Transcript Document

Toxicology – specification,
history, toxicity assessment
Lecture No. 1
Copyright © Prof. MVDr. Zdeňka
Svobodová, DrSc., Mgr. Zuzana Široká,
PhD.
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)
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
• A category sui generis are cases of domestic
pets poisoning (mainly dogs) in connection with
a suicide of their owners (mainly by carbon
dioxide)
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
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
• 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
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.
• 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.
• 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
• 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.
• 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.
- 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.
- 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.
Methods to evaluate toxicity of
chemicals
1) Based on cases of poisoning, cases studies
(case histories)
2) Methods for toxicity prediction
3) Toxicity tests
ad 1) It is not possible to perform toxicity
tests or to monitor effects of chemical
substances on people and most species of
animals. For that reason it is important to
learn as much as possible from individual
cases of poisoning, and that is also the reason
why we so often return to the history of
toxicology
ad 2) There is a relation between the chemical structure
of substances and their biological characteristics. It
cannot be assumed that knowledge of the molecule
structure of a new xenobiotic alone will suffice for an
unambiguous evaluation of biological properties. On the
other hand, it will at least allow for a group
classification. Toxicity prediction may be quite
successful if we are dealing with a series of substances
exhibiting chemical similarities. The relationship
between the chemical structure and biological activity is
expressed as Quantitative Structure – Activity
Relationship (QSAR). Computer programmes are
developed for computer-assisted toxicity predictions.
But because these predictions may differ from reality,
tests on experimental animals are necessary before a
final decision can be taken. Thanks to prediction
processes, however, the scope of these tests can be
minimized (with a minimum number of experimental
animals)
ad 3) Toxicity tests are performed at the level of
• cells and tissues (in vitro tests)
• organisms
• Biocenoses
 - For tests at the level of cells and tissues, primary cell cultures
(higher sensitivity, lower reproducibility) or stable cell cultures
(lower sensitivity, higher reproducibility) are used. Test can be
evaluated directly (numbers of dead cells and extent of cytopathic
effects) or indirectly (evaluations based on physiological reactions of
the cells).
- One example is the Neutral Red Test (NRT). It uses the ability of
undamaged lysosomes to incorporate and bind neutral red. After a
20-hour period of exposure to the test substance, a neutral red
solution is added, left there to take effect, then it is drained off and
lysing solution is added. Undamaged cells are lysed, and the neutral
red released is measured photocolorimetrically.
- The advantage of in vitro tests is their speed, reproducibility, low
financial and time demands. The disadvantage is that in vitro systems
are no substitute for the enzymatic - immune system of the living
organism. In spite of that, in vitro tests are suitable screening tests
before animal experiments.
 - The most frequently performed tests are those at the level
of organisms. They must include all trophic levels, i.e.
bacterias, invertebrates and vertebrates (experiments on fish,
birds and mammals). Methods to be used in such
experiments are unified world-wide by the Organisation for
Economic Cooperation and Development (OECD) and the
International Organization for Standardization (ISO).
 - Tests at the level of biocenoses - these tests are very
expensive and time consuming, they are used in special cases
only. The preparation is applied over a defined area of land
and its effects on soil microorganisms, earthworms, game,
birds etc., are monitored, and its residual concentrations are
studied. Similar methods are used for experiments in the
aqueous environment.
More info:
http://www.portfolio.mvm.ed.ac.uk/studentwebs/session2/gro
up12/contents.htm
http://www.oecd.org/
http://www.iso.org