1: Historical Principles and Perspectives

The term poison first appeared in the English literature around the year 1225 a.d. to describe a potion or draught that was prepared with deadly ingredients.^8,147 The history of poisons and poisoning, however, dates back thousands of years. Throughout the millennia, poisons have played an important role in human history—from political assassination in Roman times, to weapons of war, to contemporary environmental concerns, and to weapons of terrorism.

This chapter offers a perspective on the impact of poisons and poisoning on history. It also provides a historic overview of human understanding of poisons and the development of toxicology from antiquity to the present. The development of the modern poison center, the genesis of the field of medical toxicology, and the recent increasing focus on medication errors are examined. Chapter 2 describes poison plagues and unintentional disasters throughout history and examines the societal consequences of these unfortunate events. An appreciation of past failures and mistakes in dealing with poisons and poisoning promotes a keener insight and a more critical evaluation of present-day toxicologic issues and helps in the assessment and management of future toxicologic problems.

The earliest poisons consisted of plant extracts, animal venoms, and minerals. They were used for hunting, waging war, and sanctioned and unsanctioned executions. The Ebers Papyrus, an ancient Egyptian text written circa 1500 b.c. that is considered to be among the earliest medical texts, describes many ancient poisons, including aconite, antimony, arsenic, cyanogenic glycosides, hemlock, lead, mandrake, opium, and wormwood.^97,147 These poisons were thought to have mystical properties, and their use was surrounded by superstition and intrigue. Some agents, such as the Calabar bean (Physostigma venenosum) containing physostigmine, were referred to as "ordeal poisons." Ingestion of these substances was believed to be lethal to the guilty and harmless to the innocent.¹²³ The "penalty of the peach" involved the administration of peach pits, which we now know contain the cyanide precursor amygdalin, as an ordeal poison. Magicians, sorcerers, and religious figures were the toxicologists of antiquity. The Sumerians, in circa 4500 b.c., were said to worship the deity Gula, who was known as the "mistress of charms and spells" and the "controller of noxious poisons" (Table 1–1).¹⁴⁷

Arrow and Dart Poisons

The prehistoric Masai hunters of Kenya, who lived 18,000 years ago, used arrow and dart poisons to increase the lethality of their weapons.²⁰ One of these poisons appears to have consisted of extracts of Strophanthus species, an indigenous plant that contains strophanthin, a digitalislike substance.⁹⁷ Cave paintings of arrowheads and spearheads reveal that these weapons were crafted with small depressions at the end to hold the poison.¹⁴⁸ In fact, the term toxicology is derived from the Greek terms toxikos ("bow") and toxikon ("poison into which arrowheads are dipped").^6,148

References to arrow poisons are cited in a number of other important literary works. The ancient Indian text Rig Veda, written in the 12th century b.c., refers to the use of Aconitum species for arrow poisons.²⁰ In the Odyssey, Homer (ca. 850 b.c.) wrote that Ulysses anointed his arrows with a variety of poisons, including extracts of Helleborus orientalis and snake venoms. The writings of Ovid (43 b.c.–18 a.d.), describe weapons poisoned with the blood of serpents.¹⁵⁵

Classification of Poisons

The first attempts at poison identification and classification and the introduction of the first antidotes took place during Greek and Roman times. An early categorization of poisons divided them into fast poisons, such as strychnine, and slow poisons, such as arsenic. In his treatise, Materia Medica, the Greek physician Dioscorides (40–80 a.d.) categorized poisons by their origin—animal, vegetable, or mineral.¹⁴⁸ This categorization remained the standard classification for the next 1500 years.¹⁴⁸

Animal Poisons.

Animal poisons usually referred to the venom from poisonous animals. Although the venom from poisonous snakes has always been among the most commonly feared poisons, poisons from toads, salamanders, jellyfish, stingrays, and sea hares are often as lethal. Nicander of Colophon (204–135 b.c.), a Greek poet and physician who is considered to be one of the earliest toxicologists, experimented with animal poisons on condemned criminals.¹³⁴ Nicander's poems Theriaca and Alexipharmaca are considered to be the earliest extant Greek toxicologic texts, describing the presentations and treatment of poisonings from animal xenobiotics.¹⁴⁷ A notable fatality from the effects of an animal xenobiotic was Cleopatra (69–30 b.c.), who reportedly committed suicide by deliberately falling on an asp.⁷⁵

Vegetable Poisons.

Theophrastus (ca. 370–286 b.c.) described vegetable poisons in his treatise De Historia Plantarum.⁷⁶ Notorious poisonous plants included Aconitum species (monkshood aconite), Conium maculatum (poison hemlock), Hyoscyamus niger (henbane), Mandragora officinarum (mandrake), Papaver somniferum (opium poppy), and Veratrum album (hellebore). Aconite was among the most frequently encountered poisonous plants and was described as the "queen mother of poisons."¹⁴⁷ Hemlock was the official poison used by the Greeks and was used in the execution of Socrates (ca. 470–399 b.c.) and many others.¹³⁶ Poisonous plants used in India at this time included Cannabis indica (marijuana), Croton tiglium (croton oil), and Strychnos nux vomica (poison nut, strychnine).⁷⁶

Mineral Poisons.

The mineral poisons of antiquity consisted of the metals antimony, arsenic, lead, and mercury. Undoubtedly, the most famous of these was lead. Lead was discovered as early as 3500 b.c. Although controversy continues about whether an epidemic of lead poisoning among the Roman aristocracy contributed to the fall of the Roman Empire, lead was certainly used extensively during this period.^55,112 In addition to its considerable use in plumbing, lead was also used in the production of food and drink containers.⁶² It was common practice to add lead directly to wine or to intentionally prepare the wine in a lead kettle to improve its taste. Not surprisingly, chronic lead poisoning became widespread. Nicander described the first case of lead poisoning in the 2nd century b.c.¹⁵¹ Dioscorides, writing in the 1st century a.d., noted that fortified wine was "most hurtful to the nerves."¹⁵¹ Lead-induced gout ("saturnine gout") may have also been widespread among the Roman elite.¹¹²

Gases.

Although not animal, vegetable, or mineral in origin, the toxic effects of gases were also appreciated during antiquity. In the 3rd century b.c., Aristotle commented that "coal fumes (carbon monoxide) lead to a heavy head and death,"⁷³ and Cicero (106–43 b.c.) referred to the use of coal fumes in suicides and executions.

Poisoners of Antiquity

Given the increasing awareness of the toxic properties of some naturally occurring xenobiotics and the lack of analytical detection techniques, homicidal poisoning was common during Roman times. During this period, members of the aristocracy commonly used "tasters" to shield themselves from potential poisoners, a practice also in vogue during the reign of Louis XIV in 16th century France.¹⁵⁵

One of the most infamous poisoners of ancient Rome was Locusta, who was known to experiment on slaves with poisons that included aconite, arsenic, belladonna, henbane, and poisonous fungi. In 54 a.d., Nero's mother, Agrippina, hired Locusta to poison Emperor Claudius (Agrippina's husband and Nero's stepfather) as part of a scheme to make Nero emperor. As a result of these activities, Claudius, who was a great lover of mushrooms, died from Amanita phalloides poisoning,¹⁸ and in the next year, Britannicus (Nero's stepbrother) also became one of Locusta's victims. In his case, Locusta managed to fool the taster by preparing unusually hot soup that required additional cooling after the soup had been officially tasted. At the time of cooling, the poison was surreptitiously slipped into the soup. Almost immediately after drinking the soup, Britannicus collapsed and died. The exact poison remains in doubt, although some authorities suggest that it was a cyanogenic glycoside.¹³⁹

Early Quests for the Universal Antidote

The recognition, classification, and use of poisons in ancient Greece and Rome were accompanied by an intensive search for a universal antidote. In fact, many of the physicians of this period devoted significant parts of their careers to this endeavor.¹⁴⁷ Mystery and superstition surrounded the origins and sources of these proposed antidotes. One of the earliest specific references to a protective agent can be found in Homer's Odyssey, when Ulysses is advised to protect himself by taking the antidote "moli." Recent speculation suggests that moli referred to Galanthus nivalis, which contains a cholinesterase inhibitor. This agent could have been used as an antidote against poisonous plants such as Datura stramonium (jimsonweed) that contain the anticholinergic alkaloids scopolamine, atropine, and hyoscyamine.¹²⁰

Theriacs and the Mithradatum.

