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Industrial Toxicology: Origins and TrendsEula Bingham, Ph.D., John Zapp, Ph.D., (deceased)
 1 IntroductionIndustrial toxicology is a comparatively recent discipline, but its roots are shadowed in the mists of time. The beginnings of toxicology, the knowledge or science of poisons, are prehistoric. Earliesthuman beings found themselves in environments that were at the same time helpful and hostile totheir survival. They found their food among the plants, trees, animals, and fish in their immediatesurroundings, their clothing in the skins of animals, and their shelter mainly in caves. Their earliesttools and weapons were of wood and stone.It was in the very early period of prehistory that humans must have become aware of the phenomenon of toxicity. Some fruits, berries, and vegetation could be eaten with safety and to their  benefit, whereas others caused illness or even death. The bite of the asp or adder could be fatal,whereas the bite of many other snakes was not. Humans learned from experience to classify thingsinto categories of safe and harmful. Personal survival depended on recognition and avoidance, so far as possible, of the dangerous categories.In a unique difference from other animals, humans learned to construct tools and weapons thatfacilitated their survival. Stone and wood gave way in time to bronze and then to iron as materialsfor constructing these tools and weapons. The invention of the bow and arrow was a giant stepforward in weaponry, for it gave humans a chance to kill animals or other people from a safedistance. And humans soon used their knowledge of the poisonous materials they found in their natural environment to enhance the lethality of their weapons.One of the earliest examples of the deliberate use of poisons in weaponry was smearing arrowheadsand spear points with poisons to improve their lethal effectiveness. In the
Old Testament 
we find atJob 6:4, “The arrows of the Almighty find their mark in me, and their poison soaks into myspirit” (
The New English Bible
The Book of Job
is generally dated at about 400 B. C.L. G. Stevenson (1) cites the Presidential Address of F. H. Edgeworth before the Bristol Medico-Chirurgical Society in 1916, to the effect that Odysseus is credited in Homer's
withobtaining a man-killing poison from Anchialos, king of the Taphians, to smear on his bronze-tippedarrows. This particular passage does not occur in modern translations of the
and, accordingto Edgeworth, was probably expurgated from the text when Greece came under the domination of Athens, at which time the use of poisons on weapons was considered barbaric and not worthy of such a hero as Odysseus.Because the earliest literature reference to Homer is dated at 660 B. C., well before the Pan-Athenian period, an early origin of the use of poisoned arrows can be assumed. Indeed, the word “toxic”derives from the early Greek use of poisoned arrows.The Greek word for the bow was toxon and for a drug was pharmakon. Therefore, an arrow poisonwas called toxikon pharmakon, or drug pertaining to the bow. Many Latin words are derived fromthe Greek, but the Romans took only the first of the two Greek works as their equivalent of “poison,”that is, toxicum. Other Latin words for poison were venenum and virus. In the transition to English,toxicum became “toxin,” and the knowledge or science of toxins becomes “toxicology.”There were practicing toxicologists in Greece and Rome. Stevenson (1) refers to a book by Sir T. C.Albutt (2) according to which the professional toxicologists of Greece and Rome were purveyors of  poisons and dealt in three kinds: those that acted quickly, those that caused a lingering illness, andthose that had to be given repeatedly to produce a cumulative effect. These poisons were of vegetable or animal origin, except for arsenic. Although the toxicity of lead was described byHippocrates, and of mercury by Pliny the Elder, these metals were apparently not deliberatelyemployed as poisons before the Renaissance.
 There is little doubt that the customers of the early toxicologists were interested in assassination or suicide. Poisons offered a safer means for the assassin of disposing of an enemy than the morevisible alternatives that posed the risk of premature discovery and possibly effective retaliation. As ameans of suicide, poison often seemed more acceptable than other available means of self-destruction. Although poisons have continued to be used for both homicide and suicide, their  popularity for these purposes has decreased as the popularity of firearms has increased.The use of poisons as adjuncts to other weapons such as the spear or arrow ceased in WesternEurope long before the discovery of firearms. It has persisted to this day in primitive civilizationssuch as those of the African pygmies and certain tribes of South American Indians. The use of  poison on a large scale as a primary weapon of war occurred during World War I, when both sidesemployed poison gases. In the interval between World War I and World War II, the potential of chemical and biological agents as a means of coercion was thoroughly studied by most of the powers, and both sides were prepared to use them, if necessary, in World War II. Although their usein future wars has apparently been renounced, it should not be forgotten that the chemical and biological toxins remain viable means of coercion that could be utilized under appropriatecircumstances in future conflicts. It would not be prudent to forget this in thinking about nationaldefense.The early and sinister uses of poisons did result in contributions to toxicology. Furthermore, theknowledge obtained did not require extrapolation to the human species, for humans were the subjectsin early experimentation.As mentioned earlier, the professional toxicologists of Greece and Rome had recognized and dealtwith poisons that produced acute effects, those that produced lingering effects, and those that produced cumulative effects. We recognize these categories today. The “dose-effects” relationshipwas also recognized. In Plato's well-known description of the execution of Socrates, Socrates isrequired to drink a cup of hemlock, an extract