Results tagged “diethylene glycol” from Pathophilia

Fifty-four of 57 Nigerian children died between October 2008 and January 2009 after receiving a liquid acetaminophen preparation that was tainted with diethylene glycol (DEG). Exposure to the branded teething product, My Pikin,* was determined in 96% of the identified cases of unexplained acute renal failure (ARF) in the 57 children, according to a retrospective surveillance study performed by Nigerian officials, the CDC, and the US FDA. Their report is available in the latest issue of the MMWR.

The surveillance study was prompted by clusters of unexplained ARF cases in very young children (≤3 years of age) among hospitals in Lagos, Kadun, and Osun in the fall of last year. Initial reports led to the identification of the DEG-tainted product, a full product recall, and the shutting down of the responsible manufacturer in Lagos, Barewa Pharmaceuticals. Despite a nationwide recall and a press release in November of last year, which resulted in the confiscation of 7616 of 15,000 bottles of the contaminated drug, more than a quarter of the affected children received the product after the recall was announced.

Among children for whom data were available, the median time from drug exposure to ARF was 5.6 days (range, 0-24 days), and the mean time between the onset of ARF and death was 6.8 days (range, 1-19 days). Treatments with dialysis, received by 24 children, and the ethylene-glycol antidote fomepizole, received by 2 children, did not appear to prolong survival.

The MMWR editors report at least 12 episodes of DEG contamination in oral or topical medications during the last 70 years, which have caused at least 450 deaths. (Most of these episodes are described here and here.) The contamination was almost always due to the intentional economic-driven substitution of DEG for the more expensive solvents of glycerin or propylene glycol. (An account of the US deaths that occurred in 1937 due to a DEG-tainted antibiotic solution has been provided in numerous serial posts at this blog [search for "sulfanilamide" or "Massengill," for example], and the deceased are listed on this page.)

Prevention of DEG-contaminated drugs is easy and cheap, according to the editors. "Simple, rapid, and low-cost assays" that use thin-layer chromatography are available to detect and measure DEG at levels of 2% in liquid acetaminophen products and 6% in glycerin, they report.

* DEG accounted for 17%-21% of the My Pikin liquid medication by weight in sampled bottles. According to the MMWR, another contaminated acetaminophen-based syrup, made by a different manufacturer, was discovered to contain 0.5% DEG.

Photo of My Pikin Baby Teething Formula from Vanguard.

Since 1937, there have been at least 8 episodes of fatal mass poisoning caused by the oral ingestion of diethylene glycol-tainted drug products; although none has occurred in the United States.

In the summer of 1969, 7 children (ages 6-31 months) died in the area of Cape Town, South Africa, after receiving one or both of 2 liquid sedatives (Pronap or Plaxim). The products were made by the same pharmaceutical firm, which had substituted diethylene glycol for propylene glycol (the latter being an FDA-approved solvent for drugs, cosmetics, and food). Attempted treatment included rehydration, correction of metabolic acidosis, peritoneal dialysis (in 2 cases), and life support.

In 1986, 14 inpatients in a Bombay (Mumbai) hospital died of acute renal failure after receiving in-house glycerin therapy. The glycerin—which contained 18.5% diethylene glycol, 51% polyethylene glycol, and 9% glycerin—was purchased by the hospital through intermediary brokers, who had bought the product on the cheap from an industrial producer in India. Treatment with sodium bicarbonate, various diuretics, and dialysis (in 12 cases) was unsuccessful.

Between June and September of 1990, 47 children died at a Nigerian teaching hospital after ingesting paracetamol syrup that was tainted with diethylene glycol. Treatment consisted of rehydration and correction of acidosis, but none underwent dialysis. All died within 2 weeks of admission. (In a related incident, 109 Nigerian children died the same year after consuming ethylene glycol-tainted cough syrup.)

