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The doubter is a true man of science; he doubts only himself and his interpretations, but he believes in science.
Claude Bernard
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The latter part of the 19th century saw the introduction of “patent medicines” in many parts of the world.
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Toxicology evolved rapidly during the 20th century. The early controversies focusing on patent medicines and sale of consumer products of questionable safety (Kallett and Schlink) were followed by the rapid advances in analytical chemistry methods that fostered the advancement of forensic toxicology specifically at the New York City Medical Examiner’s Office. However, the exponential growth of the discipline can be traced to the World War II era with its marked increase in the production of drugs, pesticides, munitions, synthetic fibers, and industrial chemicals. The history of many sciences represents an orderly transition based on theory, hypothesis testing, and synthesis of new ideas. Toxicology, as a gathering and an applied science, has, by contrast, developed in fits and starts. It calls on almost all the basic sciences to test its hypotheses. This fact, coupled with the health and occupational regulations that have driven toxicology research since 1900, has made toxicology exceptional in the history of science. The differentiation of toxicology as an art and a science, though arbitrary, permits the presentation of historical highlights along 2 major lines.
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Modern toxicology can be viewed as a continuation of the development of the biological and physical sciences in the late 19th and 20th centuries (Table 1-1). During the second half of the 19th century, the world witnessed an explosion in science that produced the beginning of the modern era of medicine, synthetic chemistry, physics, and biology. Toxicology has drawn its strength and diversity from its proclivity to borrowing. With the advent of anesthetics and disinfectants and the advancement of experimental pharmacology in the late 1850s, toxicology as it is currently understood got its start. The introduction of ether, chloroform, and carbonic acid led to several iatrogenic deaths. These unfortunate outcomes spurred research into the causes of the deaths and early experiments on the physiological mechanisms by which these compounds caused both beneficial and adverse effects. By the late 19th century the use of organic chemicals was becoming more widespread, and benzene, toluene, and the xylenes, as well as the chlorinated solvents related to chloroform, went into large-scale commercial production. During this period, the use of patent medicines, consisting primarily of “medicinal herbs,” nonsugar sweeteners, and alcohol, was prevalent, and there were several incidents of poisonings from these medicaments. In 1902 Congress approved $5000 to fund the “Poison Squad,” professional tasters under the direction of Harvey Washington Wiley that harkened back to the food tasters used by royalty to avoid intentional poisoning from their foods. The case of “Doctor” Munyan versus Harvey Wiley, MD (1844–1930), a classic battle between the federal government and the most infamous purveyor of patent medicines, over mislabeling, false advertisement, lack of efficacy, and serious toxicity led to further Congressional action. The adverse reactions to patent medicines and mislabeled foods coupled with the response to Upton Sinclair’s exposé of the Chicago meat-packing industry in The Jungle (1905) culminated in the passage of the Wiley Bill (The Pure Foods Act of 1906). This was the first of many US pure food and drug laws (see Hutt and Hutt, 1984, for regulatory history of foods). The Wiley Bill as it was known was widely supported in Congress at its passage. However, the support did not last. The Bill required prior toxicity testing, the establishment of a government analytical laboratory, and the removal of toxic compounds, particularly ethanol, herbal mixtures, and coloring agents. It also prohibited false advertising. After enactment of the Bill, individual federal leaders including Congressmen and judges, as well as “Dr” Munyan (who claimed his remedies were effective and had cured thousands), campaigned against its enforcement. Parts of the Bill were overturned by Justice Oliver Wendell Holmes and the US Supreme Court in 1911 stating that “hype is not false advertising.” In part because of the opposition to the Bill, Wiley left the government to direct the fledgling Consumer Union in 1912. Today, a century later, similar battles are being fought over dietary supplements and food additives.