of a parsley-like plant that bears a high concentrationof the alkaloid coniine. When Socrates asks whether it is permissible to pour out a libation first toany god, the jailer replies, “We only prepare, Socrates, just as much as we deem enough.”The ancients also had some concept of the development of tolerance to poisons. There have comedown through the ages the poison damsel stories. In one of these, related by Stevenson (1), a king of India sent a beautiful damsel to Alexander the Great because he guessed rightly that Alexander wasabout to invade his kingdom. The damsel had been reared among poisonous snakes and had becomeso saturated with their venom that all of her secretions were deadly. It is said that Aristotle dissuadedAlexander from doing what seemed natural under the circumstances until Aristotle performed acertain test. The test consisted in painting a circle on the floor around the girl with an extract of dittany, believed to be a powerful snake poison. When the circle was completed, the girl is said tohave collapsed and died. The poison damsel stories continued to appear from time to time, and even Nathaniel Hawthorne wrote a short story about one entitled “Rappaccini's Daughter.”Kings and other important personages, fearing assassinations, sometimes tried to protect themselvesfrom this hazard by attempting to build up an immunity to specific poisons by taking graduallyincreasing doses until able to tolerate lethal doses, sometimes—it is said—with results disastrous tothe queen. Other kings took the precaution of having slaves taste their food before they ate. Whenslaves became too scarce or expensive, they substituted dogs as the official tasters and found that itworked about as well. Perhaps we have here the birth of experimental toxicology in which anonhuman species was deliberately used to predict human toxicity.Little of importance to the science of toxicology developed during the Middle Ages. Such researchas was done was largely empirical and involved the search for such things as the Philosopher's Stone,the Universal Solvent, the Elixir of Life, and the Universal Remedy. The search for the UniversalRemedy is rumored to have been abandoned in the twelfth century when the alchemists learned how
to make a 60% solution of ethyl alcohol through improved techniques of distillation and found that ithad some remarkable restorative properties.Although modern science is generally held to have had its beginnings in the seventeenth centurywith the work of Galileo, Descartes, and Francis Bacon, there was a precursor in the sixteenthcentury of some importance to toxicology. This was the physician-alchemist Phillipus AureolusTheophrastus Bombastus von Hohenheim, known as Paracelsus. Born in 1490, the son of a physician, Paracelsus studied medicine with his father and alchemy at various universities. He wasnot impressed with the way that either medicine or alchemy was being taught or practiced anddecided that more could be learned from the study of nature than from studying books by ancientauthorities.Through travel and observation, Paracelsus learned more than his contemporaries about the naturalhistory of diseases, to whose cure he applied his knowledge of both medicine and alchemy. Headvocated that the natural substances then used as remedies be purified and concentrated byalchemical methods to enhance their potency and efficacy. He also attempted to find specifictherapeutic agents for specific diseases and became highly successful as a practicing physician; in1526 he was appointed Town Physician to the city of Basel, Switzerland, and a lecturer in theuniversity. Being of an egotistical and quarrelsome disposition, Paracelsus quickly antagonized themedical and academic establishment.In the sixteenth century, syphilis was a more lethal disease than it was to become later, and themedical profession had no interest in it or cures for it. Paracelsus introduced and advocated the useof mercury for treating syphilis, and it worked. The establishment, however, was outraged anddenounced Paracelsus for using a poison to treat a disease. Paracelsus loved an argument andresponded to this and other accusations with a series of “Defenses,” of which the Third Defense (3)contained this statement with respect to his advocacy of the use of mercury or any other poison for therapeutic purposes: “What is it that is not poison? All things are poison and none without poison.Only the dose determines that a thing is not poison.” Paracelsus lectured and wrote in German,which was also contrary to prevailing academic tradition. When his works were eventually translatedinto Latin, the last sentence of the above quotation was usually rendered, “Dosis sola facit venenum”or “The dose alone makes a poison.” This principle is the keystone of industrial hygiene and is a basic concept in toxicology.Mercury soon became and remained the therapy of choice for syphilis for the next 300 years untilEhrlich discovered on his 606th trial an arsphenamine, Salvarsan, which was superior. Antimonywas widely used as a therapeutic agent from the seventeenth to the nineteenth century, and with themedical profession was sharply divided as to whether it was more poison than remedy or moreremedy than poison.The period from the seventeenth to the nineteenth century witnessed little decline in the use of human subjects for the initial evaluation of remedies. In 1604, a book said to have been written by amonk named Basile Valentine, but more probably by an anonymous alchemist, was published under the title
The Triumphant Chariot of Antimony
. The book states that the author had observed thatsome pigs fed food containing antimony had become fat. Therefore, he gave antimony to somemonks who had lost considerable weight through fasting, to see if it would help them to regainweight faster. Unfortunately, they all died. Up to this time, the accepted name for the element had been stibium (from which we retain the symbol Sb), but it was renamed antimony from the wordsauti-moine meaning “monk's bane.” The
Oxford English Dictionary
agrees that this might be the popular etymology of the word. This anecdote can be credited to H. W. Haggard (4).
Industrial Toxicology: Origins and Trends