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Industrial Toxicology: Origins and Trends

Eula Bingham, Ph.D., John Zapp, Ph.D., (deceased)

1 Introduction

Industrial 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. Earliest

human beings found themselves in environments that were at the same time helpful and hostile to

their survival. They found their food among the plants, trees, animals, and fish in their immediate

surroundings, their clothing in the skins of animals, and their shelter mainly in caves. Their earliest

tools 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 things

into 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 that

facilitated their survival. Stone and wood gave way in time to bronze and then to iron as materials

for constructing these tools and weapons. The invention of the bow and arrow was a giant step

forward in weaponry, for it gave humans a chance to kill animals or other people from a safe

distance. 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 arrowheads

and spear points with poisons to improve their lethal effectiveness. In the Old Testament we find at

Job 6:4, “The arrows of the Almighty find their mark in me, and their poison soaks into my

spirit” ( The New English Bible version). 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 Odyssey with

obtaining a man-killing poison from Anchialos, king of the Taphians, to smear on his bronze-tipped

arrows. This particular passage does not occur in modern translations of the Odyssey and, according

to 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 poison

was called toxikon pharmakon, or drug pertaining to the bow. Many Latin words are derived from

the 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, and

those 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 by

Hippocrates, and of mercury by Pliny the Elder, these metals were apparently not deliberately

employed 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 more

visible alternatives that posed the risk of premature discovery and possibly effective retaliation. As a

means 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 Western

Europe long before the discovery of firearms. It has persisted to this day in primitive civilizations

such 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 sides

employed 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 use

in 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 appropriate

circumstances in future conflicts. It would not be prudent to forget this in thinking about national

defense.

The early and sinister uses of poisons did result in contributions to toxicology. Furthermore, the

knowledge obtained did not require extrapolation to the human species, for humans were the subjects

in early experimentation.

As mentioned earlier, the professional toxicologists of Greece and Rome had recognized and dealt

with poisons that produced acute effects, those that produced lingering effects, and those that

produced cumulative effects. We recognize these categories today. The “dose-effects” relationship

was also recognized. In Plato's well-known description of the execution of Socrates, Socrates is

required to drink a cup of hemlock, an extract of a parsley-like plant that bears a high concentration

of the alkaloid coniine. When Socrates asks whether it is permissible to pour out a libation first to

any 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 come

down 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 was

about to invade his kingdom. The damsel had been reared among poisonous snakes and had become

so saturated with their venom that all of her secretions were deadly. It is said that Aristotle dissuaded

Alexander from doing what seemed natural under the circumstances until Aristotle performed a

certain 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 to

have 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 themselves

from this hazard by attempting to build up an immunity to specific poisons by taking gradually

increasing doses until able to tolerate lethal doses, sometimes—it is said—with results disastrous to

the queen. Other kings took the precaution of having slaves taste their food before they ate. When

slaves became too scarce or expensive, they substituted dogs as the official tasters and found that it

worked about as well. Perhaps we have here the birth of experimental toxicology in which a

nonhuman species was deliberately used to predict human toxicity.

Little of importance to the science of toxicology developed during the Middle Ages. Such research

as 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 Universal

Remedy 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 it

had some remarkable restorative properties.

Although modern science is generally held to have had its beginnings in the seventeenth century

with the work of Galileo, Descartes, and Francis Bacon, there was a precursor in the sixteenth

century of some importance to toxicology. This was the physician-alchemist Phillipus Aureolus

Theophrastus 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 was

not impressed with the way that either medicine or alchemy was being taught or practiced and

decided that more could be learned from the study of nature than from studying books by ancient

authorities.

Through travel and observation, Paracelsus learned more than his contemporaries about the natural

history of diseases, to whose cure he applied his knowledge of both medicine and alchemy. He

advocated that the natural substances then used as remedies be purified and concentrated by

alchemical methods to enhance their potency and efficacy. He also attempted to find specific

therapeutic agents for specific diseases and became highly successful as a practicing physician; in

1526 he was appointed Town Physician to the city of Basel, Switzerland, and a lecturer in the

university. Being of an egotistical and quarrelsome disposition, Paracelsus quickly antagonized the

medical and academic establishment.

In the sixteenth century, syphilis was a more lethal disease than it was to become later, and the

medical profession had no interest in it or cures for it. Paracelsus introduced and advocated the use

of mercury for treating syphilis, and it worked. The establishment, however, was outraged and

denounced Paracelsus for using a poison to treat a disease. Paracelsus loved an argument and

responded 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 translated

into 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 until

Ehrlich discovered on his 606th trial an arsphenamine, Salvarsan, which was superior. Antimony

was widely used as a therapeutic agent from the seventeenth to the nineteenth century, and with the

medical profession was sharply divided as to whether it was more poison than remedy or more

remedy 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 a

monk 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 that

some pigs fed food containing antimony had become fat. Therefore, he gave antimony to some

monks who had lost considerable weight through fasting, to see if it would help them to regain

weight 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 words

auti-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

Eula Bingham, Ph.D., John Zapp, Ph.D., (deceased)

2 Experimental Toxicology

Experimental toxicology, as we know, it followed the rise of organic chemistry, which is usually

dated at around 1800. The rise was very rapid, and it is estimated that by 1880 some 12,000

compounds had been synthesized, and of these some turned out to be very toxic, in some cases

proving fatal to the chemists who prepared them. Two of the war gases employed on a large scale in

World War I, that is, phosgene (COCl 2 ) and mustard gas, bis(b-chloroethyl) sulfide, had been

prepared in 1812 and 1822, respectively.