The Greeks referred to the universal antidote as the alexipharmaca or theriac.^77,147 The term alexipharmaca was derived from the words alexipharmakos ("which keeps off poison") and antipharmakon ("antidote"). Over the years, alexipharmaca was increasingly used to refer to a method of treatment, such as the induction of emesis by using a feather. Theriac, which originally had referred to poisonous reptiles or wild beasts, was later used to refer to the antidotes. Consumption of the early theriacs (ca. 200 b.c.) was reputed to make people "poison-proof" against bites of all venomous animals except the asp. Their ingredients included aniseed, anmi, apoponax, fennel, meru, parsley, and wild thyme.¹⁴⁷

The quest for the universal antidote was epitomized by the work of King Mithradates VI of Pontus (132–63 b.c.).⁷⁴ After repeatedly being subjected to poisoning attempts by his enemies during his youth, Mithradates sought protection by the development of universal antidotes. To find the best antidote, he performed acute toxicity experiments on criminals and slaves. The theriac he concocted, known as the "mithradatum," contained a minimum of 36 ingredients and was thought to be protective against aconite, scorpions, sea slugs, spiders, vipers, and all other poisonous substances. Mithradates took his concoction every day. Ironically, when an old man, Mithradates attempted suicide by poison but supposedly was unsuccessful because he had become poison-proof. Having failed at self-poisoning, Mithradates was compelled to have a soldier kill him with a sword. Galen described Mithradates' experiences in a series of three books: De Antidotis I, De Antidotis II, and De Theriaca ad Pisonem.^74,152

The Theriac of Andromachus, also known as the "Venice treacle" or "galene," is probably the most well known theriac.⁶⁴ According to Galen, this preparation, formulated during the 1st century a.d., was considered an improvement over the mithradatum.¹⁴⁶ It was prepared by Andromachus (37–68 a.d.), physician to Emperor Nero. Andromachus added to the mithradatum ingredients such as the flesh of vipers, squills, and generous amounts of opium.¹⁵⁸ Other ingredients were removed. Altogether, 73 ingredients were required. It was advocated to "counteract all poisons and bites of venomous animals," as well as a host of other medical problems, such as colic, dropsy, and jaundice, and it was used both therapeutically and prophylactically.^147,152 As evidence of its efficacy, Galen demonstrated that fowl receiving poison followed by theriac had a higher survival rate than fowl receiving poison alone.¹⁴⁷ It is likely, however, that the scientific rigor and methodology used differed from current scientific practice.

By the Middle Ages, the Theriac of Andromachus contained more than 100 ingredients. Its synthesis was quite elaborate; the initial phase of production lasted months followed by an aging process that lasted years, somewhat similar to that of vintage wine.⁹² The final product was often more solid than liquid in consistency.

Other theriac preparations were named after famous physicians (Damocrates, Nicolaus, Amando, Arnauld, and Abano) who contributed additional ingredients to the original formulation. Over the centuries, certain localities were celebrated for their own peculiar brand of theriac. Notable centers of theriac production included Bologna, Cairo, Florence, Genoa, Istanbul, and Venice. At times, theriac production was accompanied by great fanfare. For example, in Bologna, the mixing of the theriac could take place only under the direction of the medical professors at the university.¹⁴⁷

Whether these preparations were of actual benefit is uncertain. Some suggest that the theriac may have had an antiseptic effect on the gastrointestinal (GI) tract, but others state that the sole benefit of the theriac derived from its formulation with opium.⁹² Theriacs remained in vogue throughout the Middle Ages and Renaissance, and it was not until 1745 that their efficacy was finally questioned by William Heberden in Antitheriaka: An Essay on Mithradatum and Theriaca.⁷⁴ Nonetheless, pharmacopeias in France, Spain, and Germany continued to list these agents until the last quarter of the 19th century, and theriac was still available in Italy and Turkey in the early 20th century.^19,92

Sacred Earth.

Beginning in the 5th century b.c., an adsorbent agent called terra sigillata was promoted as a universal antidote. This xenobiotic, also known as the "sacred sealed earth," consisted of red clay that could be found on only one particular hill on the Greek island of Lemnos. Perhaps somewhat akin to the 20th-century "universal antidote," it was advocated as effective in counteracting all poisons.¹⁴⁷ With great ceremony, once per year, the terra sigillata was retrieved from this hill and prepared for subsequent use. According to Dioscorides, this clay was formulated with goat's blood to make it into a paste. At one time, it was included as part of the Theriac of Andromachus. Demand for terra sigillata continued into the 15th century. Similar antidotal clays were found in England, Italy, Malta, and Silesia.¹⁴⁷

Charms.

Charms, such as toadstones, snakestones, unicorn horns, and bezoar stones, were also promoted as universal antidotes. Toadstones, found in the heads of old toads, were reputed to have the capability to extract poison from the site of a venomous bite or sting. In addition, the toadstone was supposedly able to detect the mere presence of poison by producing a sensation of heat upon contact with a poisonous substance.¹⁴⁷

Similarly, snakestones extracted from the heads of cobras (known as piedras della cobra de Capelos) were also reported to have magical qualities.¹⁴ The 17th-century Italian philosopher Athanasius Kircher (1602–1680) became an enthusiastic supporter of snakestone therapy for the treatment of snakebite after conducting experiments demonstrating the antidotal attributes of these charms "in front of amazed spectators." Kircher attributed the efficacy of the snakestone to the theory of "attraction of like substances." Francesco Redi (1626–1698), a court physician and contemporary of Kircher, debunked this quixotic approach. A harbinger of future experimental toxicologists, Redi was unwilling to accept isolated case reports and field demonstrations as proof of the utility of the snakestone. Using a considerably more rigorous approach, provando et riprovando (by testing and retesting), Redi assessed the antidotal efficacy of snakestone on different animal species and different xenobiotics and failed to confirm any benefit.¹⁴

Much lore has surrounded the antidotal effects of the mythical unicorn horn. Ctesias, writing in 390 b.c., was the first to chronicle the wonders of the unicorn horn, claiming that drinking water or wine from the "horn of the unicorn" would protect against poison.¹⁴⁷ The horns were usually narwhal tusks or rhinoceros horns, and during the Middle Ages, the unicorn horn may have been worth as much as 10 times the price of gold. Similar to the toadstone, the unicorn horn was used both to detect poisons and to neutralize them. Supposedly, a cup made of unicorn horn would sweat if a poisonous substance was placed in it.⁹⁰ To give further credence to its use, a 1593 study on arsenic-poisoned dogs reportedly showed that the horn was protective.⁹⁰

Bezoar stones, also touted as universal antidotes, consisted of stomach or intestinal calculi formed by the deposition of calcium phosphate around a hair, fruit pit, or gallstone. They were removed from wild goats, cows, and apes and administered orally to humans. The Persian name for the bezoar stone was pad zahr ("expeller of poisons"); the ancient Hebrews referred to the bezoar stone as bel Zaard ("every cure for poisons"). Over the years, regional variations of bezoar stones were popularized, including an Asian variety from wild goat of Persia, an Occidental variety from llamas of Peru, and a European variety from chamois of the Swiss mountains.^50,147

Although it was not until the mid-19th century that the true perils of opiate addiction were first recognized, juice from the Papaver somniferum was known for its medicinal value in Egypt at least as early as the writing of the Ebers Papyrus in 1500 b.c. Egyptian pharmacologists of that time reportedly recommended opium poppy extract as a pacifier for children who exhibited incessant crying.¹³³ In Ancient Greece, Dioscorides and Galen were early advocates of opium as a therapeutic xenobiotic. During this time, it was also used as a means of suicide. Mithradates' lack of success in his own attempted suicide by poisoning may have been the result of an opium tolerance that had developed from previous repetitive use.¹³³ One of the earliest descriptions of the abuse potential of opium is attributed to Epistratos (304–257 b.c.), who criticized the use of opium for earache because it "dulled the sight and is a narcotic."¹³³

Cocaine use dates back to at least 300 b.c., when South American Indians reportedly chewed coca leaves during religious ceremonies.¹⁰⁶ Chewing coca to increase work efficacy and to elevate mood has remained commonplace in some South American societies for thousands of years. An Egyptian mummy from about 950 b.c. revealed significant amounts of cocaine in the stomach and liver, suggesting oral use of cocaine occurred during this time period.¹¹⁰ Large amounts of tetrahydrocannabinol (THC) were also found in the lung and muscle of the same mummy. Another investigation of 11 Egyptian (1079 b.c.–395 a.d.) and 72 Peruvian (200–1500 a.d.) mummies found cocaine, thought to be indigenous only to South America, and hashish, thought to be indigenous only to Asia, in both groups.¹¹⁹

Cannabis use in China dates back even further, to around 2700 b.c., when it was known as the "liberator of sin."¹⁰⁶ In India and Iran, cannabis was used as early as 1000 b.c. as an xenobiotic known as bhang.¹⁰⁹ Other currently abused xenobiotics that were known to the ancients include cannabis, hallucinogenic mushrooms, nutmeg, and peyote. As early as 1300 b.c., Peruvian Indian tribal ceremonies included the use of mescaline-containing San Pedro cacti.¹⁰⁶ The hallucinogenic mushroom Amanita muscaria, known as "fly agaric," was used as a ritual drug and may have been known in India as "soma" around 2000 b.c.

