Banned

by Frederick Rowe Davis

  Given their academic and professional experience, Massengill and Watkins should have been qualified to appreciate the inherent risks associated with their enterprise. Yet FDA investigators found Watkins to be particularly unconcerned about the hazardous effects of his products: “What impressed [Theodore G.] Klumpp and [William T.] Ford most about Watkins was what they deemed a certain callousness in his conversation. He spoke of a preparation of colloidal sulfur he had devised. When marketed, this compound resulted in the death of a number of people. ‘Mr. Watkins told about this event,’ Klumpp wrote, ‘as if it were an ordinary incident in the business of making and marketing pharmaceuticals.’ ”82 Indeed, Watkins seemed to doubt the possibility of toxic effects altogether. In his interviews with FDA officials, he claimed that when he first heard reports the Elixir Sulfanilamide had been linked to numerous deaths, he had personally taken a huge oral dose of diethylene glycol without ill effects. FDA officials doubted this story and dismissed its claim as a “futile heroic gesture,” which could not make up for Watkins’s failure to test the drug properly before its distribution.83

  Although generally regarded as inadequate, the PFDA was the only relevant legislation available to FDA in bringing charges against the S. E. Massengill Company in the Elixir Sulfanilamide case. As owner of the company, S. E. Massengill was particularly susceptible to the sanctions of this act because the two earlier prosecution charges exposed the company to more severe penalties as a second offender. For his part, Massengill continued to proclaim his innocence, arguing that Elixir Sulfanilamide had helped more people than it had harmed. The company did fire Watkins, and it admitted a level of moral responsibility when it settled numerous suits brought by the families of those who had died as a result of the elixir.84 Nevertheless, the FDA mounted a strong case against the company, confirming that diethylene glycol was the agent of toxicity in the elixir and assembling a team of experts to testify to the toxicity of the drug. These included Perrin H. Long of Johns Hopkins, who later wrote a monograph on the clinical and experimental use of sulfanilamide, as well as Geiling and Cannon of the University of Chicago. In addition, FDA scientists prepared testimony and exhibits for the trial. On the first day of the scheduled trial (October 3, 1938), Massengill appeared and revised his plea to guilty, and he received a fine of $150 on each of 174 counts amounting to a total of $26,100, the largest fine ever levied under the provisions of the 1906 act. Adding to the tragedy, Harold Watkins avoided further condemnation by committing suicide before the trial. Nevertheless, it was the calamity of Elixir Sulfanilamide that finally motivated Congress to pass new legislation regarding food and drugs.

  As the supervising agent, Henry A. Wallace, the secretary of agriculture, completed an extensive review and analysis of the deaths attributed to Elixir Sulfanilamide. The report responded to two resolutions in the United States Congress: House Resolution 352 of November 18, 1937, and Senate Resolution 194 of November 18, 1937. These resolutions mandated an investigation into the Elixir Sulfanilamide debacle and its implications for food and drug legislation. After thoroughly reviewing the case, Wallace developed four broad recommendations for legislation. First, he recommended the licensed control of new drugs to insure that they would not be generally distributed until experimental and clinical tests showed them to be safe for use. As a corollary to this recommendation, the secretary defined exactly what constituted a “new drug.” In order to justify drug licensure, he noted the importance of safety: “In the interest of safety, society has required that physicians be licensed to practice the healing art. Pharmacists are licensed to compound and dispense drugs. Electricians, plumbers and steam engineers pursue their respective trades under license. But there is no such control to prevent incompetent drug manufacturers from marketing any kind of lethal potion.”85 Another provision of the recommendations called for the prohibition of drugs that were dangerous to health when administered in accordance with the manufacturer’s directions. As self-evident as this stipulation seems, recall that the only grounds on which to prosecute S. E. Massengill Company was the minor issue that the drug was not technically an elixir as it had not been combined with alcohol. The secretary also stipulated that drug labels bear appropriate directions for use and warnings against probable misuse. Finally, he called for the prohibition of secret remedies by requiring that labels disclose fully the composition of drugs. The new language would broaden the legislative authority of the FDA, enabling the prosecution of manufacturers of dangerous drugs then on the market. Under the Pure Food and Drug Act of 1906, the FDA could not bring even the most trivial of charges against many of the dangerous drugs. In a recent analysis of the role of the tragedy in food and drug legislation, the government scholar Daniel Carpenter indicated the significance of the efforts of Wallace and FDA Chief Campbell, “Yet it is no understatement to say that Campbell and Wallace’s document forms the originary basis of modern pharmaceutical regulation the United States and much of the industrialized world.”86

  As a result of the Elixir Sulfanilamide disaster, pharmacologists developed new standards for the approval of drugs for public use. Of the many scientists who analyzed the toxicity of Elixir Sulfanilamide, one of the most outspoken was E. M. K. Geiling. It was Geiling’s conviction that drugs needed to undergo a thorough toxicological examination before release. Based on his work with Elixir Sulfanilamide, Geiling developed a nine-part analysis utilizing animal experiments for new drugs. Geiling’s proposed method required knowledge of the exact composition (qualitative and quantitative) or the detailed method of preparation of the product. Repeatedly, scientists and legislators cited lack of knowledge of the contents of Elixir Sulfanilamide and its potential effects as a serious flaw in the PFDA. The new drug analysis demanded acute and chronic toxicity studies of animals of different species at varying dosage levels given that studies of a single species at constant dosage levels could be misleading. During the course of chronic toxicity studies, Geiling encouraged careful and frequent observations of the animals in order to establish a composite picture of the clinical course of the drug. Geiling noted that the data on many drugs were very deficient in this respect.

