Banned
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Near the beginning of 1930, physicians and the media began to report a strange illness that was attacking many people across the southern states. By spring the disease had become an epidemic. In Cincinnati, for example, more than four hundred people checked in to the Cincinnati General Hospital with muscular pain, weakness in both the upper and lower extremities, and rather minimal sensory findings. Since most, if not all, of the victims associated the disease with recent consumption of Jamaica ginger, they referred to it as “ginger jake paralysis” or “jake leg.” In February 1930, Ephraim Goldfain described a man who had progressive bilateral foot drop, thus becoming the first physician to recognize the disease. That same day, he saw another case and soon developed a list of sixty-five individuals.38 Over the course of the next few months, thousands of people suffered ginger jake paralysis. So prevalent was the disease across the southern states (especially Tennessee, Oklahoma, Kentucky, and Mississippi) that “jake leg” developed into a significant theme in blues music of the 1930s.39 Later there were smaller epidemics in Massachusetts and California.
Two researchers with the U.S. Public Health Service, Maurice Smith and Elias Elvolve, isolated the toxic compound as a phenolic compound (triorthocresyl phosphate—TOCP). Moreover, they were able to determine that the poisoned extract of ginger must have originated at a single source based on the fact that it was sold under at least eight different brands in Cincinnati, Ohio, and at least four brands in Johnson City, Tennessee. To reach this conclusion, they needed to develop a toxicological profile for the contaminated samples of ginger jake. Smith and Elvolve first ruled out poisoning by heavy metals (arsenic and lead), which, as we have seen, occurred frequently during the 1920s. The two researchers eventually obtained thirteen samples of the ginger extract. Five of those were almost definitely paralytic. A test for phenols indicated that every sample that contained phenols caused paralysis. To supplement the chemical analysis and correlation with paralytic samples, the researchers administered those samples that tested positive for phenols to rabbits, which exhibited a symptom complex that included muscular tremors, hyperexcitability, and spastic rigidity. General muscular weakness and flaccid paralysis of all the extremities followed. Treated rabbits died of respiratory failure. Smith and Elvolve conducted similar tests with monkeys and dogs only to find that they did not react like the rabbits. Further experiments with a solution that included the same elements yielded essentially the same results, but Smith and Elvolve could not explain the specific relation of the phenolic compound to the various neurological effects in ginger jake victims.
In the second report on ginger paralysis, Smith considered the pharmacological action of phenol esters. The comparison of TOCP with several other phenolic esters revealed the Jamaica ginger adulterant to be far more toxic than other similar compounds. The minimum lethal dose for TOCP in rabbits was 100 mg/kg, but as little as 50 mg/kg produced definite symptoms, which occasionally led to death. It was possible to replicate these results in two monkeys by administering the TOCP subcutaneously rather than orally. Pharmacological testing procedures had not been standardized by 1930, so Smith also tested TOCP on calves and chickens, with similar results to those produced in rabbits and monkeys.
Oddly, unlike other phenols or cresyls, the systemic action of TOCP developed slowly. The initial effects of a lethal dose appeared to be limited to the effects of the alcohol in which it was administered. The characteristic group of symptoms developed after an interval of one to several days. The symptoms of TOCP poisoning combined the manifestations of mild strychnine poisoning with some aspects of phenol poisoning. After reproducing symptoms in four experimental species, Smith concluded that TOCP was “capable of producing specific paralysis of the motor nerves of the extremities in certain species of animals and under certain conditions more or less exactly the same as occurred in thousands of human victims traceable to an adulterated fluid extract of ginger.”40 The fact that the pharmacological action of TOCP did not follow any known rule or law inspired Smith to call for further investigations into the pharmacological actions of chemicals.
By summer 1930 estimates of the number of ginger jake paralysis victims had reached as high as twenty thousand. Subsequent estimates significantly increased the number to more than fifty thousand victims.41 However, since many of the victims were impoverished minorities, researchers suspected underreporting. Despite the extent of illness, the response of the FDA and other federal offices verged on nonexistent. During congressional hearings, a senator criticized the FDA’s administrator for the lack of response to ginger paralysis:
SENATOR WHEELER: There was only one thing you could do under the law and should do, and that was to seize that product.
