History of Toxicology

1. History of Toxicology

2. Toxicology
Definition:
Toxicology is the study of the adverse effects of
chemical, physical or biological agents on living
organisms and the ecosystem, including the prevention
and amelioration of such adverse effects. (Society of
Toxicology)
http://www.toxicology.org/

3. Toxicology: The study of adverse effects of
xenobiotics.
Xenobiotics: From the Greek xeno for “foreign”
and bios for “life”.
This discipline actually has its roots in the
ancient art of poisoning.
Now its scope is much broader.

4. Scope of Toxicology: Different branches
Biomedical:
◦Mechanisms of actions
◦Effects of exposure
◦Understanding biological responses through
model toxic compounds
Public Health:
◦Recognition and identification of hazards
◦Occupational exposure
◦Development and use of pesticides

5. Scope of Toxicology: Different Branches
Regulatory:
◦Development of exposure standards
◦Detection methods
Environmental:
◦Chemical effects on plants, animals &
ecosystems
Clinical:
◦Development of antidotes & treatments
◦Recognition of exposure

6. Scope of Toxicology: How we got here
Toxicology, like other disciplines, is a mixture of
science, art & creative thinking
◦Science: The observational and data-gathering
phase.

7. Scope of Toxicology: How we got here
◦Art: Utilization of the data to predict
outcomes in humans based on in vitro and in
vivo studies.
◦Creative Thinking: Determining the next
hypothesis and how to design experiments to
actually answer the questions posed.

8. Scope of Toxicology: How we got here
It is important to note that facts are different
from predictions.
Facts have been proven; predictions are based on
probabilities. They don’t have equal value, in
terms of scientific weight.
Toxicologists need to be careful when talking to
the public to make sure they don’t confuse the
two!

9. Historical background
* Toxicology dates to the earliest humans
* Poisons played an important role in the history of
mankind.
*In most cases, poisoning is caused by people's negative
characteristics
*They may either be lack of information or ignorance,
carelessness, untidiness, and at worst, anger that may
lead to cases of deliberate poisoning

10. History of Toxicology—Antiquity
Humans have a long history of using poisons
◦Hemlock (Greek capital punishment)
◦Aconite (Chinese poison arrows)
Milestones
◦Dioscorides—Greek physician who classified
poisons for Nero. He included descriptions and
drawings. This was a standard text for 1600 years!

11. History of Toxicology—Antiquity
Toxicology during this time, however, mainly
focused on poisoning (suicide, state-sanctioned
& personal usage…)
This knowledge also lead to antidotes.
◦Emetics —Agent to induce vomiting following
poisonings

12. Most known historical persons dealing
with toxicology
- Dioscorides : first classification of poisons, use of
emetics in treatment
- Paracelsus : "All substances are poisons; there is
none which is not a poison. The right dose
differentiates a poison from a remedy."
- a physician – alchemist; set the basics of
pharmacology, toxicology and
therapeutics; investigated the
dose-response relation

13. History of Toxicology—Antiquity
King Mithridates VI of Pontus—Experimented
on criminals and himself!
◦He would drink a poison cock-tail (36
ingredients!) to prevent political enemies
from being able to poison him.

14. History of Toxicology—Antiquity
Poisonings were so rampant in Rome, a law was
enacted in 82BC. It made poisoning illegal, and later
extended to careless dispensers of drugs (an early
regulatory effort!)

15. History of Toxicology—Middle Ages
Maimonides—Concept of bioavailability:
Based on the forms of toxicants, or what one
eats/drinks before ingestion, the chemical can
be more or less readily available in the body.
Milk, butter and cream could delay intestinal
absorption (due to the fat content)
Full stomach also delays absorption

16. History of Toxicology—Middle Ages
The poisoner, in Renaissance Italy, was an integral
part of society.
◦Toffana—Woman who sold arsenic-laced
cosmetics
◦Hieronyma Spara—Provided ‘services’ to local
young soon-to-be widows.

17. History of Toxicology—Middle Ages
Catherine de Medici—Systematic study of the
effects of poisons in the sick and poor to make sure
the correct concoction was delivered to her
‘customers’.
◦Noted the following:
◦Rapidity of the toxic response (onset of action)
◦Effectiveness of the compound (potency)
◦Degree and specificity of response (site of
action)
◦Complaints of victims (clinical signs and
symptoms)

18. History of Toxicology—Age of
Enlightenment
The age of Paracelsus (1493-1541)—Responsible for
the most famous saying in all of toxicology:
All substances are poisons; there is none which is
not a poison. The right dose differentiates a poison
from a remedy.