Beginning in 1990, a significant rise in the incidence of unexplained renal failure in Bengalese children was believed to be due to the ingestion of various brands of paracetamol elixir that were tainted with diethylene glycol. At least 67, and as many as 272, children were affected. After the government banned the sale of paracetamol elixirs in December 1992, pediatric hospitalizations for unexplained renal failure dropped by 84%.

In 1992, 29 people in Argentina died of acute renal failure as a result of consuming diethylene glycol-tainted propolis syrup. A study of 15 adult victims revealed a "good correlation" between the amount of diethylene glycol ingested and the anion gap. Syrup samples contained 65% diethylene glycol (w/v), and victims took between 5 and 20 mL. Therefore, the lethal dose of diethylene glycol for adults was estimated at 0.014-0.170 mg/kg body weight.

An increase in the incidence of unexplained renal failure in Haiti led to the discovery of diethylene glycol-induced disease in 109 children (ages 1 month-13 years) from the fall of 1995 to July 1996. The ingestion of locally made acetaminophen syrups (Afebril and Valodon) was significantly associated with the condition. Analysis revealed that these formulations were made with diethylene glycol-contaminated glycerin, which had been imported from a Chinese manufacturer by way of Europe. The median concentration of diethylene glycol in the final products was 14.4% (range, 1.2%-19.6%). The median estimated dose of consumed diethylene glycol (n = 32) was 1.34 mL/kg (range, 0.22-4.42 mL/kg), but toxic doses were often less than 1 mL/kg. The death rate among the children who remained in Haiti was 98% (85 of 87*). Among the 11 children transported to the United States for treatment, 8 survived, and 7 recovered renal function.

In 1998, 36 Indian children developed acute renal failure after consuming a diethylene glycol-tainted cough syrup, which was produced by a company in Gurgaon; 33 of these children died despite undergoing peritoneal dialysis. How and when diethylene glycol entered the syrup was unknown at the time of the medical report.

In the fall of 2006, an investigation into cases of unexplained renal failure in Panama ultimately led to the discovery of more than 100 deaths due to the consumption of cough syrup made with Chinese-imported glycerin. The glycerin, which was sold to the Panamanian health service, was incorporated into 260,000 bottles of the medicine. In its investigation, the New York Times traced 46 barrels of imported glycerin stock, labeled as 99.5% pure but containing ~24% diethylene glycol, from a Panamanian port to the Taxing Glycerine Factory in the Yangtze Delta (by way of Barcelona). A Panamanian government report released last year concluded that at least 174 people were poisoned and 115 were killed (66% death rate) as a direct result of the contaminated syrup (Bogdanich W. Panama releases '06 report on poisoning. NYT, February 14, 2008).

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The toxicity of diethylene glycol is believed to be due to its metabolite, HEAA—which is produced by the enzymatic activity of ADH and ALDH. But how HEAA produces cellular dysfunction is unclear, according to Kraut et al. Like other alcohols, diethylene glycol is rapidly absorbed from the gut and has a low volume of distribution (0.5 L/kg). Animal studies indicate that 30%-50% of diethylene glycol is eliminated through the liver, and 50%-70% via the kidneys. Although toxic and lethal doses in humans have been estimated in some reports of mass poisoning, susceptibility to diethylene glycol appears to vary widely for reasons that remain unknown.

Animal studies also indicate that the administration of ADH and ALDH inhibitors (eg, fomepizole) may prevent the production of HEAA, and dialysis (with or without fomepizole) has been used successfully in patients with diethylene glycol poisoning. Dialysis is not only instituted for renal failure, but may remove diethylene glycol and its toxic metabolite.

ADH = alcohol dehydrogenase; ADLH = aldehyde dehydrogenase; HEAA = 2-hydroxyethoxyacetic acid.

* Follow-up was unavailable for 11 children.

Depicted chemical structure of diethylene glycol from Wikipedia.