Nicander's Alexipharmaca (Antidotes for Poisons) recommended induction of emesis by one of several methods: (a) ingesting warm linseed oil, (b) tickling the hypopharynx with a feather, or (c) "emptying the gullet with a small twisted and curved paper."⁹² Nicander also advocated the use of suction to limit envenomation.¹⁴⁸ The Romans referred to the feather as the "vomiting feather" or "pinna." Most commonly, the feather was used after a hearty feast to avoid the GI discomfort associated with overeating. At times, the pinna was dipped into a nauseating mixture to increase its efficacy.⁹⁵

After Galen (ca. a.d. 129–200), there is relatively little documented attention to the subject of poisons until the works of Ibn Wahshiya in the 9th century. Citing Greek, Persian, and Indian texts, Wahshiya's work, titled Book of Poisons, combined contemporary science, magic, and astrology during his discussion of poison mechanisms (as they were understood at that time), symptomatology, antidotes (including his own recommendation for a universal antidote), and prophylaxis. He categorized poisons as lethal by sight, smell, touch, and sound, as well as by drinking and eating. For victims of an aconite-containing dart arrow, Ibn Wahshiya recommended excision followed by cauterization and topical treatment with onion and salt.⁸⁷

Another significant medieval contribution to toxicology can be found in Moses Maimonides' (1135–1204) Treatise on Poisons and Their Antidotes (1198). In part one of this treatise, Maimonides discussed the bites of snakes and mad dogs and the stings of bees, wasps, spiders, and scorpions.¹³¹ He also discussed the use of cupping glasses for bites (a progenitor of the modern suctioning device) and was one of the first to differentiate the hematotoxic (hot) from the neurotoxic (cold) effects of poison. In part two, he discussed mineral and vegetable poisons and their antidotes. He described belladonna poisoning as causing a "redness and a sort of excitation."¹³¹ He suggested that emesis should be induced by hot water, Anethum graveolens (dill), and oil followed by fresh milk, butter, and honey. Although he rejected some of the popular treatments of the day, he advocated the use of the great theriac and the mithradatum as first- and second-line xenobiotics in the management of snakebite.¹³¹

On the subject of oleander poisoning, Petrus Abbonus (1250–1315) wrote that those who drink the juice, spines, or bark of oleander will develop anxiety, palpitations, and syncope.²² He described the clinical presentation of opium overdose as someone who "will be dull, lazy, and sleepy, without feeling, and he will neither understand nor feel anything, and if he does not receive succor, he will die." Although this "succor" is not defined, he recommended that treatment of opium intoxication include drinking the strongest wine, rubbing the extremities with alkali and soap, and olfactory stimulation with pepper. To treat snakebite, Abbonus suggested the immediate application of a tourniquet, as well as oral suctioning of the bite wound, preferably performed by a servant. Interesting from a 21st-century perspective, Abbonus also suggested that St. John's wort had the magical power to free anything from poisons and attributed this virtue to the influence of the stars.²²

The Scientists

Paracelsus' (1493–1541) study on the dose–response relationship is usually considered the beginning of the scientific approach to toxicology (Table 1–2). He was the first to emphasize the chemical nature of toxic xenobiotics.¹¹⁷ Paracelsus stressed the need for proper observation and experimentation regarding the true response to xenobiotics. He underscored the need to differentiate between the therapeutic and toxic properties of chemicals when he stated in his Third Defense, "What is there that is not poison? All things are poison and nothing [is] without poison. Solely, the dose determines that a thing is not a poison."⁴³

Although Paracelsus is the best known Renaissance toxicologist, Ambroise Pare (1510–1590) and William Piso (1611–1678) also contributed to the field. Pare argued against the use of the unicorn horn and bezoar stone.⁹⁴ He also wrote an early treatise on carbon monoxide poisoning. Piso is credited as one of the first to recognize the emetic properties of ipecacuanha.¹²⁸

Medieval and Renaissance Poisoners

Along with these advances in toxicologic knowledge, the Renaissance is mainly remembered as the age of the poisoner, a time when the art of poisoning reached new heights (Table 1–3). In fact, poisoning was so rampant during this time that in 1531, King Henry VIII decreed that convicted poisoners should be boiled alive.⁵² From the 15th to 17th centuries, schools of poisoning existed in Venice and Rome. In Venice, poisoning services were provided by a group called the Council of Ten, whose members were hired to perform murder by poison.¹⁵⁵

Members of the infamous Borgia family were considered to be responsible for many poisonings during this period. They preferred to use a poison called "La Cantarella," a mixture of arsenic and phosphorus.¹⁴⁹ Rodrigo Borgia (1431–1503), who became Pope Alexander VI, and his son, Cesare Borgia, were reportedly responsible for the poisoning of cardinals and kings.

In the late 16th century, Catherine de Medici, wife of Henry II of France, introduced Italian poisoning techniques to France. She experimented on the poor, the sick, and the criminal. By analyzing the subsequent complaints of her victims, she is said to have learned the site of action and time of onset, the clinical signs and symptoms, and the efficacy of poisons.⁵⁶

Murder by poison remained quite popular during the latter half of the 17th and the early part of the 18th centuries in Italy and France.

The Marchioness de Brinvilliers (1630–1676) tested her poison concoctions on hospitalized patients and on her servants and allegedly murdered her husband, father, and two siblings.^54,139 Among the favorite poisons of the Marchioness were arsenic, copper sulfate, corrosive sublimate (mercury bichloride), lead, and tartar emetic (antimony potassium tartrate).¹⁴⁹ Catherine Deshayes (1640–1680), a fortuneteller and sorceress, was one of the last "poisoners for hire" and was implicated in countless poisonings, including the killing of more than 2000 infants.⁵⁶ Better known as "La Voisine," she reportedly sold poisons to women wishing to rid themselves of their husbands. Her particular brand of poison was a concoction of aconite, arsenic, belladonna, and opium known as la poudre de succession.¹⁴⁹ Ultimately, de Brinvilliers was beheaded and Deshayes was burned alive for their crimes. In an attempt to curtail these rampant poisonings, Louis XIV issued a decree in 1662 banning the sale of arsenic, mercury, and other poisons to customers not known to apothecaries and requiring buyers to sign a register declaring the purpose for their purchase.¹³⁹

A major center for poison practitioners was Naples, the home of the notorious Madame Giulia Toffana. She reportedly poisoned more than 600 people, preferring a particular solution of white arsenic (arsenic trioxide), better known as "aqua toffana," and dispensed under the guise of a cosmetic. Eventually convicted of poisoning, Madame Toffana was executed in 1719.²¹

The development of toxicology as a distinct specialty began during the 18th and 19th centuries (Table 1–2).¹¹⁸ The mythological and magical mystique of poisoners began to be gradually replaced by an increasingly rational, scientific, and experimental approach to these agents. Much of the poison lore that had survived for almost 2000 years was finally debunked and discarded. The 18th-century Italian Felice Fontana was one of the first to usher in the modern age. He was an early experimental toxicologist who studied the venom of the European viper and wrote the classic text Traite sur le Venin de la Vipere in 1781.⁷⁹ Through his exacting experimental study on the effects of venom, Fontana brought a scientific insight to toxicology previously lacking and demonstrated that clinical symptoms resulted from the poison (venom) acting on specific target organs. During the 18th and 19th centuries, attention focused on the detection of poisons and the study of toxic effects of xenobiotics in animals.¹¹¹ Issues relating to adverse effects of industrialization and unintentional poisoning in the workplace and home environment were raised. Also during this time, early experience and experimentation with methods of GI decontamination took place.

Development of Analytical Toxicology and the Study of Poisons

The French physician Bonaventure Orfila (1787–1853) is often called the father of modern toxicology.¹¹¹ He emphasized toxicology as a distinct, scientific discipline, separate from clinical medicine and pharmacology.¹¹ He was also an early medical-legal expert who championed the use of chemical analysis and autopsy material as evidence to prove that a poisoning had occurred. His treatise Traite des Poisons (1814)¹¹⁶ evolved over five editions and was regarded as the foundation of experimental and forensic toxicology.¹⁵⁴ This text classified poisons into six groups: acrids, astringents, corrosives, narcoticoacrids, septics and putrefiants, and stupefacients and narcotics.

