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  Most researchers emphasized the direct effects of DDT and dismissed indirect effects, such as the elevation of populations of aphids and red mites, both of which survived exposure to DDT and thrived after their insect predators succumbed. Economic entomologists were, however, aware of this potential problem. The greatest variation in the individual experiments was in the concentrations of DDT used. Concentrations ranged from below 1 percent to greater than 10 percent, but the actual amount applied also varied from less than 0.1 pound per acre to 5 pounds per acre and more.

  Turning to theoretical models for the analysis of DDT, we find that the laboratory studies drew heavily on pharmacology and its rigorous testing procedures (the laboratory studies were among the most consistent of all the early studies of DDT). The studies on the effects on target insects had a well-established model in economic entomology. Many of the wildlife studies did not reflect advanced ecological theory (one prominent exception was the joint research conducted by the PHS and the FWS on the effects of DDT larviciding). Finally, the human studies drew heavily on occupational exposure models and to a lesser extent on laboratory animal studies.

  All DDT studies contributed in some degree to the study of toxicology. The laboratory tests refined the use of the LD50 as the benchmark standard of acute toxicity. In addition, the FDA pharmacologists strove to develop useful gauges of chronic toxicity, such as Laug’s bioassay using houseflies as well as long-term studies that lasted up to two years (DDT was the first insecticide subject to such extended analysis). It is not entirely clear why biologists became involved in the analysis of the toxicity of DDT to wildlife. James Whorton demonstrated that wildlife did not concern the scientists who studied the pesticides that preceded DDT, such as lead arsenate.94 But unlike lead arsenate, which was sprayed from the ground, DDT would be sprayed in aerosols from airplanes, thereby greatly expanding potential exposures to wildlife, including beneficial insects and vertebrates, among them humans. Nevertheless, DDT broadened the scope of toxicology by instigating wildlife studies, which became part of toxicological evaluation. Studies of the effects of DDT on humans suggested little to no effects at low dosages or exposures, indicating an appropriate safety factor, but the accumulation of DDT metabolites like DDE necessitated further examination. DDT metabolites would later appear at toxic levels in the eggshells of birds of prey, one signal of extensive environmental contamination.

  Toxicologists (qua chemists, pharmacologists, wildlife biologists, and physicians) rose to meet the new challenges posed by DDT. So novel was this technology that scientists struggled to find ways to identify and evaluate the risks it posed. The war effort coordinated and consolidated the work of many scientists in the study of the toxicity of DDT, just as the Elixir Sulfanilamide tragedy instigated concentrated toxicological analysis. But the study of the effects of DDT was not the only subject of wartime research; the army’s Office of Scientific Research and Development sponsored many other scientific analyses of chemicals.

  CHAPTER 3

  The University of Chicago Toxicity Laboratory

  The discovery of DDT as an effective pesticide at the beginning of World War II resulted in extensive research as to its toxicity. DDT received more toxicological scrutiny—from entomologists, toxicologists, and wildlife biologists—during the first years of its release than any pesticide that preceded it. Yet the war and its aftermath produced many other new chemicals that called for toxicological screening. To assess the toxicity of these chemicals—and also their potential for wartime use—the army’s Office of Scientific Research and Development (OSRD) awarded the University of Chicago a contract to evaluate these new substances. The University of Chicago is recognized for its great contributions to the war effort through the work of its renowned physicists, but university researchers also made significant contributions through the Toxicity Laboratory.1

  The formation of the Toxicity Laboratory and the wide range of its research represents a central episode in the development of toxicology for at least two reasons. First, the Toxicity Laboratory was one of the first institutions devoted entirely to toxicological research, which was related to pharmacology but becoming increasingly distinct from it. Many prominent toxicologists began their studies or initiated their research at the Toxicity Laboratory. Second, although some of the broad research topics pursued therein seem distant from environmental risk and pesticides, there are important links in such areas as the joint toxicity of and resistance to antimalarial drugs, both factors that would be central in the analysis of insecticides.

