Introduction to
Toxicology
MEDELYN B. PAAS, RPh
Objectives of the
lesson
–To familiarize with the history and origins of
toxicology
–To learn the different terminologies and
terms used in toxicology
I. History and Scope of Toxicology
I. History and Scope of Toxicology
› Antiquity
– DIOSCORIDES: Greek physician of the Roman Emperor Nero
: made the first attempt to classify poisons into plant, animal and
mineral poisons in his book De Materia Medica (reference to 600 plants)
– KING MITHRIDATES VI OF PONTUS: Roman King who regularly
ingested a mixture of 36 ingredients as protection
against assassasination.
: lead to the creation of the word Mithridatic as an antidote or
protective mixture.
– SULLA: issued the Lex Cornelia, the FIRST law against poisoning and
later became a regulatory statute directed at careless dispensers of
drugs
I. History and Scope of Toxicology
› Middle Ages
– MAIMONDES (Moses ben Maimon)
: included a treatise (Poisons and their antidotes)
on the treatment of poisonings from insects,
snakes, and mad dogs.
:described the subject of Bioavailability, noting that
milk , butter and cream could delay intestinal
absorption
– CATHERINE DE MEDICI
: under the guise of treating the poor and sick, she tested
toxic concoctions, carefully noting the rapidity of the toxic
response (onset of action), the effectiveness of the
compound (potency), the degree of response of the parts of
the body (specificity and site of action), and the complaints
of the victim (clinical signs and symptoms).
I. History and Scope of Toxicology
› RENAISSANCE
“All substances are poisons; there is none that is not a poison. The right dose
differentiates a poison from a remedy”
-Paracelsus (1493-1541)
› PARACELSUS: Philippus Aureolus Theophrastus Bombastus von Hohenheim
: physician-alchemist, formulated many revolutionary views that remain
integral to the structure of toxicology, pharmacology and therapeutics.
: held four (4) principles, namely
1. experimentation is essential in the examination of the responses to
chemicals
2. make a distinction between the therapeutic and toxic properties of
chemicals
3. these properties are not always indistinguishable except by dose
4. one can ascertain a degree of the specificity of the chemicals and
their therapeutic or toxic effects
: led to the articulation of the dose-response relation as a bulwark of
toxicology.
I. History and Scope of Toxicology
› RENAISSANCE
› ELLENBOG: warned of mercury and lead toxicity from goldsmithing
› AGRICOLA: published a short treatise on mining diseases
› On the Miner’s Sickness and other Diseases of Miners(1556)
– Published by Paracelsus
– Adressed etiology of miner’s disease, along with treatment and
prevention strategies
› BERNARDINO RAMAZZINI: published Discourse on the Diseases of Workers which
discussed Occupational toxicology from miners to midwives.
› PERCIVAL POTTS- recognized the role of soot in scrotal cancer among chimney
sweeps
- first reported polyaromatic hydrocarbon carcinogenicity.
I. History and Scope of Toxicology
› AGE OF ENLIGHTENMENT
› ORFILA: Spanish physician who used autopsy material and
chemical analysis as legal proof of poisoning
: his work serves as the underpinning of forensic
toxicology
: often referred to as the founder of toxicology.
› MAGENDIE: studied the mechanism of action of emetine and
strychnine.
› CLAUDE BERNARD: Magendie’s student who contributed to
the treatise An Introduction to the Study of
Experimental Medicine
› LOUIS LEWIN: published much of the early work on the
toxicity of narcotics, methanol, glycerol, acrolein and
chloroform.
I. History and Scope of Toxicology
› MODERN TOXICOLOGY
› 1890S-EARLY 1900S: discovery of radioactivity and vitamins or “vital amines” led
to the first large scale bioassays (multiple animal studies) to
determine whether these new substances were harmful or
beneficial to lab animals
› ARCHIV FUR TOXIKOLOGIE (1930): first journal dedicated to experimental
toxicology
› AFTER WORLD WAR 2
› Thalidomide incident (1960s): several
thousand children were born with severe
defects due to the sedative thalidomide, used
to be prescribed to women to relieve
pregnancy nausea.
Terms and Terminologies used in Toxicology
› Toxicology- science of poisons
*Greek word “toxicon” – arrow poison
“logia” – to speak
-"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."
Poison- any agent which may cause serious
body injury, disease or death when applied,
introduced to, or developed within the body.
Lex Cornelia & Mattieu Bonarentura
- founders of the science of Toxicology.
Did you know?
› The study of toxicology may appear to
focus only on poisonings or disasters,
but some toxic chemicals can have
positive effects. Animal venoms,
whether from bees, wasps, snakes, or
Gila monsters, are composed of
hundreds of chemicals that are being
studied as treatments for human
diseases.
› For example, exantide, a drug derived
from Gila monster saliva, has been
approved for use in Type 2 diabetes.
Captopril, which is used to treat
hypertension and heart failure, was
developed from studies on the chemical
bradykinin-potentiating factor (BPF) in
the venom of a South American snake
Bothrops jararaca. Melitten, which
comes from honeybee venom, is being
investigated for its anticancer and
antifungal properties.
Figure 1. Gila monster (top); Bothrops jararaca (bottom)
(Image Source: Wikipedia, adapted under GNU Free
Documentation License - Original Images)
Terms and Terminologies used in Toxicology
Toxin
Poison
Figure 2. Amanita muscaria mushroom contains
a neurotoxin
Figure 3. Black Widow spiders produce a poison
that is a toxin
Toxins:
Poisons:
Peptides or proteins produced
by living organisms.