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A working hypothesis about the development of toxicology is that the discipline expands in response to legislation, which itself is a response to a real or perceived tragedy. The Wiley Bill was the first such reaction in the area of food and drugs, and the workers’ compensation laws cited above were a response to occupational toxicities. In addition, the National Safety Council was established in 1911, and the Division of Industrial Hygiene was established by the US Public Health Service in 1914. A corollary to this hypothesis might be that the founding of scientific journals and/or societies is sparked by the development of a new field. The Journal of Industrial Hygiene began in 1918. The major chemical manufacturers in the United States (Dow, Union Carbide, and Du Pont) established internal toxicology research laboratories to help guide decisions on worker health and product safety.
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During the 1890s and early 1900s, European scientists Becquerel, Roentgen, and the Curies reported the discovery of radioactivity and x-rays. This opened up for exploration a very large area in physics, biology, and medicine. Interestingly, many of these early researchers died of radiation poisoning. Radiation exposure became widespread in consumer usage. Radium-containing rocks were touted as health cures, and the Radiothor and radium dial watches were widespread. The adverse effects were virtually unknown and radiation would not actively affect the science of toxicology until the World War II era.
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However, another discovery, that of vitamins, or “vital amines,” led to the use of the first large-scale bioassays (multiple animal studies) to determine whether these new synthetic chemicals were beneficial or harmful to laboratory animals, and by extension to humans. The initial work in this area took place at around the time of World War I in several laboratories, including the laboratory of Philip B. Hawk in Philadelphia. Hawk and a young associate, Bernard L. Oser, were responsible for the development and verification of many early toxicological assays that are still used in a slightly amended form. The results from these animal studies formed the underpinnings of risk assessment. Oser’s contributions to food and regulatory toxicology were extraordinary. These early bioassays were made possible by a major advance in toxicology: the availability of developed and refined strains of inbred laboratory rodents (Donaldson, 1912) and the rapid development of analytical chemistry.
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The 1920s saw many events that began to mold the fledgling field of toxicology. The discovery by Paul Ehrlich (1854–1915) of arsenicals for the treatment of syphilis (arsenicals had been used in agriculture since the mid-19th century) resulted in acute and chronic toxicity. Arsenic remains a major toxicant in many developing nations. Prohibition of alcoholic beverages in the United States opened the door for early studies of neurotoxicology, with the discovery that triorthocresyl phosphate (TOCP), methanol, and lead (all found in bootleg liquor) are neurotoxicants. TOCP, which was a recent gasoline additive, caused a syndrome that became known as “ginger-jake” walk, a spastic gait resulting from drinking ginger beer adulterated with TOCP. Methanol, used as a cheap ethanol substitute, blinded and killed many unsuspecting people (see Poisoners Handbook, 2011). Mueller’s discovery of dichlorodiphenyltrichloroethane (DDT) and several other organohalides, such as hexachlorobenzene and hexachlorocyclohexane, during the late 1920s resulted in widespread use of these insecticidal agents. Toxicity testing of the new organohalide compounds was in its infancy. Understanding of the modes of action and persistence of these compounds would have to wait 40 years.
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Other scientists were hard at work attempting to elucidate the structures and activity of the estrogens and androgens. Work on the steroid hormones led to the use of several assays for the determination of the biological activity of organ extracts and synthetic compounds. Allen and Doisy published the first uterotrophic assay (1928) that accelerated the study of estrogenic chemicals. Modifications of this assay are used today in studying endocrine disruption by xenobiotics. Efforts to synthesize estrogen-active chemicals were spearheaded by E. C. Dodds and his co-workers, one of whom was Leon Golberg, a young organic chemist and a future leader in toxicology. Dodds’s work on the bioactivity of the estrogenic compounds resulted in the synthesis of diethylstilbestrol (DES), hexestrol, other stilbenes, and bisphenol A (BPA) and the discovery of the strong estrogenic activity of substituted stilbenes. Golberg’s intimate involvement in this work stimulated his interest in biology, leading to degrees in biochemistry and medicine and a career in toxicology in which he oversaw the creation of the laboratories of the British Industrial Biological Research Association (BIBRA) and the Chemical Industry Institute of Toxicology (CIIT). Interestingly, the initial observations that led to the discovery of DES were the findings of feminization of animals treated with the experimental carcinogen 7,12-dimethylbenz[a]anthracene (DMBA).