The diethylene-glycol-containing "My Pikin Baby Teething Formula" has now killed 84 infants in Nigeria, according to Reuters. A report in November had placed the number of related deaths at 25. Many of those affected to date, 111 total (including the dead), are children between 2 months and 7 years of age.

A nationwide recall has recovered more than 400 bottles of the product, and the Nigerian government has shut down the responsible company, Barewa Pharmaceuticals, in Lagos. Reuters also indicates that "a number of people involved in distributing [the product] have been arrested."

The AP writes that DEG entered the product when a Barewa official attempted to purchase propylene glycol, a "normal" ingredient in teething formula, from an unregistered chemical dealer on the slum fringes of Lagos. Historically DEG has been a cheap (and very toxic) substitute for glycerin in consumer products. The active ingredient in My Pikin is reported as paracetamol, aka acetaminophen.

Death due to the consumption of DEG is almost universally due to renal shutdown. For a list of previous incidents of DEG-contaminated consumer products, go here, and read ongoing posts about the 1937 Elixir Sulfanilamide disaster in the United States at this blog.

Photo of My Pikin Baby Teething Formula from Vanguard.

In 1937, more than 100 US citizens—many children—died after consuming Elixir Sulfanilamide, a raspberry-flavored antibiotic syrup manufactured by the S. E. Massengill Pharmaceutical Company of Bristol, Tennessee. The difficult-to-dissolve antibiotic was mixed with diethylene glycol (DEG), a known toxin, by the company's uninformed head chemist, Harold Cole Watkins. Watkins reportedly tested the elixir only for its appearance and palatability before its nationwide distribution. The catastrophic event led to the passage of the 1938 Federal Food, Drug, and Cosmetic Act.

In a series of posts (and perhaps what may be a very lengthy series), the Pathophilia blog will attempt to provide a chronology of this US pharmaceutical disaster, drawing on primary sources when available. The effort is intended to be a kind of memorial to those who died as a result of the catastrophe and an homage to those who attempted to avert further disaster. However, the reader's indulgence is requested for what may frequently resemble a patchwork construction: Because the series is a work in progress, newly discovered and rediscovered information, as it emerges, may need to be incorporated into existing posts for clarity, accuracy, and completeness. For those individuals whose family, friends, or colleagues were directly affected by the event, your input and corrections are urged.

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In the fall of 1937, the first reports of deaths that were suspected to be related to the S. E. Massengill Company's "Elixir Sulfanilamide" came from Homer A. Ruprecht, MD, of the Springer Clinic of Tulsa, Oklahoma, and James Stephenson, MD, president of the Tulsa County Medical Society. Their correspondence, by telegraph and letter, to the American Medical Association indicates the historical importance of the national association and its journal editor, Morris Fishbein, MD, as primary sources of medical and pharmaceutical guidance for physicians in the country (in contradistinction to the Food and Drug Administration or any other government agency, at the time). Specifically the AMA had formed the Council on Pharmacy and Chemistry in 1905, an organization created to examine the composition of industry-submitted pharmaceutical products for sale in the United States.

On Saturday, October 9, 1937, the following telegram was sent from the Springer Clinic in Tulsa to Dr. Fishbein in Chicago.

ATTENTION IS CALLED TO AT LEAST SIX DEATHS IN TULSA FOLLOWING ADMINISTRATION OF ELIXIR OF SULFANILAMIDE SYMPTOMS OF ANURIA AND TOXIC DEGENERATION OF LIVER AND KIDNEYS

In Dr. Fishbein's absence, Paul Nicholas Leech, PhD, Secretary of the AMA's Council on Pharmacy and Chemistry responded:

YOUR TELEGRAM WILL BE BROUGHT TO DR FISHBEINS ATTENTION ON HIS RETURN THURSDAY STOP IN MEANTIME WOULD APPRECIATE RECEIVING FULL DETAILS CONCERNING DEATHS IF THIS OFFICE CAN AID YOU FURTHER PLEASE ADVISE

