Historical Principles and Perspectives




INTRODUCTION



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The term poison first appeared in the English literature around 1225 A.D. to describe a potion or draught that was prepared with deadly ingredients.8,155 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 control center, the genesis of the field of medical toxicology, and the 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.




POISONS, POISONERS, AND ANTIDOTES OF ANTIQUITY



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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.102,155 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.130 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).155




TABLE 1–1Important Early People in the History of Toxicology



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.102 Cave paintings of arrowheads and spearheads reveal that these weapons were crafted with small depressions at the end to hold the poison.156 In fact, the term toxicology is derived from the Greek terms toxikos (“bow”) and toxikon (“poison into which arrowheads are dipped”).6,156



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.164



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.156 This categorization remained the standard classification for the next 1,500 years.156



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.142 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.155 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.76



Vegetable Poisons



Theophrastus (ca. 370–286 B.C.) described vegetable poisons in his treatise De Historia Plantarum.77 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.”155 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.144 Poisonous plants used in India at this time included Cannabis indica (marijuana), Croton tiglium (croton oil), and Strychnos nux vomica (poison nut, strychnine).77



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.55,118 In addition to its considerable use in plumbing,44 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.159 Dioscorides, writing in the 1st century A.D., noted that fortified wine was “most hurtful to the nerves.”159 Lead-induced gout (“saturnine gout”) may have also been widespread among the Roman elite.118



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 lead to a heavy head and death,”74 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 17th-century France.164



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 this 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.147



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.155 Mystery and superstition surrounded the origins and sources of these proposed antidotes. One of the earliest specific references to a protective therapy 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. Moli could have been used as an antidote against poisonous plants such as Datura stramonium (jimsonweed) that contain the anticholinergic alkaloids scopolamine, atropine, and hyoscyamine.127



Theriacs and the Mithridatum



The Greeks referred to the universal antidote as the alexipharmaca or theriac.79,155 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.155



The quest for the universal antidote was epitomized by the work of King Mithridates VI of Pontus (135–63 B.C.).75 After repeatedly being subjected to poisoning attempts by his enemies during his youth, Mithridates 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 “mithridatum,” contained a minimum of 36 ingredients and was thought to be protective against aconite, scorpions, sea slugs, spiders, vipers, and all other poisonous substances. Mithridates took his concoction every day. Ironically, when an old man, Mithridates attempted suicide by poison but supposedly was unsuccessful because he had become poison proof. Having failed at self-poisoning, Mithridates was compelled to have a soldier kill him with a sword. Galen described Mithridates’ experiences in a series of three books: De Antidotis I, De Antidotis II, and De Theriaca ad Pisonem.75,160



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 mithridatum.146 It was prepared by Andromachus (37–68 A.D.), physician to Emperor Nero. Andromachus added to the mithridatum ingredients such as the flesh of vipers, squills, and generous amounts of opium.167 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.155,160 As evidence of its efficacy, Galen demonstrated that fowl receiving poison followed by theriac had a higher survival rate than fowl receiving poison alone.155 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.98 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.155



Whether these preparations were of actual benefit is uncertain. Some suggest that the theriac 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.98 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 Mithridatum and Theriaca.75 Nonetheless, pharmacopeias in France, Spain, and Germany continued to list these preparations until the last quarter of the 19th century, and theriac was still available in Italy and Turkey in the early 20th century.19,98



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.155 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 Italy, Malta, Silesia, and England.155



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.155



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.155 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.96 To give further credence to its use, a 1593 study on dogs poisoned by arsenic reportedly showed that the horn was protective.96



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.50,155




OPIUM, COCA, CANNABIS, AND HALLUCINOGENS IN ANTIQUITY



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Although it was not until the mid-19th century that the true perils of opioid 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.141 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. Mithridates’ 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.141 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.”141



Cocaine use dates back to at least 300 B.C., when South American Indians reportedly chewed coca leaves during religious ceremonies.112 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.116 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.126



Cannabis use in China dates back even further, to around 2700 B.C., when it was known as the “liberator of sin.”112 In India and Iran, cannabis was used as early as 1000 B.C. as an xenobiotic known as bhang.115 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.112 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.




EARLY ATTEMPTS AT GASTROINTESTINAL DECONTAMINATION



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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.”98 Nicander also advocated the use of suction to limit envenomation.156 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.101




TOXICOLOGY DURING THE MEDIEVAL AND RENAISSANCE PERIODS



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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.93



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.139 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.”139 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 mithridatum as first- and second-line xenobiotics in the management of snakebite.139



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 toxicity 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. Interestingly, 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.123 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




TABLE 1–2Important People in the Later History of Toxicology



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.100 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.136



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.164




TABLE 1–3Notable Poisoners from Antiquity to the Present



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.157 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 sites of action and times of onset, the clinical signs and symptoms, and the efficacies 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.54,147 Among the favorite poisons of the Marchioness were arsenic, copper sulfate, corrosive sublimate (mercury bichloride), lead, and tartar emetic (antimony potassium tartrate).157 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 2,000 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.”157 Ultimately, de Brinvilliers was beheaded, and Deshayes was burned alive for her 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.147



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




EIGHTEENTH- AND NINETEENTH-CENTURY DEVELOPMENTS IN TOXICOLOGY



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The development of toxicology as a distinct specialty began during the 18th and 19th centuries (Table 1–2).125 The mythological and magical mystique of poisoners began to be gradually replaced by an increasingly rational, scientific, and experimental approach to these xenobiotics. Much of the poison lore that had survived for almost 2,000 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 1781.82 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.117 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.

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