A number of other landmark works on poisoning also appeared during this period. In 1829, Robert Christison (1797–1882), a professor of medical jurisprudence and Orfila's student, wrote A Treatise on Poisons.³² This work simplified Orfila's poison classification schema by categorizing poisons into three groups: irritants, narcotics, and narcoticoacrids. Less concerned with jurisprudence than with clinical toxicology, O.H. Costill's A Practical Treatise on Poisons, published in 1848, was the first modern clinically oriented text to emphasize the symptoms and treatment of poisoning.³⁶ In 1867, Theodore Wormley (1826–1897) published the first American book written exclusively on poisons titled Micro-Chemistry of Poisons.^48,157

During this time, important breakthroughs in the chemical analysis of poisons resulted from the search for a more reliable assay for arsenic. Arsenic was widely available and was the suspected cause of a large number of deaths. In one study, arsenic was used in 31% of 679 homicidal poisonings.¹⁴⁹ A reliable means of detecting arsenic was much needed by the courts.

Until the 19th century, poisoning was mainly diagnosed by its resultant symptoms rather than by analytic tests. The first use of a chemical test as evidence in a poisoning trial occurred in the 1752 trial of Mary Blandy, who was accused of poisoning her father with arsenic.⁹⁹ Although Blandy was convicted and hanged publicly, the test used in this case was not very sensitive and depended in part on eliciting a garlic odor upon heating the gruel that the accused had fed to her father.

During the 19th century, James Marsh (1794–1846), Hugo Reinsch (1842–1884), and Max Gutzeit (1847–1915) each worked on this problem. Assays bearing their names are important contributions to the early history of analytic toxicology.^100,111 The "Marsh test" to detect arsenic was first used in a criminal case in 1839 during the trial of Marie Lefarge, who was accused of using arsenic to murder her husband.¹³⁹ Orfila's trial testimony that the victim's viscera contained minute amounts of arsenic helped to convict the defendant, although subsequent debate suggested that contamination of the forensic specimen may have also played a role.

In a further attempt to curtail criminal poisoning by arsenic, the British Parliament passed the Arsenic Act in 1851. This bill, which was one of the first modern laws to regulate the sale of poisons, required that the retail sale of arsenic be restricted to chemists, druggists, and apothecaries and that a poison book be maintained to record all arsenic sales.¹⁵

Homicidal poisonings remained common during the 19th century and early 20th century. Infamous poisoners of that time included William Palmer, Edward Pritchard, Harvey Crippen, and Frederick Seddon.¹⁴⁹ Many of these poisoners were physicians who used their knowledge of medicine and toxicology in an attempt to solve their domestic and financial difficulties by committing the "perfect" murder. Some of the poisons used were aconitine (by Lamson, who was a classmate of Christison), Amanita phalloides (by Girard), arsenic (by Maybrick, Seddon, and others), antimony (by Pritchard), cyanide (by Molineux and Tawell), digitalis (by Pommerais), hyoscine (by Crippen), and strychnine (by Palmer and Cream) (Table 1–3).^{24,86,147,149}

In the early 20th century, forensic investigation into suspicious deaths, including poisonings, was significantly advanced with the development of the medical examiner system replacing the much-flawed coroner system that was subject to widespread corruption. In 1918, the first centrally controlled medical examiner system was established in New York City. Alexander Gettler, considered the father of forensic toxicology in the United States, established a toxicology laboratory within the newly created New York City Medical Examiner's Office. Gettler pioneered new techniques for the detection of a variety of substances in biologic fluids, including carbon monoxide, chloroform, cyanide, and heavy metals.^49,111

Systematic investigation into the underlying mechanisms of toxic substances also commenced during the 19th century. Francois Magendie (1783–1855) studied the mechanisms of toxicity and sites of action of cyanide, emetine, and strychnine.⁴⁷ Claude Bernard (1813–1878), a pioneering physiologist and a student of Magendie, made important contributions to the understanding of the toxicity of carbon monoxide and curare.⁸⁵ Rudolf Kobert (1854–1918) studied digitalis and ergot alkaloids and authored a textbook on toxicology for physicians and students.^83,114 Louis Lewin (1850–1929) was the first person to intensively study the differences between the pharmacologic and toxicologic actions of xenobiotics. Lewin studied chronic opium intoxication, as well as the toxicity of carbon monoxide, chloroform, lead, methanol, and snake venom. He also developed a classification system for psychoactive drugs, dividing them into euphorics, phantastics, inebriants, hypnotics, and excitants.⁹³

The Origin of Occupational Toxicology

The origins of occupational toxicology can be traced to the early 18th century and to the contributions of Bernardino Ramazzini (1633–1714). Considered the father of occupational medicine, Ramazzini wrote De Morbis Artificum Diatriba (Diseases of Workers) in 1700, which was the first comprehensive text discussing the relationship between disease and workplace hazards.⁵³ Ramazzini's essential contribution to patient care is epitomized by the addition of a standard question to a patient's medical history: "What occupation does the patient follow?"⁵¹ Altogether Ramazzini described diseases associated with 54 occupations, including hydrocarbon poisoning in painters, mercury poisoning in mirror makers, and pulmonary diseases in miners.

In 1775, Sir Percivall Pott proposed the first association between workplace exposure and cancer when he noticed a high incidence of scrotal cancer in English chimney sweeps. Pott's belief that the scrotal cancer was caused by prolonged exposure to tar and soot was confirmed by further investigation in the 1920s, indicating the carcinogenic nature of the polycyclic aromatic hydrocarbons contained in coal tar (including benzo[a]pyrene).⁷²

Dr. Alice Hamilton (1869–1970) was another pioneer in occupational toxicology whose rigorous scientific inquiry had a profound impact on linking chemical xenobiotics with human disease. A physician, scientist, humanitarian, and social reformer, Hamilton became the first female professor at Harvard University and conducted groundbreaking studies of many different occupational exposures and problems, including carbon monoxide poisoning in steelworkers, mercury poisoning in hatters, and wrist drop in lead workers. Hamilton's overriding concerns about these "dangerous trades" and her commitment to improving the health of workers led to extensive voluntary and regulatory reforms in the workplace.^60,65

Advances in Gastrointestinal Decontamination

Using gastric lavage and activated charcoal to treat poisoned patients was introduced in the late 18th and early 19th century. A stomach pump was first designed by Munro Secundus in 1769 to administer neutralizing substances to sheep and cattle for the treatment of bloat.²⁴ The American surgeon Philip Physick (1768–1837) and the French surgeon Baron Guillaume Dupuytren (1777–1835) were two of the first physicians to advocate gastric lavage for the removal of poisons.²⁵ As early as 1805, Physick demonstrated the use of a "stomach tube" for this purpose. Using brandy and water as the irrigation fluid, he performed stomach washings in twins to wash out excessive doses of tincture of opium.²⁵ Dupuytren performed gastric emptying by first introducing warm water into the stomach via a large syringe attached to a long flexible sound and then withdrawing the "same water charged with poison."²⁵ Edward Jukes, a British surgeon, was another early advocate of poison removal by gastric lavage. Jukes first experimented on animals, performing gastric lavage after the oral administration of tincture of opium. Attempting to gain human experience, he experimented on himself, by first ingesting 10 drams (600 g) of tincture of opium and then performing gastric lavage using a 25-inch-long, 0.5-inch-diameter tube, which became known as Jukes' syringe.¹⁰⁵ Other than some nausea and a 3-hour sleep, he suffered no ill effects, and the experiment was deemed a success.