  Drug analysis also called for careful pathologic examination of the tissues with appropriate stains. Animal experiments would also facilitate the study of the effects of experimental lesions of various important excretory or detoxifying organs, particularly the kidneys and liver, on the action of the drug. Related to this requirement is the determination of the rate of absorption and elimination of the drug, its path and manner of excretion, and the concentration levels in the blood and tissues at varying times after administration. Another strategy that Geiling recommended was the analysis of potential interactions between the drug and foods or other drugs (as an example, Geiling offered the contraindication of sulfanilamide and magnesium sulfide). Finally, Geiling called for careful examination for idiosyncrasies or untoward reactions of new drugs.87

  With this method of analysis, Geiling defined the toxicological assessment of drugs, but he acknowledged that his expectations probably exceeded the dedication of pharmaceutical chemists: “It is recognized that some will consider these safeguards to be too rigid and that they may simply be considered an ideal. It can correctly be charged, in fact, that some of the pharmacopeia drugs have not been studied along such lines.”88 Geiling intended, however, to elevate the standards of drug approval to new levels and thereby avoid other disasters: “Admitting this, it is nevertheless regrettably true that many human lives have been sacrificed by the failure to meet the standards of these preliminary tests and that many more lives will be sacrificed if such standards are not put into effect. Any essential compromise with these requirements will inevitably exact a toll of deaths or injuries among the public. The life and safety of the individual should not be subordinated to the competitive system of drug exploitation.”89 Geiling believed that such standards would protect the public from untested drugs with unknown effects. Finally, Geiling hoped that new standard
s would direct drug manufacturers toward the development of new and genuinely valuable agents in the treatment of disease in place of spending enormous sums on advertisements.90

  Industry representatives contradicted Geiling’s notion of the role of advertising in drug manufacture and public health. A former president of the National Association of Insecticide and Disinfectant Manufacturers, Lee H. Bristol (vice president of the Bristol-Meyers Company) claimed that manufacturers of proprietary drug products favored drastic control over untried potentially dangerous drugs. He also noted that the sulfanilamide elixir was not a consumer-proprietary product intended for self-medication, but one prescribed by physicians. The responsibility for the calamity rested with the drug manufacturer who used an inadequately tested and dangerous solvent for a potent drug and the physician who prescribed or used the elixir without being familiar with its therapeutic effects. The New York Times reported an interesting inversion of Geiling’s statements cited above: Bristol argued that “advertising was the greatest safety measure ever devised for the protection of the consumer” and pointed out that Elixir Sulfanilamide was an unadvertised product belonging to a group of so-called ethical specialties.91 Bristol went on to concede that government should have control over such potent drugs as sulfanilamide elixir and said that no reputable manufacturer of packaged medicine stands in the way or opposes legislation to protect the public from such calamities. He added the following qualification to his statements, however, “Experienced and responsible manufacturers of carefully compounded products should not be penalized simply because their products are advertised to the public.”92

  Bristol’s comments were particularly significant in light of his association with the National Association of Insecticide and Disinfectant Manufacturers for his statements applied equally well to insecticides and drugs. The difference between Geiling’s perspective and Bristol’s was one of emphasis. Whereas Geiling believed that advertising drugs necessarily detracted from meticulous evaluation of the toxicology and pharmacology of new drugs, Bristol argued that advertising served to inform consumers as to the qualities of new pharmaceutical agents. Neither position was wholly sustainable independent of a deeper understanding of how pharmaceutical companies conducted their research, development, production, and advertising. Geiling and Bristol both clearly recognized that the Elixir Sulfanilamide case revealed an urgent need for change in food and drug law but differed as to the precise form of such legislation.

  Other calls for new legislation were more explicit. In an editorial for Hygeia, a family health journal, Fishbein argued that the PFDA of 1906 was passed at a time when modern advertising was in its infancy and that more food and drugs were sold in 1937 by advertising than by claims made in other ways. More troubling was Hygeia’s contention that present food and drugs law provided no potent weapon against false and fraudulent advertising of foods, drugs, devices, or cosmetics. At its core, the 1906 Act did not provide for standards of purity, potency, wholesomeness, or labeling of foods and drugs. Geiling added toxicity standards to this list. Hygeia also decried the many loopholes contained in existing legislation.93 More than any other incident, the Elixir Sulfanilamide disaster crystallized ideas regarding food and drug legislation.