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Occupational illnesses became more pronounced after the 1920s, and occupational toxicology developed into a field of its own. The seminal works of Alice Hamilton (1869–1970) (Exploring the Dangerous Trades) and Ethel Browning (Toxicity of Industrial Solvents, 1937) are critical readings.
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The 1930s saw the world preparing for World War II and a major effort by the pharmaceutical and chemical industry in Europe and the United States to manufacture the first mass-produced antibiotics. One of the first journals expressly dedicated to experimental toxicology, Archiv für Toxikologie, began publication in Europe in 1930, the same year that Herbert Hoover signed the act that established the National Institutes of Health (NIH) in the United States.
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The discovery of sulfanilamide was heralded as a major event in combating bacterial diseases. However, for a drug to be effective, there must be a reasonable delivery system, and sulfanilamide is highly insoluble in an aqueous medium. Therefore, it was originally prepared in ethanol (elixir). However, it was soon discovered that the drug was more soluble in diethylene glycol. The drug was sold in glycol solutions but was labeled as an elixir, and several patients (mostly children) died of acute kidney failure resulting from the metabolism of the glycol to oxalic acid and glycolic acid, with the acids and the active drug crystallizing in the kidney tubules. This tragic event led to the passage of the Copeland Bill in 1938, the second major bill involving the formation of the US Food and Drug Administration (FDA). The sulfanilamide disaster played a critical role in the further development of toxicology, resulting in work by Eugene Maximillian Geiling in the Pharmacology Department of the University of Chicago that elucidated the mechanism of toxicity of both sulfanilamide and diethylene glycol. Studies of the glycols were simultaneously carried out at the US FDA by a group led by Arnold Lehman. The scientists associated with Lehman and Geiling were to become the leaders of toxicology (especially the Society of Toxicology) over the next 40 years. With few exceptions, toxicology in the United States owes its heritage to Geiling’s innovativeness and ability to stimulate and direct young scientists, and Lehman’s vision of the use of experimental toxicology in public health decision making. Because of Geiling’s reputation, the US government turned to this group for help in the war effort. There were 3 main areas in which the Chicago group took part during World War II: the toxicology and pharmacology of organophosphate (OP) chemicals, antimalarial drugs, and radionuclides. Each of these areas produced teams of toxicologists who became academic, governmental, and industrial leaders in the field.
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It was also during this time that DDT and the phenoxy herbicides were developed for increased food production and, in the case of DDT, control of insect-borne diseases. These efforts between 1940 and 1946 led to an explosion in toxicology. Thus, in line with the hypothesis advanced above, the crisis of World War II caused the next major leap in the development of toxicology.
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If one traces the history of the toxicology of metals over the past 45 years, the role of the Chicago and Rochester groups is quite visible. This story commences with the use of uranium for the “bomb” and continues today with research on the role of metals in their interactions with DNA, RNA, and growth factors. Indeed, the Manhattan Project created a fertile environment that resulted in the initiation of quantitative biology, radiotracer technology, and inhalation toxicology. These innovations have revolutionized modern biology, chemistry, therapeutics, and toxicology.
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Inhalation toxicology began at the University of Rochester under the direction of Stafford Warren, who headed the Department of Radiology. He developed a program with colleagues such as Harold Hodge (pharmacologist), Herb Stokinger (chemist), Sid Laskin (inhalation toxicologist), and Lou and George Casarett (toxicologists). These young scientists were to go on to become giants in the field. The other sites for the study of radionuclides were Chicago for the “internal” effects of radioactivity and Oak Ridge, Tennessee, for the effects of “external” radiation. The work of the scientists on these teams gave the scientific community data that contributed to the early understanding of macromolecular binding of xenobiotics, cellular mutational events, methods for inhalation toxicology and therapy, and toxicological properties of trace metals, along with a better appreciation of the complexities of the dose–response curve.