The principle of using activated charcoal to adsorb xenobiotics was first described by Scheele (1773) and Lowitz (1785), but the medicinal use of activated charcoal dates to ancient times.³⁵ The earliest reference to the medicinal uses of activated charcoal is found in Egyptian papyrus from about 1500 b.c.³⁵ The activated charcoal used during Greek and Roman times, referred to as "wood charcoal," was used to treat those with anthrax, chlorosis, epilepsy, and vertigo. By the late 18th century, topical application of activated charcoal was recommended for gangrenous skin ulcers, and internal use of an activated charcoal-water suspension was recommended for use as a mouthwash and in the treatment of bilious conditions.³⁵

The first hint that activated charcoal might have a role in the treatment of poisoning came from a series of courageous self-experiments in France during the early 19th century. In 1813, the French chemist Bertrand publicly demonstrated the antidotal properties of activated charcoal by surviving a 5 g ingestion of arsenic trioxide that had been mixed with activated charcoal.⁶⁸ Eighteen years later, before the French Academy of Medicine, the pharmacist Touery survived an ingestion consisting of 10 times the lethal dose of strychnine mixed with 15 g of activated charcoal.⁶⁸ One of the first reports of activated charcoal used in a poisoned patient was in 1834 by the American Hort, who successfully treated a mercury bichloride–poisoned patient with large amounts of powdered activated charcoal.³

In the 1840s, Garrod performed the first controlled study of activated charcoal when he examined its utility on a variety of poisons in animal models.⁶⁸ Garrod used dogs, cats, guinea pigs, and rabbits to demonstrate the potential benefits of activated charcoal in the management of strychnine poisoning. He also emphasized the importance of early use of activated charcoal and the proper ratio of activated charcoal to poison. Other toxic substances, such as aconite, hemlock, mercury bichloride, and morphine, were also studied during this period. The first activated charcoal efficacy studies in humans were performed by the American physician B. Rand in 1848.⁶⁸

But it was not until the early 20th century that an activation process was added to the manufacture of activated charcoal to increase its effectiveness. In 1900, the Russian Ostrejko demonstrated that treating activated charcoal with superheated steam significantly enhanced its adsorbing power.³⁵ Despite this improvement and the favorable reports mentioned, activated charcoal was only occasionally used in GI decontamination until the early 1960s, when Holt and Holz repopularized its use.⁶³

The Increasing Recognition of the Perils of Drug Abuse

Opioids.

Although the medical use of opium was promoted by Paracelsus in the 16th century, the popularity of this agent was given a significant boost when the distinguished British physician Thomas Sydenham (1624–1689) formulated laudanum, which was a tincture of opium containing cinnamon, cloves, saffron, and sherry. Sydenham also formulated a different opium concoction known as "syrup of poppies."⁸² A third opium preparation called Dover's powder was designed by Sydenham's protégé, Thomas Dover; this preparation contained syrup of ipecac, licorice, opium, salt-peter, and tartaric acid.

John Jones, the author of the 18th century text The Mysteries of Opium Reveal'd, was another enthusiastic advocate of its "medicinal" uses.⁸² A well-known opium user himself, Jones provided one of the earliest descriptions of opioid addiction. He insisted that opium offered many benefits if the dose was moderate but that discontinuation or a decrease in dose, particularly after "leaving off after long and lavish use," would result in such symptoms as sweating, itching, diarrhea, and melancholy. His recommendation for the treatment of these withdrawal symptoms included decreasing the dose of opium by 1% each day until the drug was totally withdrawn. During this period, the number of English writers who became well-known opium addicts included Elizabeth Barrett Browning, Samuel Taylor Coleridge, and Thomas De Quincey. De Quincey, author of Confessions of an English Opium Eater, was an early advocate of the recreational use of opiates. The famed Coleridge poem Kubla Khan referred to opium as the "milk of paradise," and De Quincey's Confessions suggested that opium held the "key to paradise." In many of these cases, the initiation of opium use for medical reasons led to recreational use, tolerance, and dependence.⁸²

Although opium was first introduced to Asian societies by Arab physicians some time after the fall of the Roman Empire, the use of opium in Asian countries grew considerably during the 18th and 19th centuries. China's growing dependence on opium was spurred on by the English desire to establish and profit from a flourishing drug trade.¹³³ Opium was grown in India and exported east. Despite Chinese protests and edicts against this practice, the importation of opium persisted throughout the 19th century, with the British going to war twice in order to maintain their right to sell opium. Not surprisingly, by the beginning of the 20th century, opium abuse in China was endemic.

In England, opium use continued to increase during the first half of the 19th century. During this period, opium was legal and freely available from the neighborhood grocer. To many, its use was considered no more problematic than alcohol use.⁵⁸ The Chinese usually self-administered opium by smoking, a custom that was brought to the United States by Chinese immigrants in the mid-19th century; the English use of opium was more often by ingestion, that is, "opium eating."

The liberal use of opioids as infant-soothing agents was one of the most unfortunate aspects of this period of unregulated opioid use.⁸³ Godfrey's Cordial, Mother's Friend, Mrs. Winslow's Soothing Syrup, and Quietness were among the most popular opioids for children.⁸⁸ They were advertised as producing a natural sleep and recommended for teething and bowel regulation, as well as for crying. Because of the wide availability of opioids during this period, the number of acute opioid overdoses in children was consequential and would remain problematic until these unsavory remedies were condemned and removed from the market.

With the discovery of morphine in 1805 and Alexander Wood's invention of the hypodermic syringe in 1853, parenteral administration of morphine became the preferred route of opioid administration for therapeutic use and abuse.⁷⁰ A legacy of the generous use of opium and morphine during the United States Civil War was "soldiers' disease," referring to a rather large veteran population that returned from the war with a lingering opioid habit.¹²⁵ One hundred years later, opioid abuse and addiction would again become common among the US military serving during the Vietnam War. Surveys indicated that as many as 20% of American soldiers in Vietnam were addicted to opioids during the war, partly because of its widespread availability and high purity there.¹³⁰

Growing concerns about opioid abuse in England led to the passing of the Pharmacy Act of 1868, which restricted the sale of opium to registered chemists. But in 1898, the Bayer Pharmaceutical Company of Germany synthesized heroin from opium (Bayer also introduced aspirin that same year).¹⁴⁰ Although initially touted as a nonaddictive morphine substitute, problems with heroin use quickly became evident in the United States. Illicit heroin use reached epidemic proportions after World War II and again in the late 1960s.⁷¹ Although heroin use appeared to have leveled off by the end of the 20th century, an epidemic of prescription opioid abuse exploded during the first decade of the 21st century.⁹⁶

Cocaine.

Ironically, during the later part of the 19th century, Sigmund Freud and Robert Christison, among others, promoted cocaine as a treatment for opiate addiction. After Albert Niemann's isolation of cocaine alkaloid from coca leaf in 1860, growing enthusiasm for cocaine as a panacea ensued.⁷⁸ Some of the most important medical figures of the time, including William Halsted, the famed Johns Hopkins surgeon, also extolled the virtues of cocaine use. Halsted championed the anesthetic properties of this drug, although his own use of cocaine and subsequent morphine use in an attempt to overcome his cocaine dependency would later take a considerable toll.¹¹⁵ In 1884, Freud wrote Uber Cocaine,²⁷ advocating cocaine as a cure for opium and morphine addiction and as a treatment for fatigue and hysteria.

During the last third of the 19th century, cocaine was added to many popular nonprescription tonics. In 1863, Angelo Mariani, a Frenchman, introduced a new wine, "Vin Mariani," that consisted of a mixture of cocaine and wine (6 mg of cocaine alkaloid per ounce) and was sold as a digestive aid and restorative.¹⁰⁶ In direct competition with the French tonic was the American-made Coca-Cola, developed by J.S. Pemberton. It was originally formulated with coca and caffeine and marketed as a headache remedy and invigorator. With the public demand for cocaine increasing, patent medication manufacturers were adding cocaine to thousands of products. One such asthma remedy was "Dr. Tucker's Asthma Specific," which contained 420 mg of cocaine per ounce and was applied directly to the nasal mucosa.⁷⁸ By the end of the 19th century, the first American cocaine epidemic was underway.¹⁰⁸

Similar to the medical and societal adversities associated with opiate use, the increasing use of cocaine led to a growing concern about comparable adverse effects. In 1886, the first reports of cocaine-related cardiac arrest and stroke were published.¹²⁶ Reports of cocaine habituation occurring in patients using cocaine to treat their underlying opiate addiction also began to appear. In 1902, a popular book Eight Years in Cocaine Hell described some of these problems. Century Magazine called cocaine "the most harmful of all habit-forming drugs," and a report in The New York Times stated that cocaine was destroying "its victims more swiftly and surely than opium."⁴² In 1910, President William Taft proclaimed cocaine to be "public enemy number one."

In an attempt to curb the increasing problems associated with drug abuse and addiction, the 1914 Harrison Narcotics Act mandated stringent control over the sale and distribution of narcotics (defined as opium, opium derivatives, and cocaine).⁴² It was the first federal law in the United States to criminalize the nonmedical use of drugs. The bill required doctors, pharmacists, and others who prescribed narcotics to register and to pay a tax. A similar law, the Dangerous Drugs Act, was passed in the United Kingdom in 1920.⁵⁸ To help enforce these drug laws in the United States, the Narcotics Division of the Prohibition Unit of the Internal Revenue Service (a progenitor of the Drug Enforcement Agency) was established in 1920. In 1924, the Harrison Act was further strengthened with the passage of new legislation that banned the importation of opium for the purpose of manufacturing heroin, essentially outlawing the medicinal uses of heroin. With the legal venues to purchase these drugs now eliminated, users were forced to buy from illegal street dealers, creating a burgeoning black market that still exists today.