The following day, Sunday, Dr. Stephenson telegraphed the AMA with a brief description of the deaths and asked for information regarding the contents of the elixir:

ELIXIR SULFANILAMIDE MASSENGILL THERAPY MANY CASES COMPLETE ANURIA WITH UREMIA TULSA COUNTY MEDICAL SOCIETY MEETS SUNDAY NIGHT DESIRE ALL POSSIBLE INFORMATION AT ONCE WIRE OR PHONE ME MY EXPENSE

Leech responded, indicating that the Council had not examined any such elixir:

NO PRODUCT MASSENGILL COMPANY ACCEPTED BY COUNCIL ON PHARMACY AND CHEMISTRY STOP SULFANILAMIDE IN ELIXIRS NOT RECOMMENDED STOP PHYSICIANS WOULD DO WELL TO USE ONLY ACCEPTED BRANDS AND DOSAGE FORMS STOP SEE EDITORIAL IN JOURNAL OCTOBER SECOND COMMA TEN ARTICLES IN JOURNAL SEPTEMBER TWENTY FIFTH AND COUNCIL REPORTS IN JOURNAL MAY TWENTY NINTH AND JULY THIRTY FIRST

The October 2nd editorial, referred to by Leech (Sulfanilamide—a warning. J Am Med Assoc. 1937;109:1128), advised of the potential toxicities of the wildly popular antibiotic—namely, dermatitis, photosensitization, granulocytopenia, and sulfhemoglobinemia—and the indiscriminate use of the product and its unvetted derivatives. These warnings were initially provided in reports to the journal and published in its September 25th issue. The Council on Pharmacy and Chemistry also submitted its review of the antibiotic, related compounds, and proprietary US formulations in the May and July issues of the journal (Sulfanilamide. J Am Med Assoc. 1937;108:1888-1890; New and nonofficial remedies: sulfanilamide. J Am Med Assoc. 1937;109:358-359). 

In a letter to the AMA, dated Monday, October 11, Dr. Ruprecht of the Springer Clinic further described the affected Tulsa patients and their symptoms:

Received your telegram in response to our wire regarding elixir of sulfanilamide. The details are as follows:

We have a list of ten patients who have received an elixir of sulfanilamide, all of which, so far as we have been able to determine, has been manufactured by the S. E. Massengill Company. Of these ten patients, four are living, two of whom have definitely recovered, and the other two will probably die. Eight of these patients were children and the drug was given because of an upper respiratory infection. The other two patients were young men and the drug was used for a gonorrheal infection. One of the latter two patients had received tablets of sulfanilamide over a period of two weeks without any bad effects and then changed doctors and the second doctor put him on the elixir of sulfanilamide and the typical train of symptoms followed shortly afterwards.

The onset is usually with nausea, vomiting, malaise, sometimes diarrhea, and then complete anuria. The N.P.N. [nonprotein nitrogen] urea nitrogen and creatinine rise rapidly. A fixed acid acidosis develops and death follows. Autopsy shows a marked accumulation of fluid in all the serous cavities and intense hydropic degeneration of the kidney tubules and a marked periferal[sic] type of liver necrosis.

We have asked Getman Drug Company of Tulsa to forward a sample of the material for analysis. Would appreciate any information which you can give me at the earliest opportunity.

In a separate letter, Dr. Darwin B. Childs of Tulsa indicated that he was providing a bottle of elixir to the AMA:

Under separate cover I am sending you a sample in the originally dispensed bottle, of "Elixir of Sulfanilamide".

This medicine was purchased by my patient, from the Quaker Drug Store of this City, and was sold from a stock bottle manufactured by the S. E. Massengill Company of Bristol, Tenn.-Va.

At least six deaths have been reported in this city during the last ten days as a result of so-called streptococcic throat. Each and every one of these patients had various amounts of the above drug. All of them took medicine manufactured by S. E. Massengill and Company. These patients developed, after about three days, an acute nephritis, with total anuria.