MR. CAMPBELL: And we did, promptly.
SENATOR WHEELER: You did, promptly—two or three months afterwards.42
Kallet and Schlink, in 100,000,000 Guinea Pigs, cited the case as a prime example of the failing of the 1906 law: by 1932, only three companies had been fined, but only $50 in two cases and $150 in the third. Later, Gross delayed federal prosecution by promising to cooperate and implicate the “real poisoners.” Before a trial could proceed, Gross (and his associates) pled guilty in front of a Boston judge, who released him on two years’ probation and with a fine of $1,000.
The ginger paralysis epidemic raised a number of questions regarding food and drug legislation, the responsibility of producers, and the role of toxicology. First, the practice of adulterating products with substances to deliberately change the taste or appearance appears to have received at least tacit sanction. If a manufacturer could replace a harmless substance with one of unknown toxicity, consumers were at considerable risk of exposure. In his search for a solvent to replace castor oil, Gross considered ethylene glycol, diethylene glycol, and TOCP. None of these compounds had clear toxicological profiles. In developing the pharmacology of TOCP, the Public Health Service (PHS) scientists first ruled out arsenic and lead, presumably because these were two of the most prevalent poisons that consumers encountered. Tests of samples of ginger jake on rabbits revealed effects similar to those human victims suffered, but monkeys seemed unaffected. Further tests of phenol and several cresols focused on the minimum lethal dose. Compared to similar compounds, TOCP exhibited a much greater toxicity (100 mg/kg and even 50 mg/kg resulted in symptoms and sometimes death). By administering doses to monkeys subcutaneously, researchers produced symptoms comparable to those experienced by humans and rabbits, but the fact that simian system cleared oral doses without toxicity underscored the importance of multiple test species. Chickens and calves also exhibited symptoms. Nevertheless, a clear toxicological profile for TOCP did not facilitate prosecution of litigation against the manufacturers or distributors, who claimed ignorance. Nor did it follow from the ginger paralysis epidemic that manufacturers should be required by federal statute to conduct toxicity tests on compounds before releasing them for public consumption. The fines levied against the companies that poisoned fifty thousand victims struck contemporaries as trivial. Rather than look to the federal government for protection or consideration, jake leg victims turned to music, finding a measure of comfort in the blues.
The best-known instance of public exposure to a lethal compound was the Elixir Sulfanilamide tragedy. The therapeutic properties of sulfanilamide first came to light in 1932, when two German laboratory scientists developed a red dye by combining sulfanilamide to a naphthalene-containing chemical that they called Prontosil. For the next three years, physicians experimented with the new drug for possible applications in their clinics. The real breakthrough came in 1935 when researchers treated streptococci-infected mice with Prontosil with allegedly remarkable therapeutic results. Gerhardt Domagk, who was a researcher for I. G. Farbenindustrie, announced the discovery of Prontosil, but it was largely unheralded due to the limited details of dubiously perfect results. Although cultures of streptococci did not respond to Prontosil in vitro, scientists at the Pasteur Institute in Paris discovered that the
mouse systems broke the bond between the naphthalene and sulfanilamide, leaving sulfanilamide to destroy the streptococcus germs. In making this discovery, the Pasteur Institute clarified that it was sulfanilamide that produced therapeutic effects. Moreover, the French results undermined any hopes that I. G. Farbenindustrie may have held that Prontosil could be patented (sulfanilamide’s patent of 1909 had expired).43
Americans had also participated in early tests on sulfanilamide. The weak bond between naphthalene and sulfanilamide that characterized Prontosil had not met the standards of earlier researchers. During the 1920s, Rockefeller Institute scientists successfully produced a strong bond between sulfanilamide and quinine, but the bond was so strong that sulfanilamide was never released into the system and thus had no effect on disease. This apparent success was ultimately a significant failure, in that it delayed for nearly a decade research on the chemotherapeutic effects of sulfanilamide, until the German researchers utilized the naphthalene combination.44