Sedative–Hypnotics.

The introduction to medical practice of the anesthetic agents nitrous oxide, ether, and chloroform during the 19th century was accompanied by the recreational use of these agents and the first reports of volatile substance abuse. Chloroform "jags," ether "frolics," and nitrous parties became a new type of entertainment. Humphrey Davies was an early self-experimenter with the exhilarating effects associated with nitrous oxide inhalation. In certain Irish towns, especially where the temperance movement was strong, ether drinking became quite popular.¹⁰² Horace Wells, the American dentist who introduced chloroform as an anesthetic, became dependent on this volatile solvent and later committed suicide.

Until the last half of the 19th century, aconite, alcohol, hemlock, opium, and prussic acid (cyanide) were the primary agents used for sedation.³³ During the 1860s, new, more specific sedative–hypnotics, such as chloral hydrate and potassium bromide, were introduced into medical practice. In particular, chloral hydrate was hailed as a wonder drug that was relatively safe compared with opium and was recommended for insomnia, anxiety, and delirium tremens, as well as for scarlet fever, asthma, and cancer. But within a few years, problems with acute toxicity of chloral hydrate, as well as its potential to produce tolerance and physical dependence, became apparent.³³ Mixing chloral hydrate with ethanol, both of which inhibit each other's metabolism by competing with alcohol dehydrogenase, was noted to produce a rather powerful "knockout" combination that would become known as a "Mickey Finn" allegedly named after a Chicago saloon proprietor.¹⁶ Abuse of chloral hydrate, as well as other new sedatives such as potassium bromide, would prove to be a harbinger of 20th-century sedative–hypnotic abuse.

Absinthe, an ethanol-containing beverage that was manufactured with an extract from wormwood (Artemisia absinthium), was very popular during the last half of the 19th century.⁸⁴ This emerald-colored, very bitter drink was memorialized in the paintings of Degas, Toulouse-Lautrec, and Van Gogh and was a staple of French society during this period.¹² α-Thujone, a psychoactive component of wormwood and a noncompetitive γ-aminobutyric acid type A GABA_A blocker, is thought to be responsible for the pleasant feelings, hyperexcitability, and significant neurotoxicity associated with this drink.⁶⁷ Van Gogh's debilitating episodes of psychosis were likely exacerbated by absinthe drinking.¹⁴⁴ Because of the medical problems associated with its use, absinthe was banned throughout most of Europe by the early 20th century.

Hallucinogens.

Native Americans used peyote in religious ceremonies since at least the 17th century. Hallucinogenic mushrooms, particularly Psilocybe mushrooms, were also used in the religious life of Native Americans. These were called "teonanacatl," which means "God's sacred mushrooms" or "God's flesh."¹²¹ Interest in the recreational use of cannabis also accelerated during the 19th century after Napoleon's troops brought the drug back from Egypt, where its use among the lower classes was widespread. In 1843, several French Romantics, including Balzac, Baudelaire, Gautier, and Hugo, formed a hashish club called "Le Club des Hachichins" in the Parisian apartment of a young French painter. Fitz Hugh Ludlow's The Hasheesh Eater, published in 1857, was an early American text espousing the virtues of marijuana.⁹¹

A more recent event that had significant impact on modern-day hallucinogen use was the synthesis of lysergic acid diethylamide (LSD) by Albert Hofmann in 1938.⁶⁶ Working for Sandoz Pharmaceutical Company, Hofmann synthesized LSD while investigating the pharmacologic properties of ergot alkaloids. Subsequent self-experimentation by Hofmann led to the first description of its hallucinogenic effects and stimulated research into the therapeutic use of LSD. Hofmann is also credited with isolating psilocybin as the active ingredient in Psilocybe mexicana mushrooms in 1958.¹⁰⁶

Early Regulatory Initiatives

The development of medical toxicology as a medical subspecialty and the important role of poison control centers began shortly after World War II. Before then, serious attention to the problem of household poisonings in the United States had been limited to a few federal legislative antipoisoning initiatives (Table 1–4). The 1906 Pure Food and Drug Act was the first federal legislation that sought to protect the public from problematic and potentially unsafe drugs and food. The driving force behind this reform was Harvey Wiley, the chief chemist at the Department of Agriculture. Beginning in the 1880s, Wiley investigated the problems of contaminated food. In 1902, he organized the "poison squad," which consisted of a group of volunteers who did self-experiments with food preservatives.⁴ Revelations from the "poison squad," as well as the publication of Upton Sinclair's muckraking novel The Jungle¹³⁸ in 1906, exposed unhygienic practices of the meatpacking industry and led to growing support for legislative intervention. Samuel Hopkins Adams' reports about the patent medicine industry revealed that some drug manufacturers added opiates to soothing syrups for infants and led to the call for reform.¹²⁷ Although the 1906 regulations were mostly concerned with protecting the public from adulterated food, regulations protecting against misbranded patent medications were also included.

The Federal Caustic Poison Act of 1927 was the first federal legislation to specifically address household poisoning. As early as 1859, bottles clearly demarcated "poison" were manufactured in response to a rash of unfortunate dispensing errors that occurred when oxalic acid was unintentionally substituted for a similarly appearing Epsom salts solution.²⁸ Before 1927, however, "poison" warning labels were not required on chemical containers, regardless of toxicity or availability. The 1927 Caustic Act was spearheaded by the efforts of Chevalier Jackson, an otolaryngologist, who showed that unintentional exposures to household caustic agents were an increasingly frequent cause of severe oropharyngeal and GI burns. Under this statute, for the first time, alkali- and acid-containing products had to clearly display a "poison" warning label.¹⁴⁶

The most pivotal regulatory initiative the United States before World War II—and perhaps the most significant American toxicologic regulation of the 20th century—was the Federal Food, Drug, and Cosmetic Act of 1938. Although the Food and Drug Administration (FDA) had been established in 1930 and legislation to strengthen the 1906 Pure Food and Drug Act was considered by Congress in 1933, the proposed revisions still had not been passed by 1938. Then the elixir of sulfanilamide tragedy in 1938 (Chap. 2) claimed the lives of 105 people who had ingested a prescribed liquid preparation of the antibiotic sulfanilamide inappropriately dissolved in diethylene glycol. This event finally provided the catalyst for legislative intervention.^104,153 Before the elixir disaster, proposed legislation called only for the banning of false and misleading drug labeling and for the outlawing of dangerous drugs without mandatory drug safety testing. After the tragedy, the proposal was strengthened to require assessment of drug safety before marketing, and the legislation was ultimately passed.

The Development of Poison Centers

World War II led to the rapid proliferation of new drugs and chemicals in the marketplace and in the household.³⁹ At the same time, suicide was recognized as a leading cause of death from these xenobiotics.⁹ Both of these factors led the medical community to develop a response to the serious problems of unintentional and intentional poisonings. In Europe during the late 1940s, special toxicology wards were organized in Copenhagen and Budapest,⁵⁹ and a poison information service was begun in the Netherlands (Table 1–5).¹⁵⁰ A 1952 American Academy of Pediatrics study revealed that more than 50% of childhood "accidents" in the United States were the result of unintentional poisonings.⁶¹ This study led Edward Press to open the first US poison center in Chicago in 1953.¹²² Press believed that it had become extremely difficult for individual physicians to keep abreast of product information, toxicity, and treatment for the rapidly increasing number of potentially poisonous household products. His initial center was organized as a cooperative effort among the departments of pediatrics at several Chicago medical schools, with the goal of collecting and disseminating product information to inquiring physicians, mainly pediatricians.¹²⁴

By 1957, 17 poison centers were operating in the United States.³⁹ With the Chicago center serving as a model, these early centers responded to physician callers by providing ingredient and toxicity information about drug and household products and making treatment recommendations. Records were kept of the calls, and preventive strategies were introduced into the community. As more poison centers opened, a second important function, providing information to calls from the general public, became increasingly common. The physician pioneers in poison prevention and poison treatment were predominantly pediatricians who focused on unintentional childhood ingestions.¹²⁹

During these early years in the development of poison centers, each center had to collect its own product information, which was a laborious and often redundant task.³⁸ In an effort to coordinate its operations and to avoid unnecessary duplication, Surgeon General James Goddard responded to the recommendation of the American Public Health Service and established the National Clearinghouse for Poison Control Centers in 1957.¹⁰¹ This organization, placed under the Bureau of Product Safety of the Food and Drug Administration, disseminated 5-inch by 8-inch index cards containing poison information to each center to help standardize poison center information resources. The Clearinghouse also collected and tabulated poison data from each of the centers.