My patient, a 20 year old adult, who had an acute gonorrhea, took a total of 220 grains, as represented by 55 teaspoonfuls of the elixir of sulfanilamide. Twenty-four hours after the ingestion of this amount, he began to have symptoms of an acute nephritis, and forty-eight hours later he was totally anuric. He died four days after receiving the last dose. The clinical picture and autopsy reports of this case closely resemble each of the other cases.

It is my opinion, and the opinion of the other physicians here who have had such cases, and that probably your chemistry department will be able to give us some light on this matter. We have asked Massengill's representative to discontinue the sale of this product until we have a report from you. 

On Monday, Leech telegraphed the Massengill company, requesting the composition of the elixir, and on the following day, October 12, the company wired its response—collect:

ACCEPT CONFIDENTIALLY ELIXIR SULFANILAMIDE CONTAINS SULFANILAMIDE FORTY GRAINS TO EACH FLUIDOUNCE DISSOLVED IN A MIXTURE OF TWENTY FIVE PERCENT WATER AND SEVENTY FIVE PERCENT DIETHYLENE GLYCOL WITH MINUTE QUANTITIES OF FLAVOR AND COLOR STOP WAS GIVEN CLINICAL TESTS AND WIDELY USED IN PRACTICE WITHOUT UNTOWARD RESULTS EXCEPT YESTERDAY SPRINGER CLINIC TULSA OKLAHOMA MADE COMPLAINT STOP WILL APPRECIATE ALL INFORMATION YOU MAY HAVE OR ACCUMULATE STOP
WIRE COLLECT BY WESTERNUNION

Leech then wired Dr. Ruprecht that day, warning him of the elixir's contents:

THANKS FOR YOUR LETTER OCTOBER ELEVENTH WOULD APPRECIATE FURTHER DETAILS WHEN AVAILABLE PARTICULARLY DOSAGE OF ELIXIR AND POSTMORTEN[sic] FINDINGS STOP PRODUCT CONTAINS MUCH DIETHYLENE GLYCOL AS SOLVENT THIS IS TOXIC AND REPORTED TO CAUSE NEPHROSIS POSSIBLY MAY BE OXIDIZED TO OXALIC ACID SEE JOURNAL PHARMACOLOGY AND EXPERIMENTAL THERAPEUTIC VOLUME FORTY TWO PAGE THREE FIVE FIVE COMMA NINETEEN THIRTY ONE STOP SUGGEST PATHOLOGISTS DETERMINE IF OXALATE POISONING IS INDICATED STOP WILL MAKE CHEMICAL EXAMINATION OF YOUR PRODUCT WHEN RECEIVED

Leech was referring Ruprecht to, "The pharmacology of ethylene glycol and some of its derivatives in relation to their chemical constitution and physical chemical properties" (J Pharmacol Exp Ther. 1931;42:355), in which investigators reported the minimum lethal dose of a 50% diethylene glycol solution in mice (5 mL/kg). Another study, published in early 1937, had also examined the lethality of diethylene glycol in animals: these investigators found that a 3% solution was rapidly fatal in rats (Haag HB, Ambrose AM. Studies on the physiological effect of diethylene glycol. J Pharmacol Exp Ther. 1937;59:93-100).

As would soon become apparent, the Massengill Company had manufactured 240 gallons of its DEG-loaded Elixir Sulfanilamide and had begun distributing the product nationwide on September 4, 1937.

Primary sources:
AMA correspondence. October 13, 1937. Food and Drug Administration Records. Record Group 88. National Archives; College Park, MD.
Wallace HA. Report of the Secretary of Agriculture on the deaths due to Elixir-Sulfanilamide-Massengill. November 16, 1937.

Picture of bottle of DEG-tainted Elixir Sulfanilamide from the FDA.

If history has taught us anything,* it's that rogue companies will substitute the renal toxin diethylene glycol (DEG) for the more-expensive glycerin in their products—regardless of the known, lethal consequences.