The quest for new chemical therapies following the success of Paul Ehrlich’s Salvarsan inspired a campaign to discover new applications and solutions for sulfanilamide.45 By 1937 more than one hundred firms manufactured proprietary forms of the drug. When the public became aware that sulfanilamide might be a cure for gonorrhea, people began using the medication independently of a doctor’s orders, thereby raising the problem of self-dosing. Compounding this problem was the low cost of sulfanilamide on a daily basis. Whereas the most popular patented medicine for treatment of infections like streptococcus cost up to six dollars each day, the cost of sulfanilamide was only thirty cents daily.46
The search for chemicals to combine with sulfanilamide in order to create flexible drug-delivery systems led directly to the Elixir Sulfanilamide tragedy. One of the problems with sulfanilamide was the size of the tablets necessary to contain the correct dosage. Because children were most frequently infected by streptococcus, pharmaceutical companies sought a liquid form of the drug. After a few days of research in July 1937, Harold Cole Watkins, the chief chemist and pharmacist at the S. E. Massengill Company, appeared to have solved the problem by mixing sulfanilamide with diethylene glycol, which the Massengill Company had employed successfully in other drugs in extremely small amounts. Ultimately, Watkins determined that forty grains of sulfanilamide per ounce (91.4 g/kg) of diethylene glycol was the optimum proportion, and he prepared a mixture of eighty gallons (302.8 l) of water, sixty gallons (227.1 l) of diethylene glycol, and fifty-eight pounds (26.3 kg) of powdered sulfanilamide, as well as small amounts of the following flavor-enhancing substances: elixir flavor, saccharin, caramel, amaranth solution, and raspberry extract.
After calling the new drug Elixir Sulfanilamide, Watkins sent it to the Massengill laboratory, where it underwent examination for appearance, flavor, and fragrance. Notably, no one tested the new solution for toxicity.47 In Watkins’s view, Elixir Sulfanilamide was exempt from such testing since, he believed, “The glycols, related to glycerine, had been widely used by drug companies, and, Watkins averred, were well known not to be toxic.”48 With quality control completed, Massengill began commercial distribution of Elixir Sulfanilamide on September 4, 1937, a scant two months after Watkins had initiated experiments with diethylene glycol.
As the Massengill Company was distributing Elixir Sulfanilamide around the United States and Canada, the Journal of the American Medical Association published an editorial by Morris Fishbein, the journal’s editor. The editorial opened with a generous appraisal of sulfanilamide in general: “Seldom has any new drug introduced in medical practice aroused the enthusiasm that has developed for sulfanilamide. Much of this enthusiasm is warranted. The drug is truly remarkable, as indicated by startling results reported in the treatment of various infections.”49 Yet Fishbein expressed concern that chemical companies were studying similar and associated preparations in the search for therapeutic agents that they could market as new products superior to sulfanilamide. Fishbein warned the medical profession to proceed with caution regarding new preparations of sulfanilamide. His particular concern was that the therapeutic and toxic properties of new drugs could not be predicted from their chemical formulas: “Many months of investigations of the pharmacology, toxicology, and clinical application of new preparations under carefully controlled conditions are needed to provide evidence of clinical value.”50 There had already been reports of toxic reactions to the self-medication brought about by rumors that sulfanilamide could cure gonorrhea in forty-eight hours. (Fishbein placed considerable blame for such incidents on unscrupulous pharmacists who willingly sold drugs to anyone over the counter.) In a statement that proved to be tragically prophetic, Fishbein concluded, “Sulfanilamide should not be administered in association with other drugs until definite information is available as to toxic effects.”51
Given the early concern of the American Medical Association (AMA) with the risks of sulfanilamide, it was appropriate that the AMA was one of the first official bodies to learn of the Elixir Sulfanilamide crisis. Two doctors from the Springer Clinic in Tulsa, Oklahoma, sent a telegram detailing clinical and pathologic effects of poisonings in Tulsa to the AMA on October 15. Even allowing for the constraints of communication by telegram and the restrictions of medical reports, the following excerpt seemed particularly stark:
Total of ten cases. Eight dead. One recovered. One critical. Ages from eleven months to twenty-six years. All received Elixir Sulfanilamide in amounts varying from one-half to seven ounces. Characteristic onset with nausea, vomiting, occasional diarrhea, malaise, later pain over kidney region and abdomen. All developed anuria within two to five days after beginning medication. Indications for the use of sulfanilamide were varied. Nine cases hospitalized.52
It was in fact this report and the cluster of cases it represents that prompted action by the AMA and the FDA.