Between 1953 and 1972, a rapid, uncoordinated proliferation of poison centers occurred in the United States.⁹⁸ In 1962, there were 462 poison centers. By 1970, this number had risen to 590,⁸⁹ and by 1978, there were 661 poison centers in the United States, including 100 centers in the state of Illinois alone.¹³⁵ The nature of calls to centers changed as lay public–generated calls began to outnumber physician-generated calls. Recognizing the public relations value and strong popular support associated with poison centers, some hospitals started poison centers without adequately recognizing or providing for the associated responsibilities. Unfortunately, many of these centers offered no more than a part-time telephone service located in the back of the emergency department or pharmacy staffed by poorly trained personnel.¹³⁵

Despite the "growing pains" of these poison services during this period, many significant achievements were made. A dedicated group of physicians and other health care professionals began devoting an increasing proportion of their time to poison-related matters. In 1958, the American Association of Poison Control Centers (AAPCC) was founded to promote closer cooperation between poison centers, to establish uniform standards, and to develop educational programs for the general public and health care professionals.⁶¹ Annual research meetings were held, and important legislative initiatives were stimulated by the organization's efforts.¹⁰¹ Examples of such legislation include the Federal Hazardous Substances Labeling Act of 1960, which improved product labeling; the Child Protection Act of 1966, which extended labeling statutes to pesticides and other hazardous substances; and the Poison Prevention Packaging Act of 1970, which mandated safety packaging. In 1961, in an attempt to heighten public awareness of the dangers of unintentional poisoning, the third week of March was designated as the Annual National Poison Prevention Week.

Another organization that would become important, the American Academy of Clinical Toxicology (AACT), was founded in 1968 by a diverse group of toxicologists.³⁴ This group was "interested in applying principles of rational toxicology to patient treatment" and in improving the standards of care on a national basis.¹³² The first modern textbooks of clinical toxicology began to appear in the mid-1950s with the publication of Dreisbach's Handbook of Poisoning (1955)⁴⁵; Gleason, Gosselin, and Hodge's Clinical Toxicology of Commercial Products (1957)⁵⁷; and Arena's Poisoning (1963).¹⁰ Major advancements in the storage and retrieval of poison information were also instituted during these years. Information as noted above on consumer products initially appeared on index cards distributed regularly to poison centers by the National Clearinghouse, and by 1978, more than 16,000 individual product cards had been issued.¹³⁵ The introduction of microfiche technology in 1972 enabled the storage of much larger amounts of data in much smaller spaces at the individual poison centers. Toxifile and POISINDEX, two large drug and poison databases using microfiche technology, were introduced and gradually replaced the much more limited index card system.¹³⁵ During the 1980s, POISINDEX, which had become the standard database, was made more accessible by using CD-ROM technology. Sophisticated information about the most obscure xenobiotics was now instantaneously available by computer at every poison center.

In 1978, the poison center movement entered an important new stage in its development when the AAPCC introduced standards for regional poison center designation.⁹⁸ By defining strict criteria, the AAPCC sought to upgrade poison center operations significantly and to offer a national standard of service. These criteria included using poison specialists dedicated exclusively to operating the poison center 24 hours per day and serving a catchment area of between 1 and 10 million people. Not surprisingly, this professionalization of the poison center movement led to a rapid consolidation of services. An AAPCC credentialing examination for poison information specialists was inaugurated in 1983 to help ensure the quality and standards of poison center staff.⁷

In 2000, the Poison Control Center Enhancement and Awareness Act was passed by Congress and signed into law by President Clinton. For the first time, federal funding became available to provide assistance for poison prevention and to stabilize the funding of regional poison centers. This federal assistance permitted the establishment of a single nationwide toll-free phone number (800-222-1222) to access poison centers. At present, 57 centers contribute data to a National Poison Database System (NPDS) which from 1983 to 2006 was known as Toxic Exposure Surveillance System (TESS). Recently, the Centers for Disease Control and Prevention (CDC) has been collaborating with the AAPCC to conduct real-time surveillance of this data to help facilitate the early detection of chemical exposures of public health importance.¹⁵⁶

A poison center movement has also grown and evolved in Europe over the past 35 years, but unlike the movement in the United States, it focused from the beginning on establishing strong centralized toxicology treatment centers. In the late 1950s, Gaultier in Paris developed an inpatient unit dedicated to the care of poisoned patients.⁵⁹ In the United Kingdom, the National Poison Information Service developed at Guys Hospital in 1963 under Roy Goulding. Henry Matthew initiated a regional poisoning treatment center in Edinburgh about the same time.¹²⁴ In 1964, the European Association for Poison Control Centers was formed in Tours, France.⁵⁹

The Rise of Environmental Toxicology and Further Regulatory Protection from Toxic Substances

The rise of the environmental movement during the 1960s can be traced, in part, to the publication of Rachel Carson's Silent Spring in 1962, which revealed the perils of an increasingly toxic environment.²⁹ The movement also benefited from the new awareness by those involved with the poison movement of the growing menace of xenobiotics in the home environment.²⁶ Battery casing fume poisoning, resulting from the burning of discarded lead battery cases, and acrodynia, resulting from exposure to a variety of mercury-containing products,⁴¹ both demonstrated that young children are particularly vulnerable to low-dose exposures from certain xenobiotics. Worries about the persistence of pesticides in the ecosystem and the increasing number of chemicals introduced into the environment added to concerns of the environment as a potential source of illness, heralding a drive for additional regulatory protection.

Starting with the Clean Air Act in 1963, laws were passed to help reduce the toxic burden on our environment (Table 1–4). The establishment of the Environmental Protection Agency (EPA) in 1970 spearheaded this attempt at protecting our environment, and during the next 10 years, numerous protective regulations were introduced. Among the most important initiatives was the Occupational Safety and Health Act of 1970, which established the Occupational Safety and Health Administration (OSHA). This act mandates that employers provide safe work conditions for their employees. Specific exposure limits to toxic chemicals in the workplace were promulgated. The Consumer Product Safety Commission was created in 1972 to protect the public from consumer products that posed an unreasonable risk of illness or injury. Cancer-producing substances, such as asbestos, benzene, and vinyl chloride, were banned from consumer products as a result of these new regulations. Toxic waste disasters such as those at Love Canal, New York, and Times Beach, Missouri, led to the passing of the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA, also known as the Superfund) in 1980. This fund is designed to help pay for cleanup of hazardous substance releases posing a potential threat to public health. The Superfund legislation also led to the creation of the Agency for Toxic Substances and Disease Registry (ATSDR), a federal public health agency charged with determining the nature and extent of health problems at Superfund sites and advising the US EPA and state health and environmental agencies on the need for cleanup and other actions to protect the public's health. In 2003, the ATSDR became part of the National Center for Environmental Health of the CDC.

Medical Toxicology Comes of Age

Over the past 25 years, the primary specialties of medical toxicologists have changed. The development of emergency medicine and preventive medicine as medical specialties led to the training of more physicians with a dedicated interest in toxicology. By the early 1990s, emergency physicians accounted for more than half the number of practicing medical toxicologists. The increased diversity of medical toxicologists with primary training in emergency medicine, pediatrics, preventive medicine, or internal medicine has helped broaden the goals of poison centers and medical toxicologists beyond the treatment of acute unintentional childhood ingestions. The scope of medical toxicology now includes a much wider array of toxic exposures, including acute and chronic, adult and pediatric, unintentional and intentional, and occupational and environmental exposures.

The development of medical toxicology as a medical subspecialty began in 1974, when the AACT created the American Board of Medical Toxicology (ABMT) to recognize physician practitioners of medical toxicology.⁵ From 1974 to 1992, 209 physicians obtained board certification, and formal subspecialty recognition of medical toxicology by the American Board of Medical Specialties (ABMS) was granted in 1992. In that year, a conjoint subboard with representatives from the American Board of Emergency Medicine, American Board of Pediatrics, and American Board of Preventive Medicine was established, and the first ABMS-sanctioned examination in medical toxicology was offered in 1994. By 2013, a total of more than 450 physicians were board certified in medical toxicology. The American College of Medical Toxicology (ACMT) was founded in 1994 as a physician-based organization designed to advance clinical, educational, and research goals in medical toxicology. In 1999, the Accreditation Council of Graduate Medical Education (ACGME) in the United States formally recognized postgraduate education in medical toxicology, and by 2013, 29 fellowship training programs had been approved.

During the 1990s in the United States, some medical toxicologists began to work on establishing regional toxicology treatment centers. Adapting the European model, such toxicology treatment centers could serve as referral centers for patients requiring advanced toxicologic evaluation and treatment. Goals of such inpatient regional centers included enhancing care of poisoned patients, strengthening toxicology training, and facilitating research. The evaluation of the clinical efficacy and fiscal viability of such programs is ongoing.