  As chair of the Department of Pharmacology at the University of Chicago, E. M. K. Geiling directed several simultaneous programs on behalf of the war through the Toxicity Laboratory. Geiling and his growing group of collaborators and students screened antimalarial drugs, evaluated the cancer-inhibiting effects of derivatives of the mustard gases, studied the fate of certain drugs through the use of radioisotopes, and explored the toxicity and pharmacology of organophosphate chemicals. Geiling had achieved considerable success as a faculty member at Johns Hopkins University and as professor and later chair of the Department of Pharmacology at the University of Chicago, where he oversaw critical studies. Federal authorities at the FDA were familiar with Geiling’s research on Elixir Sulfanilamide (see chapter 1). The centrality of the University of Chicago in scientific efforts to support World War II made the incorporation of Geiling and the Department of Pharmacology a logical extension of ongoing research there.2

  In 1936, the School of Medicine at the University of Chicago established a separate Department of Pharmacology and appointed Geiling as its first chairman. Geiling organized the department as an academic unit balancing teaching and graduate research. His first graduate student, Frances Oldham Kelsey, received her doctorate in 1938. Kelsey believed her admission to the graduate program might have been an oversight on Geiling’s part, since it was not yet common practice to admit women, and Geiling addressed her acceptance letter to “Mr. Oldham” (Kelsey’s maiden name). After Kelsey accepted the spot in the doctoral program. Geiling refused to admit whether or not he had been confused. Kelsey thrived as doctoral student then colleague before she joined the FDA.3

  Well in advance of the formal entrance of the United States into World War II, a defense contract established the Toxicity Laboratory at the University of Chicago. The Orlando Laboratory for the study of medical entomology originated along the same lines. With the intensification of World War II, the National Defense Research Committee (NDRC) contracted the University of Chicago to establish a facility capable of evaluating the toxicity of chemical agents for the Chemical Warfare Service (CWS). In doing so, military officials hoped to avoid the crippling injuries inflicted on American troops by chemical warfare during World War I. One of the main reasons the NDRC selected Chicago was that the university had, in an old powerhouse, an unused smokestack, which could be used to ventilate the laboratory. In addition, Chicago had emerged as a center for research on the development of the atomic bomb. Finally, Geiling, recognized for his research on the toxicity of diethylene glycol (see chapter 1), was an ideal unifying force for the project.

  E. M. K. Geiling, preparing marine toad for bufagin extraction. Courtesy of the University of Chicago Photographic Archives apf 1–06326, Special Collections Research Center, University of Chicago Library.

  With approval of the NDRC contract, Geiling became the principal investigator of the newly established Toxicity Laboratory on April 1, 1941, with Franklin D. McLean serving as the first director. During the war, Geiling and McLean developed the Tox Lab from a staff of six in a single building to a research cooperative numbering more than sixty investigators divided among seven large buildings. The physical size of the laboratory was a minor concern compared to assembling a skilled staff, defining research problems, and gaining the experience needed to interpret experimental results in terms of the needs of the armed services.4 Lab scientists later recalled that at the outset they struggled to frame research questions in s
uch a way that the results would contribute to the war effort. As a group, scientists were completely unfamiliar with tactical and strategic problems of the military. Nor were Chicago pharmacologists informed of the ongoing efforts of a small number of scientists in the laboratories of the CWS in Edgewood, Maryland, which left them isolated. Staffing was also a major challenge for the Toxicity Laboratory. As in the Manhattan Project, pharmacologists and other scientists were virtually conscripted from prewar jobs and graduate schools. On June 28, 1941, an executive order established the OSRD under Dr. Vannevar Bush. The OSRD comprised the existing NDRC and a new Committee on Medical Research (CMR).5 Each of these groups negotiated contracts with many research universities and medical schools.6

  In 1943, McLean resigned from the Tox Lab to accept a commission in the CWS and Dr. Keith Cannan from New York University became the new director.7 Even as Geiling and other members of the Tox Lab confronted questions about research, space, and staffing, chemicals needing evaluation arrived by the dozen; eventually more than a thousand chemicals would arrive at a time. In order to analyze such a vast quantity of new chemicals, Tox Lab scientists were drawn from many scientific fields, among them biology, medicine, and physics. Numerous specialists, including pharmacologists, physiologists, biochemists, pathologists, chemists, physicists, mathematicians, ophthalmologists, and dermatologists joined the laboratory.8 The new chemicals challenged Tox Lab researchers far beyond such initial questions as the chemical’s toxicity when inhaled. Other questions included: “Did [a given chemical] cloud the eye or blister the skin as did mustard gas? Did it make a man cry, or sneeze, or his skin itch? And then, if it did any of these things, why? And what could be done about it? How good were the gas masks, the antigas ointments, and protective clothing?”9