19. History of Toxicology—Age of
Enlightenment
Paracelsus focused on the importance of the
‘toxicon’—a primary toxic agent and a single chemical
entity.
This was in contrast to previous schools of thought
that included the concept of mixtures.

20. History of Toxicology—Age of
Enlightenment
Fundamental contributions:
◦Experimentation is essential in the examination
of responses.
◦There is a difference between the therapeutic
and toxic properties.
◦The above are not easily determined, except by
dose.
◦It is possible to ascertain a degree of specificity
of chemicals and their therapeutic or toxic
effects.

21. History of Toxicology—Age of
Enlightenment
Seminal texts:
◦On the Miners’ Sickness and other Diseases of
Miners (1567) by Paracelsus
◦Included treatment and prevention strategies
◦Discourse on the Diseases of Workers (1700) by
Bernardino Ramazzini
◦Set the standard for occupational medicine.
◦Also included information about miners,
midwives, printers, weavers and potters.

22. History of Toxicology—Age of
Enlightenment
developments:
◦1775—Role of soot in scrotal cancer in chimney
sweeps (due to polyaromatic hydrocarbons)
◦1825—Synthesis of phosgene and mustard gas
(chemical warfare)
◦1880—Boom in organic chemical synthesis led to
over 10,000 new compounds.

23. History of Toxicology—Age of
Enlightenment
Major developments:
◦Orfila (1787-1853): Introduced the use of
autopsy material to toxicology to provide
legal proof of poisoning.
◦Magendie (1783-1885): Detailed the
absorption and distribution of various
compounds in the body.

24. Modern Toxicology
Toxicologists must understand aspects of
biology, chemistry and metabolism.
◦They tend to function as detectives who must
utilize many clues.
Initial growth in the field spurred by need to
explain deaths occurring after administration of
ether, chloroform and carbonic acid in
iatrogenic deaths.
◦Iatrogenic: From the Greek iatros for doctor

25. Modern Toxicology
1890s-1900s
◦Discovery of vital amines (vitamins) led to the
wide-spread usage of bioassays to determine
whether these new chemicals were beneficial.
◦Development of neurotoxicity field due to the
production of bootleg liquor by-products
(methanol & lead).
◦Toxicology of metals due to the production of
‘the bomb’.

26. Modern Toxicology
Post World War II
◦Discovery of organophosphates (OPs) as
cholinesterase inhibitors.
◦Today used as non-bioaccumulating pesticides
Production of quinine as an antimalarial.
◦Based on derivative of chincona bark
◦First use of non-human primates
Discovery of mixed-function oxidases (MFOs)

27. Modern Toxicology
Two major discoveries (1948):
◦Paper chromatography for chemical
separation.
◦Use of blood and urine for testing presence of
various chemical metabolites (biomarkers).

28. Modern Toxicology
Formalization of the experimental program for the
testing of food, drug and cosmetic safety in 1955.
◦Basically states that any chemical found to be
carcinogenic in lab animals or humans cannot be
added to the US food supply.

29. Modern Toxicology
Toxicology and Applied Pharmacology started
around 1958—First journal dedicated to
toxicology.
Textbook of Toxicology published in 1959.
Society of Toxicology (SOT) founded in 1965.

30. Modern Toxicology
Major events in the 1960s:
◦Thalidomide babies
◦Silent Spring by Rachel Carsonin (1958, Carson's
interest in writing about the dangers of DDT was
rekindled when she received a letter from a friend
in Massachusetts bemoaning the large bird kills
that had occurred on Cape Cod as the result of DDT
sprayings.)
◦Equipment for detecting parts per billion (ppb)
◦Genetic assays for point mutations (Ames assay)

33. Currently
Now a unique and separate discipline
◦Offered at many graduate schools
◦“Surprisingly, courses in toxicology are now being
offered in several liberal arts undergraduate
schools as part of their biology and chemistry
curricula.”