The professional maturation of advanced practice pharmacists and nurses with primary interests in clinical toxicology has also taken place over the past 2 decades. In 1985, the AACT established the American Board of Applied Toxicology (ABAT) to administer certifying examinations for nonphysician practitioners of medical toxicology who meet their rigorous standards.⁴ By 2013, more than 85 toxicologists, who mostly held either a PharmD or a PhD in pharmacology or toxicology, were certified by this board.

Recent Poisonings and Poisoners

Although accounting for just a tiny fraction of all homicidal deaths (0.16% in the United States), notorious lethal poisonings continued throughout the 20th century (Table 1–3).¹

In England, Graham Frederick Young developed a macabre fascination with poisons.³⁰ In 1971, at age 14 years, he killed his stepmother and other family members with arsenic and antimony. Sent away to a psychiatric hospital, he was released at age 24 years, when he was no longer considered to be a threat to society. Within months of his release, he again engaged in lethal poisonings, killing several of his coworkers with thallium. Ultimately, he died in prison in 1990.

In 1978, Georgi Markov, a Bulgarian defector living in London, developed multisystem failure and died 4 days after having been stabbed by an umbrella carried by an unknown assailant. The postmortem examination revealed a pinhead-sized metal sphere embedded in his thigh where he had been stabbed. Investigators hypothesized that this sphere had most likely carried a lethal dose of ricin into the victim.³⁷ This theory was greatly supported when ricin was isolated from the pellet of a second victim who was stabbed under similar circumstances.

In 1982, deliberate tampering of nonprescription Tylenol preparations with potassium cyanide caused seven deaths in Chicago.⁴⁶ Because of this tragedy, packaging of nonprescription medications was changed to decrease the possibility of future product tampering.¹⁰⁷ The perpetrator(s) were never apprehended, and other deaths from nonprescription product tampering were reported in 1991.³¹

In 1998, Judias Buenoano, known as the "black widow," was executed for murdering her husband with arsenic in 1971 to collect insurance money. She was the first woman executed in Florida in 150 years. The fatal poisoning had remained undetected until 1983, when Buenoano was accused of trying to murder her fiancé with arsenic and by car bombing. Exhumation of the husband's body, 12 years after he died, revealed substantial amounts of arsenic in the remains.²

Health care providers have been implicated in several poisoning homicides as well. An epidemic of mysterious cardiopulmonary arrests at the Ann Arbor Veterans Administration Hospital in Michigan in July and August 1975 was attributed to the homicidal use of pancuronium by two nurses.¹⁴⁵ Intentional digoxin poisoning by hospital personnel may have explained some of the increased number of deaths on a cardiology ward of a Toronto pediatric hospital in 1981, but the cause of the high mortality rate remained unclear.²³ In 2000, an English general practitioner Harold Shipman was convicted of murdering 15 women patients with heroin and may have murdered as many as 297 patients during his 24-year career. These recent revelations prompted calls for strengthening the death certification process, improving preservation of case records, and developing better procedures to monitor controlled drugs.⁶⁹

Also in 2000, Michael Swango, an American physician, pleaded guilty to the charge of poisoning a number of patients under his care during his residency training. Succinylcholine, potassium chloride, and arsenic were used to kill his patients.¹⁴³ Attention to more careful physician credentialing and to maintenance of a national physician database arose from this case because the poisonings occurred at multiple hospitals across the country. Continuing concerns about health care providers acting as serial killers is highlighted by a recent case in New Jersey in which a nurse, Charles Cullen, was found responsible for killing patients with digoxin.¹⁷

By the end of the 20th century, 24 centuries after Socrates was executed by poison hemlock, the means of implementing capital punishment had come full circle. Government-sanctioned execution in the United States again favored the use of a "state" poison—this time, the combination of sodium thiopental, pancuronium, and potassium chloride.

The use of a poison to achieve political ends has again resurfaced in several incidents from the former Soviet Union. In December 2004, it was announced that the Ukrainian presidential candidate Viktor Yushchenko was poisoned with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent dioxin.¹⁴¹ The dramatic development of chloracne over the face of this public person during the previous several months suggested dioxin as a possibly culprit. Given the paucity of reports of acute dioxin poisoning, however, it was not until laboratory tests confirmed that Yushenko's dioxin concentrations were more than 6000 times normal that this diagnosis was confirmed. In another case, a former KGB agent and Russian dissident Alexander Litvinenko was murdered with polonium-210. Initially thought to be a possible case of heavy metal poisoning, Litvinenko developed acute radiation syndrome manifested by acute GI symptoms followed by alopecia and pancytopenia before he died.¹⁰³

Other Developments

Medical Errors.

Beginning in the 1980s, several highly publicized medication errors received considerable public attention and provided a stimulus for the initiation of change in policies and systems. Ironically, all of the cases occurred at nationally preeminent university teaching hospitals. In 1984, 18 year-old Libby Zion died from severe hyperthermia soon after hospital admission. Although the cause of her death was likely multifactorial, drug–drug interactions and the failure to recognize and appropriately treat her agitated delirium also contributed to her death.¹³ State and national guidelines for closer house staff supervision, improved working conditions, and a heightened awareness of consequential drug–drug interactions resulted from the medical, legislative, and legal issues of this case. In 1994, a prominent health journalist for the Boston Globe, Betsy Lehman, was the unfortunate victim of another preventable dosing error when she inadvertently received four times the dose of the chemotherapeutic cyclophosphamide as part of an experimental protocol.⁸⁰ Despite treatment at a world-renowned cancer center, multiple physicians, nurses, and pharmacists failed to notice this erroneous medication order. An overhaul of the medication-ordering system was implemented at that institution after this tragic event.

Another highly publicized death occurred in 1999 when 18-year-old Jesse Gelsinger died after enrolling in an experimental gene-therapy study. Gelsinger, who had ornithine transcarbamylase deficiency, died from multiorgan failure 4 days after receiving, by hepatic infusion, the first dose of an engineered adenovirus containing the normal gene. Although this unexpected death was not the direct result of a dosing or drug–drug interaction error, the FDA review concluded that major research violations had occurred, including failure to report adverse effects with this therapy in animals and earlier clinical trials and to properly obtain informed consent.¹³⁷ In 2001, Ellen Roche, a 24 year-old healthy volunteer in an asthma study at John Hopkins University, developed a progressive pulmonary illness and died one month after receiving 1 g of hexamethonium by inhalation as part of the study protocol.¹⁴² Hexamethonium, a ganglionic blocker, was once used to treat hypertension but was removed from the market in 1972. The investigators were cited for failing to indicate on the consent form that hexamethonium was experimental and not FDA approved. Calls for additional safeguards to protect patients in research studies resulted from these cases.

In late 1999, the problems of medical errors finally received the high visibility and deserved attention in the United States with the publication and subsequent reaction to an Institute of Medicine (IOM) report suggesting that 44,000 to 98,000 fatalities each year were the result of medical errors.⁸¹ Many of these errors were attributed to preventable medication errors. The IOM report focused on its findings that errors usually resulted from system faults and not solely from the carelessness of individuals.

Toxicology in the Twenty-First Century

As new challenges and opportunities arise in the 21st century, two new toxicologic disciplines have emerged: toxicogenomics and nanotoxicology.^40,44,113 These nascent fields constitute the toxicologic responses to rapid advances in genetics and material sciences. Toxicogenomics combines toxicology with genomics dealing with how genes and proteins respond to toxic substances. The study of toxicogenomics attempts to better decipher the molecular events underlying toxicologic mechanisms, develop predictors of toxicity through the establishment of better molecular biomarkers, and better understand genetic susceptibilities that pertain to toxic substances such as unanticipated idiosyncratic drug reactions.

Nanotoxicology refers to the toxicology of engineered tiny particles, usually smaller than 100 nm. Given the extremely small size of nanoparticles, typical barriers at portals of entry may not prevent absorption or may themselves be adversely affected by the nanoparticles. Ongoing studies focus on the translocation of these particles to sensitive target sites such as the central nervous system or bone marrow (Chap. 129).¹¹³

• Since the dawn of recorded history, toxicology has impacted greatly on human events and our ecosystem.

• Over the millennia, although the important poisons of the day have changed to some degree, toxic substances continue to challenge our safety.

• The era of poisoners for hire may have long ago reached its pinnacle, but problems with drug abuse, intentional self-poisoning, and exposure to environmental chemicals continue to challenge us.

• Knowledge acquired by one generation is often forgotten or discarded inappropriately by the next generation, leading to a cyclical historic course.

References