The Haitian Diethylene Glycol Poisoning Tragedy: Title and subTitle BreakA Dark Wood Revisited

Dante Alighieri begins his masterwork poem,The Divine Comedy,¹ by recounting how he came to embark on his journey through the Inferno: "In the middle of the journey of our life I found myself in a dark wood, having lost the straight path." In this issue of JAMA, O'Brien and colleagues² take us to the dark wood of a public health disaster: the contamination of a medication, acetaminophen, with a toxic chemical, diethylene glycol (DEG), which occurred in Haiti in 1995 and 1996. Composed of 2 ethylene glycol residues joined by an ether bond, DEG has many industrial uses as a humectant, plasticizer, antifreeze, and solvent. In the confiscated medicines tested in Port-au-Prince, the median DEG concentration was 14.4%; a trace-back investigation revealed formulation of the syrups using glycerin of Chinese origin that was contaminated with 24% DEG. The somber results: at least 109 children sustained a variety of toxic effects including acute renal failure, which the case-control study results reported by O'Brien et al confirm as attributable to the DEG. Of 87 children who stayed in Haiti and were available to the researchers for follow-up, 85 died—a death toll of 98%. Of the 11 patients who were evacuated to the United States, only 8 survived.

Such a tragedy alone is heartrending, but within the context of the pharmaceutical history of previous DEG poisonings, it is even more unbearable. For unlike the redoubtable poet, who was required to traverse the rings of hell and the plateaus of purgatory only once, we seem to be returning to this dark wood again and again. As the authors point out, previous similar epidemics, involving the contamination of medicines by DEG, have been reported in Argentina, Bangladesh, Spain, Nigeria, and South Africa.^{3 - 8} The first reported DEG contamination occurred in the United States, as chronicled in JAMA more than 60 years ago, and involved the mistaken use of a 72% solution of DEG as the vehicle in which to dissolve sulfanilamide, manufactured by the Massengill Company.^{9 - 11} More than 105 deaths resulted.^{12 - 13} The sulfanilamide disaster prompted the US Congress to enact the 1938 Federal Food, Drug, and Cosmetic Act, legislation that thereafter closely regulated the formulation and safety of medicinal products.¹⁴

Surprisingly, although autopsies performed after the 1937 mass poisoning documented the destruction of renal and hepatic tissue,^{9 ,13 ,15} the toxicology and toxicokinetics of DEG in humans still remain a mystery. Only 1 study has reported blood DEG concentrations in humans, and the authors' conclusions about the implications of this finding were ambiguous.¹⁶ Animal studies have confirmed the toxic effects of DEG.^{9 ,11 ,13 ,17 - 18} Less clear are its toxicokinetics and how it causes cellular injury in humans. The ether bond apparently is not broken during the metabolism of DEG in humans; there is no production of glycolic acid, glycoaldehyde, glyoxalate, or calcium oxalate. In both rat and dog models, researchers have detected a single metabolite, 2-(hydroxy) ethoxyacetic acid (HEAA), which accounts for 10% to 30% of a loading dose, but the relationship of HEAA to the pathogenesis of DEG poisoning remains obscure.^{19 - 20} The toxic effects caused by both DEG and ethylene glycol involve the kidneys and brain, yet injuries caused by these chemicals are not identical. The analogy to other toxic glycols would dictate that an active hepatically produced metabolite of DEG is responsible for its toxic effects rather than the parent compound itself, although no information in humans is available as to what the putative toxin might be.

Likewise there is only speculation about what medical management besides hemodialysis and supportive care may improve the outcome in affected patients. While use of ethanol, the antidote for ethylene glycol, seems logical, in that it occupies the hepatic alcohol dehydrogenase enzyme and prevents metabolism of any glycol to its presumably more toxic metabolites, ethanol has never been studied as an antidote for DEG poisoning in humans. A newer antidote recently released for ethylene glycol poisoning, fomepizole (4-methylpyrazole [4-MP]), also effectively inhibits the hepatic enzyme and generally is less toxic than ethanol.²¹ In rat studies, pyrazole has been shown to be effective in blocking the formation of HEAA and lessening the lethality of a median lethal dose of DEG.²² Whether fomepizole might be an effective antidote in DEG poisoning remains unknown; it currently is not approved for use in children.

Preliminary reports of the Haitian tragedy have been published elsewhere.^{23 - 24} Further analysis of clinical data from the Haitian tragedy is necessary and is promised by O'Brien et al.² Any additional information about pathogenesis, diagnosis, or management of DEG poisoning that can be learned from this unfortunate episode will be a contribution welcomed by toxicologists, poison control center workers, and clinicians everywhere.

Of the 8 published outbreaks of poisoning involving DEG contamination (including the Haitian disaster), it is significant that in 4 epidemics the only victims were children. In a fifth, the sulfanilamide disaster of 1937, children accounted for 34 of the 105 reported deaths.^{12 - 13} Because of their smaller size and dose-related vulnerability to toxins, children often seem to be the sentinels in this cruel and unintended form of toxicosurveillance. Children are overrepresented as victims of incidents involving DEG-adulterated medication. Parents were only treating the minor fevers and illnesses that children commonly get with a known, "safe," over-the-counter medicine. It never occurred to them that such a routine act could be accompanied by a lethal outcome. This disaster portrays a betrayal of the basic trust between caregiver and care provider—a trust that is within the scope of the right to health care of every child and every citizen, a right that every manufacturer of pharmaceuticals and every government must strive to ensure and protect.

It is significant that the outbreak of DEG poisoning reported by O'Brien et al² occurred in an impoverished developing country. In the global accounting of richer developed vs poorer developing countries, inadequate regulation and surveillance of the safety of medications seem an extraordinarily regressive tax. The glycerin vehicle of the medicine seemed to be the "smoking gun" causing this epidemic, but the authors provide no information about the root cause. How or why did the glycerin get contaminated? Was the cause ignorance, negligence, cost savings, or some other error? Further investigation into the root cause of why this contamination occurred may reveal additional insights into prevention. The authors imply that such incidents will continue to occur until the resources are appropriated to stop them. We can ill afford this purgatory.

O'Brien et al suggest ways to end these calamities. Strict quality control measures in the formulation and dispensing of medications and the passage and enforcement of governmental regulations that ensure the safety of pharmaceuticals are mandatory. The new initiatives that the Haitian government will surely undertake to safeguard their most vulnerable populations against such a mishap in the future must be implemented everywhere; global action is necessary to prevent repeat occurrences. Improved surveillance and early detection of DEG in adulterated medications using inexpensive methods applicable in the field, as suggested by O'Brien et al,² may be additional strategies implemented in a successful global approach.

The Haitian epidemic replays all the past folly involved with DEG contamination. There are no new public health lessons from the Haitian tragedy. Rather we simply must be better students of the old lessons to avoid returning in the future to this particular dark and dangerous wood.