  The group evaluated the toxicity of several thousand potential chemical warfare agents, including nitrogen mustards, antimalarial drugs, radioisotope markers, and organophosphate poisons. Along with extensive laboratory space for researchers, the Toxicity Laboratory contained facilities for lab animals. The Tox Lab experiments used large numbers of monkeys, dogs, rabbits, rats, and mice, not to mention cockroaches and silkworms, in toxicity studies. Animals were kept in the “zoology pens,” which included dog runs. In contrast to most animal testing labs today, the pens were outside. The few trees provided the animals a minimum of shade but otherwise little protection, but the presence of dog runs suggested some concern for the well-being of the animals.10

  To the leadership of the Department of Pharmacology, and in effect the Toxicity Laboratory as well, Geiling brought a dynamic style that inspired personal and professional loyalty in his staff. Never having married (and only grudgingly tolerant of marriage in his staff), Geiling treated the faculty, staff, and students of the Department of Pharmacology and Toxicity Laboratory like family, even personally selecting Christmas gifts (generally books that reflected an individual’s interests). The responsibility of faculty promotions fell to Geiling, and each year when he submitted his recommendations to the dean, he dramatically attached his own letter of resignation in case the dean refused to accept of his recommendations. Geiling delivered the news of such decisions at the end of a breakfast at the University Club. John Doull recalled his experience at one meeting: “We discussed my going to medical school at one such breakfast and when I indicated that I would like to think about it, he suggested that I do so quickly since I was already enrolled in gross anatomy starting the following week.”11 The strength of Geiling’s leadership drove the Department of Pharmacology and the Toxicity Laboratory forward, producing scores of papers and dozens of graduate students who would be central to the formation of the discipline of toxicology. Several important research programs distinguished the early years of the Tox Lab: the joint toxicity of antimalarial drugs, antimalarial drug resistance, nitrogen mustard compounds, and tracing minute doses with radioisotopes.

  After its extensive effort to screen the toxicity of chemical warfare agents, the Department of Pharmacology under Geiling undertook an important research program to address the problem arising from the shortage of two antimalarial agents: quinine and atabrine. As a perennially deadly disease, malaria posed a great threat during times of war, especially in tropical regions.12 The endemic and widespread presence of malaria, particularly in the Pacific theater, required the U.S. armed forces to find an effective therapy against it. DDT controlled malaria by reducing or eliminating mosquitoes, but infected soldiers needed immediate treatment after contracting the disease. During World War I, malaria had exacerbated the challenges of war, leaving troops debilitated and demoralized.13 Malaria wreaked havoc among troops largely because medical personnel had received no special training on how to address the threat it posed. With the advent of World War II, officials recognized the danger of the disease and directed concerted efforts at its control, which incorporated staffs of the army, navy, the PHS, International Health Division of the Rockefeller Foundation, universities, and corporations, as well as the National Research Council and the OSRD.14 Thus, on several levels, military public health officials sought to address the threats posed by malaria.

  Certainly part of the reason for the increased awareness of malaria was the significant potential for exposure to the disease. American troops were deployed in Panama and the Caribbean, the west coast of Africa, the Balkans, Sicily and Southern Italy, India, Burma, Indonesia and the islands of the South Pacific, Formosa, and southern China, which were among of the most concentrated malarial regions of the world. Because medical entomologists had brought malaria under control in the United States during the early part of the twentieth century, few American soldiers had previous contact with the disease and virtually none had acquired immunity. Even those who had developed a level of immunity in the U.S. or elsewhere had not acquired immunity to the malaria strains found in Africa, Asia, and Europe.