On October 16, 1937, a representative of the Kansas City Station of the FDA who had been dispatched to Tulsa, Oklahoma, confirmed the doctors’ report by telegram to the FDA headquarters, reporting the deaths of nine individuals attributable to a preparation of sulfanilamide. Of these nine, eight of the victims had been children with streptococcic sore throat and one an adult with gonorrhea. All had taken Elixir Sulfanilamide. The FDA immediately sent inspectors to the Massengill Company headquarters in Bristol, Tennessee, and to distribution centers in Kansas City, New York, and San Francisco. Upon receiving news of the deaths, the Massengill Company issued more than a thousand telegrams recalling all outstanding shipments. These messages warned consumers, salesmen, druggists, and doctors not to use Elixir Sulfanilamide and to return all stocks for credit at the manufacturer’s expense.53 While the telegrams conveyed Massengill’s desire to collect all outstanding quantities of Elixir Sulfanilamide, they gave no indication of the dangerous character of the product or the emergency that necessitated the recall of the drug. On October 19 the FDA inspector on location in Bristol issued another telegram to all persons known to have received shipments of the drug from Bristol: “Imperative you take up immediately all elixir sulfanilamide you dispensed. Product may be dangerous to life. Return our expense.”54 On the insistence of FDA field agents, similar telegrams were sent from the Massengill branches in Kansas City, San Francisco, and New York, also on October 19 or shortly thereafter.
Despite the return of numerous shipments to the four distribution centers, the FDA faced the considerable task of confiscating all outstanding supplies of Elixir Sulfanilamide. To accomplish this, the FDA diverted most of its field force of inspectors and chemists to review the thousands of order slips in each of the four distribution centers as well as in wholesale and retail drug stores. Complicating matters was the fact that many of the sales of Elixir Sufanilamide were over-the-counter (not by prescription) to unknown individuals. In the most problematic cases, doctors had either no names or fictitious names for individuals who received the drug. Massengill salesmen also proved hard to locate, and at least one went to jail rather than cooperate wi
th the FDA officials. Most doctors and pharmacists contributed willingly to the confiscation campaign, but a few refused to cooperate and even denied the adverse effects of the drug. One South Carolina doctor admitted to inspectors that he had dispensed just under two pints of the elixir to three white patients and two black patients, none of whom died. Further investigation revealed that in fact the doctor administered the elixir to seven patients, of whom four had died: one white man, one white girl, and two black men. The inspector tracked the cause of death to the gravestone of one of the black victims, where a grieving relative had left a small bottle of Elixir Sulfanilamide with the prescription label of the doctor’s office still intact.55
Notwithstanding the considerable effort of the FDA, as well as state and local food, drug, and health authorities, Elixir Sulfanilamide caused numerous deaths. The tragedy progressed rapidly throughout the Southeast with deaths reported in Mississippi, Alabama, Georgia, South Carolina, and Texas. On November 1, the AMA Chemical Laboratory calculated the total number to be sixty-one. Later that month, the New York Times reported that ninety-three individuals had died from Elixir Sulfanilamide, but the official toll stood at seventy-three as a direct result of the elixir and twenty more deaths associated with the drug, according to the report of the secretary of agriculture regarding the sulfanilamide tragedy. Deaths occurred in fifteen states from Ohio to Texas. Most of the deaths were in southeastern states, perhaps due to the proximity of the Massengill headquarters in Bristol, Tennessee. The AMA Chemical Laboratory mapped the epidemiology of the tragedy.56 Nevertheless, by seizing 228 gallons (863.0 l) of the 240 gallons (908.5 l) manufactured and more than half of the 11 gallons dispensed in prescriptions or over-the-counter sales the FDA surely avoided a much greater disaster.57
While the FDA was containing and controlling the immediate crisis, the AMA began a detailed analysis of the chemistry, pharmacology, pathology, and necropsy of Elixir Sulfanilamide. Three scientists at the University of Chicago performed the chemical examination. Their analysis revealed Elixir Sulfanilamide to be a reddish, somewhat viscous liquid with an aromatic odor resembling raspberry and anise and a sweet taste. The drug resembled glycerin in general physical character. Further analysis yielded the proportions of the major ingredients of the drug: