical approach to identifying and quantifying DEG during each of these outbreaks. Furthermore, the reoccurrence of outbreaks has prompted us to establish standard technology to use in potential future outbreaks to allow an even more timely response. This methodology includes the development of biomarkers of DEG exposure, which would be extremely useful in instances where pharmaceuticals are not clearly implicated.

The historic and current use of glycol ethers: a picture of change.

The use of glycol ethers has changed significantly over the past 30 years. Low molecular weight E-series have been phased-out and progressively replaced by low molecular weight P-series whenever possible. There is a trend to shift from E-series to P-series and an obvious willingness to substitute where alternative solutions exist or as a consequence of strengthening regulation and voluntary measures to reduce exposure in the workplace.

It's happening again--another diethylene glycol mass poisoning.

What lessons have we learned? Certainly, the similarities among these DEG poisoning tragedies are striking. Their raison d'êrre, especially in the last few poisoning epidemics, appears to be financially driven. DEG, an inexpensive solvent, is more profitable to use than the more expensive propylene glycol or glycerin. Despite the world wide proliferation of chemicals, pharmaceutical regulation is carried out at a national level. Certainly this sort of poisoning is bound to occur again unless much stricter pharmaceutical manufacturing oversight is employed and enforced throughout the world. Developing countries with fewer resources to implement such quality control monitoring will continue to be at higher risk for such poisoning epidemics. For now, we need to remain vigilant or such history will continue to repeat itself.

Elixirs, diluents, and the passage of the 1938 Federal Food, Drug and Cosmetic Act.

The Elixir Sulfanilamide disaster of 1937 was one of the most consequential mass poisonings of the 20th century. This tragedy occurred shortly after the introduction of sulfanilamide, the first sulfa antimicrobial drug, when diethylene glycol was used as the diluent in the formulation of a liquid preparation of sulfanilamide known as Elixir Sulfanilamide. One hundred five patients died from its therapeutic use. Under the existing drug regulations, premarketing toxicity testing was not required. In reaction to this calamity, the U.S. Congress passed the 1938 Federal Food, Drug and Cosmetic Act, which required proof of safety before the release of a new drug. The 1938 law changed the drug focus of the Food and Drug Administration from that of a policing agency primarily concerned with the confiscation of adulterated drugs to a regulatory agency increasingly involved with overseeing the evaluation of new drugs. The Elixir Sulfanilamide tragedy, its effect on drug regulations, and the history of other diethylene glycol and diluent mass poisonings are discussed.