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Another seminal event in toxicology that occurred during the World War II era was the discovery by Lange and Schrader in 1938 of OP cholinesterase inhibitors including sarin, tabun (chemical warfare agents), and less potent OP insecticides. This class of chemicals was destined to become a driving force in the study of neurophysiology and toxicology for several decades. Again, the scientists in Chicago played major roles in elucidating the mechanisms of action of this new class of compounds. Geiling’s group, Kenneth DuBois in particular, was the leader in this area of toxicology and pharmacology. DuBois’s colleagues, particularly Sheldon Murphy, continued to be in the forefront of this special area. The importance of the early research on the OPs has taken on special meaning in the years since 1960, when these nonbioaccumulating insecticides were destined to replace DDT and other organochlorine insecticides. Today, a third generation of insecticides has replaced much of the OP use.
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Early in the 20th century, it was demonstrated experimentally that quinine has a marked effect on the malaria parasite (it had been known for centuries that cinchona bark extract is efficacious for “Jesuit fever” [malaria]). This discovery led to the development of quinine derivatives for the treatment of the disease and the formulation of the early principles of chemotherapy. The Pharmacology Department of the University of Chicago was charged with the development of antimalarials for the war effort. The original protocols called for testing of efficacy and toxicity in rodents and perhaps dogs and then the testing of efficacy in human volunteers. One of the investigators charged with generating the data needed to move a candidate drug from animals to humans was Fredrick Coulston. This young parasitologist and his colleagues, working in Chicago, were to evaluate potential drugs in animal models and then establish human clinical trials. It was during these experiments that the use of nonhuman primates came into vogue for toxicology testing. It had been noted by Russian scientists that some antimalarial compounds caused retinopathies in humans but did not apparently have the same adverse effect in rodents and dogs. This finding led the Chicago team to add 1 more step in the development process: toxicity testing in rhesus monkeys just before efficacy studies in people. This resulted in the prevention of blindness in untold numbers of volunteers and perhaps some of the troops in the field. It also led to the school of thought that nonhuman primates may be one of the better models for humans and the establishment of primate colonies for the study of toxicity. Coulston pioneered this area of toxicology and remained committed to it.
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Another area not traditionally thought of as toxicology but one that evolved during the 1940s as an exciting and innovative field is experimental pathology. This branch of experimental biology developed from bioassays of estrogens and early experiments in chemical- and radiation-induced carcinogenesis. It is from these early studies that hypotheses on tumor promotion and cancer progression have evolved.
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Toxicologists today owe a great deal to the researchers of chemical carcinogenesis of the 1940s. Much of today’s work can be traced to Elizabeth and James Miller at Wisconsin. This husband and wife team started under the mentorship of Professor Rusch, the director of the newly formed McArdle Laboratory for Cancer Research, and Professor Baumann. The seminal research of the Millers led to the discovery of the role of reactive intermediates in carcinogenicity and that of mixed-function oxidases in the endoplasmic reticulum. These findings, which initiated the great works on the cytochrome P450 family of proteins, were aided by 2 other major discoveries for which toxicologists (and all other biological scientists) are deeply indebted: paper chromatography in 1944 and the use of radiolabeled dibenzanthracene in 1948. Other major events of note in drug metabolism included the work of Bernard Brodie on the metabolism of methyl orange in 1947. This piece of seminal research led to the examination of blood and urine for chemical and drug metabolites. It became the tool with which one could study the relationship between blood levels and biological action. The classic treatise of R. T. Williams, Detoxication Mechanisms, was published in 1947. This text described the many pathways and possible mechanisms of detoxication and opened the field to several new areas of study.
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The decade after World War II was not as boisterous as the period from 1935 to 1945. The first major US pesticide act was signed into law in 1947. The significance of the initial Federal Insecticide, Fungicide, and Rodenticide Act was that for the first time in US history a substance that was neither a drug nor a food had to be shown to be safe and efficacious. This decade, which coincided with the Eisenhower years, saw the dispersion of the groups from Chicago, Rochester, and Oak Ridge and the establishment of new centers of research. Adrian Albert’s classic Selective Toxicity was published in 1951. This treatise, which has appeared in several editions, presented a concise documentation of the principles of the site-specific action of chemicals.