The latest incident involves a Nigerian drug manufacturer, which sold a DEG-contaminated teething formula ("My Pikin") that killed 25 infants and led to the hospitalization of 10 others, according to Reuters. Reports of possible contamination began 1 week ago, and the government has since shut down the responsible company, Barewa Pharmaceuticals, in Lagos.

A list of previous discoveries of DEG in consumer goods:

• Last year, Chinese-made toothpaste was found to be contaminated with low levels of DEG. The tubes, some of which were marketed for pediatric use, were found throughout Latin America, Canada, and the United States. Most of the contaminated toothpaste in the United States was imported through Long Beach, CA. Approximately 78,000 tubes were sold and distributed by at least one importer between December 2005 and May 2007 to prisons, luxury hotels, hospitals, and discount stores. In March of this year, a Los Angeles city attorney filed criminal charges against executives from 2 LA-based importers of the tainted toothpaste. However, it is believed that the low concentration of DEG in the toothpaste, which is unlikely to be consumed in significant quantities, did not result in reportable adverse events.
• In 2006, more than 100 Panamanians died after consuming cough syrup made with contaminated Chinese glycerin. The NYT traced 46 barrels of imported glycerin stock, labeled as 99.5% pure but containing ~24% DEG, from a Panamanian port to Spain to the Taxing Glycerine Factory in the Yangtze Delta.
• In 1998, 36 Indian children developed acute renal failure after consuming a DEG-tainted cough syrup (17.5%), which was produced by a company in Gurgaon; 33 of the children died.
• Between the fall of 1995 and July 1996, 109 children in Haiti experienced acute renal failure after consuming a locally made acetaminophen syrup that was tainted with DEG (14.4%); 91 children died.
• Beginning in 1990 and for several years thereafter, unexplained renal failure was identified in several hundred Bengalese children; 70% died in hospital. Renal failure was believed to be due to the ingestion of paracetamol elixir that was contaminated with DEG.
• In 1990, 47 children died in Nigeria (again) after ingesting paracetamol syrup that was contaminated with DEG.
• In 1986, 14 hospital inpatients died in India after being given glycerol that was contaminated with DEG (18.5%).
• In 1937, more than 100 US citizens—many children—died after consuming Elixir Sulfanilamide, a raspberry-flavored antibiotic syrup manufactured by the S. E. Massengill Pharmaceutical Company of Bristol, TN. The difficult-to-dissolve antibiotic was mixed with DEG by the company's head chemist, Harold Cole Watkins, who reportedly tested the elixir only for its appearance and palatability. The catastrophic event led to the passage of the 1938 Federal Food, Drug, and Cosmetic Act.

While frequently, but mistakenly, described as a component of engine coolants, DEG is chemically related to a common antifreeze ingredient, ethylene glycol. DEG is a cheap substitute for glycerin in the manufacture of consumer products.

HT: Pharmalot

* Other than, "you can kill anybody," according to Michael Corleone in The Godfather: Part II.

Picture of bottle of DEG-tainted Elixir Sulfanilamide from the FDA.

By way of the WSJ Law Blog from the NYT: A Los Angeles city attorney filed criminal charges yesterday against executives from 2 LA-based importers of Chinese-made toothpaste that was tainted with diethylene glycol. According to the NYT report, most of the toothpaste was brought into the United States through Long Beach, CA, and ~78,000 tubes were sold and distributed by at least one importer between December 2005 and May 2007 to prisons, luxury hotels, hospitals, and discount stores. The importers' predictable response: We didn't know the toothpaste was contaminated.

On January 16, 2008, NBC aired episode 397 ("Bottomless") of "Law and Order," in which a murder investigation leads to the discovery of diethylene-glycol-tainted Chinese-made toothpaste sold by a Wal-Mart-like corporation. The discovery led to criminal charges in the show.