US Deaths From Elixir Sulfanilamide: The Beginning—Tulsa

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.