  To this point in the story, we have seen how several health tragedies, particularly the Elixir Sulfanilamide disaster, transformed toxicology. Moreover, we have seen how researchers at universities, government agencies, and industry refined the toxicological approach. But how did such developments influence food and drug law? The journalist Philip J. Hilts argued that there were two basic requirements for novel legislation: “A bill must already be present in Congress, and legislators and significant elements of the public must already be educated and paying attention when the crisis hits.”94 He added the corollary that the crisis must also involve children. When the Elixir Sulfanilamide disaster first appeared in newspapers, and 100,000,000 Guinea Pigs reached bookstores and libraries, Congress was reviewing the Pure Food and Drug Act of 1906, which regulators and the public regarded as inadequate protection for consumers. Republican control of Congress during the 1920s was not conducive to legislative reform, but the arrival of Franklin Delano Roosevelt and the New Deal promised change. As we have seen, when the story of the Elixir Sulfanilamide tragedy broke in 1937, a compromise bill combining elements of the Tugwell bill and the Copeland bill had passed the Senate but remained stalled in a House committee.

  It was the sulfanilamide tragedy that prompted sharp demands for more effective legislation from Campbell, Wallace, and Fishbein of the AMA. Reinforcing these demands were those of the media and the public. Congress reopened its consideration of revising the PFDA. Although drug licensing authority and continuous inspection of drug manufacturing did not become part of the new law as the FDA had hoped, Congress did include a “new drugs” provision: Section 505. This provision clearly defined a new drug and forbade the sale of new drugs in interstate commerce before their manufacturers had demonstrated to the FDA that they were safe. In their application to the FDA, manufacturers had to include samples of the drug, a description of the methods of manufacture, and full reports of investigations made to determine whether or not the drug was safe for use. In the absence of protest by the FDA within a specified amount of time, the drug could be released for interstate sale. Alternatively, the FDA reserved the right to refuse an application, effectively barring a drug from interstate commerce pending appeal. Thus the Federal Food, Drugs, and Cosmetics Act of 1938 (FFDCA) significantly promoted the regulatory authority of the FDA, albeit still falling short of licensing.95 In an insightful analysis of the bureaucratic history of the FDA’s efforts toward revision of food and drug legislation, the historian of medicine Gwen Kay concluded: “Ultimately, one tragedy did what five years of public relations by the FDA could not do, which was to convince members of the House of Representatives that revision of the 1906 act was important.”96

  Although arsenic and lead spray residues and the ginger jake paralysis epidemic affected thousands of lives and caught the attention of regulators and consumer advocates, it was the Elixir Sulfanilamide tragedy that ultimately set the stage for the development of a scientific understanding of environmental risk as posed by pesticides. Discontinuation of congressional appropriations restricted the FDA from the study of lead and arsenic insecticides, but this shift proved to be inspirational. The Division of Pharmacology at the FDA developed the LD50 in order to determine the toxicity of glycols and derivatives. Meanwhile, at the University of Chicago, E. M. K. Geiling developed a broad-based approach to the toxicology of new and unfamiliar chemicals. The Division of Pharmacology at the FDA and the Department of Pharmacology at the University of Chicago served as centers for toxicological research during World War II. The research programs at the two institutions diverged after the Elixir Sulfanilamide tragedy, but they would converge in time. In addition, the study of industrial disease had developed as researchers studied workers in lead factories. This research led to the establishment of in-house toxicology laboratories at DuPont, Dow, and Union Carbide. Meanwhile, partially in response to consumer advocacy and partially in response to the Elixir Sulfanilamide tragedy, federal legislators significantly revised the PFDA to produce the Food, Drugs, and Cosmetics Act of 1938, which would define pesticides regulation for several decades. The FFDCA expanded the FDA’s authority in regulating insecticides but failed to provide a provision for licensing. During and after World War II, the Division of Pharmacology at the FDA applied the new techniques of toxicology to DDT, a new insecticide introduced for the control of insect-borne disease in World War II.

  CHAPTER 2

  DDT and Environmental Toxicology

  After the conclusion of the World War II, Time magazine attributed the Allied victory to two new technologies (among others): the atomic bomb and DDT.1 Years later, Rachel Carson would compare DDT to the effects of atomic radiation in a less favorable light. Early tests of the toxicity of DDT were conducted during the war,
and initial reports indicated that the compound was one of the most effective insecticides ever created. In addition, results from Naples, Italy, and islands in the South Pacific indicated that human toxicity was very low. Was DDT the magic bullet that economic entomologists had sought for so long? How effective was DDT on the many insects that threatened crops in the United States and elsewhere? What acute and chronic effects might this new chemical pose for human, animals, and other plants?

  During and immediately after World War II, DDT (dichloro-diphenyltrichloroethane) underwent extensive scrutiny by a range of scientists, including economic entomologists; public health officials; and wildlife biologists from such organizations as the USDA, PHS, FDA, the U.S. Fish and Wildlife Service (FWS), research universities, agrochemical companies, and private institutions. Moreover, scientists’ experience with DDT established modes of analysis for assessing other synthetic insecticides and chemicals. Indeed, scientific scrutiny of DDT transformed toxicology as scientists struggled to determine the toxicity of the new chemical to target insects, including most economically significant species—bedbugs, lice, cockroaches, mosquitoes, fleas, flies—and many others, but economic entomologists also needed to determine the impact of DDT on beneficial insects, for example, on honeybees.