  Researchers in Germany, France, and the U.S. developed antimalarial therapies with widely variable results. For example, in the course of preparing and testing more than twelve thousand antimalarial compounds, Bayer, a division of I. G. Farben Industrie, which developed sulfanilamide (see chapter 1), produced in short order two new drugs: plasmochin (known as pamaquine in Great Britain) and quinacrine (mepacrine in Britain). U.S. researchers independently synthesized chloroquine and amodiaquin. In the early years of the war, American researchers studied several antimalarial drugs including atabrine and plasmochin.15

  DDT significantly reduced the swarms of mosquitoes that carried the disease to human beings, but medical officials also sought to control the disease once it had invaded the human system. At the Tox Lab, Geiling and his collaborators tested existing drugs and searched for new ones, a program that proved highly successful not only in its immediate mission but also as a contribution to the growing methodology of environmental toxicology.

  At the University of Chicago, Graham Chen in the Department of Pharmacology supervised the clinical investigations. Tox Lab scientists initially screened more than fourteen thousand drugs, of which approximately one hundred reached the clinical stage of investigation. Chicago became involved with the study of chloroquine after unforeseen toxicity developed in Marines treated with the drug by Coggeshall at Klamath Falls. This mishap prompted the OSRD to request that Chen and Geiling conduct toxicity studies on chloroquine at an Illinois prison. After some very quick arrangements, the Chicago researchers transferred their research from Manteno State Hospital to Stateville Penitentiary more than eighty miles away.16 The toxicity studies of chloroquine at Stateville Hospital began on October 25, 1944. After several months spent establishing the facility, the Chicago toxicologists administered mosquito-induced malaria of the Chesson strain, Southwest Pacific Vivax, to thirty prison volunteers on March 8, 1945. This process demanded the better part of twenty-four hours and not all of the infections took hold. As the national malaria program turned from suppression of the disease to cure, the Chicago researchers quickly acquired a major portion of the available res
earch funds.

  Biomedical historian Nathaniel Comfort has shown that the Stateville malaria program occupies a precarious position in the history of biomedical ethics. On one hand, the Chicago researchers obtained what they understood to be informed consent from all the prisoners who “volunteered” for the malaria research. On the other, Comfort determined that many of the experiments conducted on prisoners could not have been performed on civilians in accordance with ethical standards at the time (or any time since). Yet Comfort argues that the Stateville malaria project defies simple ethical or moral formulas: prisoners willingly consented to “degrading, painful, dangerous, even life-threatening procedures” in spite of the risks.17

  With the disbanding of the OSRD on July 1, 1946, funding for the project was transferred to the PHS. Less than eighteen months later, Chen, Geiling, and other researchers at Chicago had carefully screened thirty-five 8-aminoquinolines and had shown that isopentaquine was superior to pentaquine, which was better than pamaquin. Despite these promising results, the majority of the members of the Malaria Study Section at NIH believed that the examination of such compounds should be terminated.18

  After submitting an application to NIH for a terminal grant in the amount of $15,000 on March 26, 1948, Chen and the University of Chicago team focused on the primary amines, which had been generally neglected. One of these compounds, which became known as primaquine, was one of the most promising discoveries of the antimalarial research at Chicago. Volunteers at the Stateville Penitentiary first received primaquine in the amount of 15 mg per day beginning on February 22, 1948. Researchers deliberately minimized the dose in response to earlier reports by Schmidt that primaquine was as toxic as pamaquin (later studies with monkeys refuted Schmidt’s findings). On March 30, 1948 (only a few months before the termination of the grant), researchers raised the dose of primaquine to 30 mg per day. It was not until July 1, 1948, that Chen realized the considerable potential of primaquine. Given the imminent termination of research funding, Chen turned to Lowell Coggeshall, another malariologist, who was dean of the University of Chicago School of Medicine. Chen thought that he could run the antimalarial project at the most basic level (protecting infected volunteers without initiating new studies) or run the project at its fullest extent, an effort demanding $25,000 to $30,000 per year in order to explore primaquine. Coggeshall strongly encouraged Chen to explore the new drug: “Run Stateville full blast. If primaquine is as good as it seems to be, I do not believe you will have any difficulty finding sponsors for your work. If it turns out to be a false alarm, I will guarantee that University of Chicago will give you enough funds to protect you from trouble at Stateville.”19