34. Famous poisonings and poisoners
The King Mithridates Eupator (1st century BC)
Is said to have taken small doses of 36 poisons to build tolerance against
them. When his son sent assassins to murder him, he attempted suicide by
poison but the poison had no effect on him, and he had one of his servants
kill him by the spear. This is where immunity from poison got its name of
mithridatism.
- The principle of addiction:
The organism already responds during resorption, mainly at the level of
intestinal wall, and reduces the penetration of exogenous substances from
the gastrointestinal tract to blood
As part of adaptation, the organism enhances the capacity of detoxification
processes

35. The organism incorporates the poison into its
biochemical processes, and the poison then becomes part
of those processes. If the regular intake of the poison is
interrupted,
the so-called withdrawal syndrome evolves
Examples of addictive substances are arsenic
(arsenic used to be given to horses as a stimulant,
but interrupting the supply may have led even to
the death of the horse), NaCl, morphine, some plant
toxins

36. Socrates
One of the greatest ancient philosophers was
executed by a solution of the hemlock plant
(Conium maculatum) in 399 BC.
Poison hemlock (Conium maculatum) grows
on rubbish heaps. It contains the alkaloid
coniine (most of the alkaloids are in fruit).
The onset of toxic effects is in 20 – 30 minutes. The
death is most frequently caused by the cessation of
breathing at full consciousness and before cardiac arrest.

38. Coniine is a curare-like poison, such alkaloids block
the transmission of stimuli from motor nerve endings
to striated muscles, which subsequent leads to muscle
paralysis.
The paralysis progresses from the lower limbs
upwards to respiratory muscles, and when these
muscles are paralyzed, the victim dies of asphyxia.
The brain is not affected and the victim retains
consciousness.

39. In the Middle Ages, many of the greatest poisoners
were women
The best known of them were Catherine de Medici
and Lucrezia Borgia (a daughter of Pope Alexander VI.)
Catherine had a cabinet full of different poisons at
home, and she made the use of poisons a standard
political tool. She was the wife of the French king
Henry II, and later became Queen of France. She tried
to prevent any weakening of the royal family's political
power.
In Italy, an infamous poisoner was a woman named
Tofana, who made her mark by her arsenic-containing
cosmetics ("Aqua Tofana").
Catherine
de Medici
Lucrezia
Borgia

40. There are also many examples of the use of poison
in more recent history
In World War 2, German generals had a glass
poison capsule (containing e.g. potassium cyanide)
set in one of the tooth under a removable crown
A case from a very recently past is that of the
Ukrainian president Yushchenko, who was
poisoned by dioxin (which left typical symptoms of
acne on his face)
Descriptions of animal poisoning also abound.

41. There have also been many cases of food poisoning:
* Minamata Disease (Japan, 1950s – 1960s) This was a
case of methylmercury poisoning of both people and
animals. A chemical factory dumped its mercury-containing
waste to the Minamata Bay for dozens of years. Inorganic
mercury in mercury compounds that accumulated in
sediments on the bay bed began to transform to
methylmercury (the most toxic form of mercury) under the
action of bacteria. Methylmercury penetrated to the food
chain of the aquatic environment, i.e. fish and subsequently
to man. People (mostly fishermen) suffered of central
nervous system disorders, loss of hearing and speech
disturbance. Several cases of limb paralysis and severe
mental disorders were also reported. Children were born
with defects. Several dozen people die.

43. * Poisoning of people in Iraq in 1960s. Poisoning was
caused because seed wheat was mistaken for food wheat.
The wheat had been treated with phenylmercurychloride-
based fungicidal agent. Although exported as seed, the
wheat was eventually by mistake used as food wheat.
* Itai-Itai Disease (the ouch-ouch disease) In the 1950,
Japan witnessed mass poisoned of its citizens with rice
heavily contaminated with cadmium.
The source of cadmium were ore dumps from which
cadmium was washed by rainwater to the river. The name
of the disease came from characteristic painful screams of
the victims who suffered severe pain in the joints and the
lower part of spine.
-

44. The oil disease (Yusho) In 1968 about 1600 people in Japan
were poisoned by rice oil contaminated with polychlorinated
biphenyls (PCB) during the manufacturing process.
The PCB leaked into edible oil from corroded pipes of the
cooling system. The main symptoms of the poisoning were
impaired immunity (people died of common infectious
diseases – flu, pneumonia – rather than of PCB poisoning),
damage to the nervous system, hyperkeratosis,
hyperpigmentation, etc.

47. Methods to evaluate toxicity of
chemicals
1) Based on cases of poisoning, cases studies (case
histories)
2) Methods for toxicity prediction
3) Toxicity tests

48. Toxicology testing, also known as safety
assessment, or toxicity testing, is conducted to
determine the degree to which a substance can
damage a living or non-living organisms

49. THANK YOU ...