Early organic chemists were not deliberately looking for poisons, but for dyes, solvents, or

pharmaceuticals. For example, toxicity was an unwanted side effect, but if it was there, it had to be

recognized. The sheer number of new organic compounds synthesized in the laboratory, along with a

growing public disapproval of the practice of letting toxicity be discovered by its effects on people,

led to a more extensive use of convenient and available animals such as dogs, cats, or rabbits as

surrogates for human beings, much as some of the ancient kings used dogs instead of slaves to test

their food before they dined.

Loomis ( 5 ) credits M. J. B. Orfila ( 6 ) with being the father of modern toxicology. A Spaniard by

birth, Orfila studied medicine in Paris. According to Loomis:

He is said to be the father of modern toxicology because his interests centered on the harmful effects

of chemicals as well as therapy of chemical effects, and because he introduced quantitative

methodology into the study of the action of chemicals on animals. He was the author of the first

book devoted entirely to studies of the harmful effects of chemicals ( 6 ). He was the first to point out

the valuable use of chemical analyses for proof that existing symptomatology was related to the

presence of the chemical in the body. He criticized and demonstrated the inefficiency of many of the

antidotes that were recommended for therapy in those days. Many of his concepts regarding the

treatment of poisoning by chemicals remain valid today, for he recognized the value of such

procedures as artificial respiration, and he understood some of the principles involved in the

elimination of the drug or chemical from the body. Like many of his immediate followers, he was

concerned primarily with naturally occurring substances for which considerable folklore existed with

respect to the harmfulness of such compounds.

A reading of some of the earlier nineteenth century reports indicates a lack of recognition of and

concern with either intraspecies or interspecies variation. Sometimes it is not possible to determine

from the report which species of animal was tested. Some reports were based on dosage of only one

animal, it being assumed that all others would react similarly. In reports of inhalation toxicity, a

lethal concentration might be identified without designating the length of the exposure time.

The initial recognition of biological variability comes from the study of the action of drugs rather

than from the study of the action of chemicals as such. The increased interest in the action of drugs

resulted from the availability of so many new organic compounds that could be explored for possible

therapeutic activity.

In the second half of the nineteenth century, the phenomenon of biological variability was

recognized by pharmacologists, as was also the necessity for establishing the margin of safety

between a therapeutically effective dose and a toxic dose of a drug. Clinical trials of new drugs with

adequate controls began to be accepted as good science. The traditional wisdom and beliefs about

therapeutic practice were reexamined by pharmacologists.

Early European efforts are credited by Warren Cook to Gruber ( 7 ) who used animals and himself in

1883 to set the boundaries for carbon monoxide poisoning. Lehmann and his colleagues ( 8 )

performed toxicity testing on numerous compounds using animals, and these provided the basis for

establishing many exposure limits. Korbert ( 9 ) provided dose response data on acute exposures for

twenty substances that gave information on levels that produced minimal symptoms after several

hours, ½ to 1 hour exposures without serious disturbances, and ½ to 1 hour exposures that range

from dangerous to rapidly fatal to man and animals. Many of these evaluations are still valid today.

Industrial Toxicology: Origins and Trends

Eula Bingham, Ph.D., John Zapp, Ph.D., (deceased)

3 Industrial Toxicology

Concerns for the safety of the workplace drove the development of industrial toxicology. The British

physician, C.T. Thackrah, noted that, “Most persons who reflect on the subject will be inclined to

admit that our employments are to a considerable degree injurious to health ... ” and “Evils are

suffered to exist, even when the means of correction are known and easily applied. Thoughtlessness

or apathy is the only obstacle to success” ( 10 ).

In the United States, the first recognition of occupational disease by Benjamin McCready appeared

( 11 ) in an essay published by the Medical Society of New York. Illnesses including dermatoses were

noted as well as long hours, poor ventilation, and child labor. Certainly, some of the illnesses were

from chemical exposures and dust, but it should be noted that ergonomic and human performance

concepts are raised in these early writings. Working conditions became a cause for concern among

social movements mainly because of child labor. More than a century and a half later we still are

concerned about child labor.

Recognition of the relationship between chemical agents and disease (industrial toxicology) moved

rapidly in Europe during the last decade of the nineteenth century. This activity may have been

stimulated in Germany by the passage during Bismarck's rule of the Workingmen's Insurance Law,

which set up an insurance fund into which both employers and employees contributed that amounted

to about 6% of total wages paid out. For this, the workers obtained free medical care, as well as some

compensation during periods of disability.

Industrial toxicology in the United States grew out of work in occupational and industrial health by

such investigators as Hamilton and Hardy ( 12 ), the Drinkers at Harvard ( 13 , 14 ), Hatch at Pittsburgh

( 15 ), and Kehoe ( 16 ) and Heyroth ( 17 ) at Cincinnati. Government and industry provided financial

support for these efforts.

There had been no organic chemical industry in the United States before World War I. It was born

just after the war, because during the war, the United States felt the lack of useful products such as

aniline dyes (used for printing our stamps and currency, among other things) and pharmaceuticals

(e.g., aspirin), which had been imported from Germany. Manpower and facilities used during the war

for manufacturing munitions became available after 1918, and several companies decided to use

them to get into the organic chemical business. Because neither employers nor workers had any

previous experience in making and handling organic chemicals, the effects of unanticipated toxicity

began to be encountered. That toxicity was not wanted because it was counterproductive and, along

with other problems, had to be managed if the industry was to survive.

To manage a problem, it must be anticipated, the causes must be identified and analyzed, and

practical means of overcoming the problem must be available. As a means to this end, industrial

preventive medicine, industrial toxicology, and industrial hygiene became valuable tools. By the

mid-1930s, several large chemical companies in the United States had established in-house

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