Venoms are toxins injected by
a bite or sting.
Toxins produced by organisms.
Toxicant
Figure 1. Pesticide chemicals are
toxicants
Toxicants:
Substances producing adverse
biological effects of any kind.
May be chemical or physical
in nature.
Effects may be acute or
chronic.
Terms and Terminologies used in Toxicology
Toxic agent- anything that can produce an adverse biological effect. It can be chemical,
physical or biological in form
Chemical (such as
cyanide)
Physical (such as
radiation)
Biological (such as
snake venom)
› A distinction is made for
diseases people get from
living organisms. Organisms
that invade and multiply
within another organism
and produce their effects by
biological activity are not
classified as toxic agents
but as biological agents. An
example of this is a virus
that damages cell
membranes resulting in cell
death.
› If the invading organisms
excrete chemicals which are
the basis for their toxicity,
the excreted substances are
known as biological toxins.
In that case, the organisms
are called toxic organisms. A
specific example is tetanus.
Tetanus is caused by a
bacterium, Clostridium
tetani. The bacteria C. tetani
itself does not cause disease
by invading and destroying
cells. Rather, a toxin
(neurotoxin) that the
bacteria excrete travels to
the nervous system and
produces the disease
Micrograph of a group of Clostridium tetani
bacteria
(Image Source: CDC)
› A toxic substance is simply a
material that has toxic properties. It
may be a discrete toxic chemical or
a mixture of toxic chemicals. For
example, lead chromate, asbestos,
and gasoline are all toxic
substances. More specifically:
› Lead chromate is a discrete toxic
chemical.
› Asbestos is a toxic material that
does not have an exact chemical
composition but comprises a variety
of fibers and minerals.
› Gasoline is a toxic substance rather
than a toxic chemical in that it
contains a mixture of many
chemicals. Toxic substances may not
always have a constant composition.
Examples of toxic substances: lead chromate (left), asbestos (center), and gasoline (right)
The composition of gasoline varies
with octane level, manufacturer,
time of season, and other factors.
› A systemic toxicant affects the entire
body or many organs rather than a
specific site. For example, potassium
cyanide is a systemic toxicant in that it
affects virtually every cell and organ
in the body by interfering with the
cells’ ability to use oxygen.
› Toxicants may also affect only specific
tissues or organs while not producing
damage to the body as a whole. These
specific sites are known as the target
organs or target tissues.
› Benzene is a specific organ toxicant in
that it is primarily toxic to the bloodforming tissues.
› Lead is also a specific organ toxicant;
however, it has three target organs: the
central nervous system, the kidneys,
and the hematopoietic system.
› A toxicant may affect a specific type of
tissue (such as connective tissue) that is
present in several organs. The toxic site
is then considered the target tissue.
Terms and Terminologies used in Toxicology
› Xenobiotics- general term for a foreign substance taken into
the body. It is derived from the Greek term “xeno”
which means foreigner. Xenobiotics may produce
beneficial effects (such as pharmaceuticals), or they
may be toxic (such as lead).
As Paracelsus proposed centuries ago, dose differentiates
whether a substance will be a remedy or a poison. A xenobiotic
in small amounts may be nontoxic and even beneficial, but when
the dose is increased, toxic and lethal effects may result.
Terms and Terminologies used in Toxicology
› Hazard- is the potential for the toxicity to be realized in a
specific setting or situation.
› Risk- probability of a specific adverse effect to occur. It is often
expressed as the percentage of cases in a given population
and during a specific time period. A risk estimte can be
based upon actual cases or a projection of future cases,
based upon extrapolations.
› Toxicity rating- arbitrary grading of doses or exposure levels
causing toxic effects. The grading can be “supertoxic,” “highly
toxic,” “moderately toxic” and so on. The most common
ratings concern acute toxicity.
› Toxicity classification- the grouping of chemicals into general
categories according to their most important toxic effect. Such
categories can include allergenic, neurotoxic, carcinogenic and
so on. This classification can be of administrative value as a
warning and as information.
Terms and Terminologies used in Toxicology
› Dose- is the amount of a substance administered at one time.
A dose can be considered either:
1. A measurement of environmental exposures.
2. The amount of a substance administered over a period of time.
Types of doses include:
Absorbed dose — the amount of a substance that entered the body through the
skin, eyes, lungs, or digestive tract and was taken up by organs or particular
tissues. Absorbed dose can also be called internal dose.
Administered dose — the quantity administered usually orally or by injection
(note that an administered dose taken orally may not necessarily be absorbed).
Total dose — the sum of all individual doses.
Not all substances that enter the body are necessarily absorbed by it. This
concept applies to water intake. When a person drinks a large quantity of water at
one time, some of it is absorbed while the rest of the water is eliminated.
Terms and Terminologies used in Toxicology
› Dose effect relationship- relationship between dose and
effect on the individual level. An increase in dose may increase the intensity of an effect, or a more severe effect
may result.
› Dose-response relationship- relationship between dose and
the percentage of individuals showing a specific effect.
With increasing dose a greater number of individuals in
the exposed population will usually be affected.
It is essential to toxicology to establish dose-effect and doseresponse relationships. In medical (epidemiological) studies a
criterion often used for accepting a causal relationship between
an agent and a disease is that effect or response is proportional
to dose.
Terms and Terminologies used in Toxicology
› Additive effects- occur as a result of exposure to a
combination of chemicals, where the individual toxicities
are simply added to each other (1+1= 2).
ANTAGONISM- interaction between chemicals that
may result into inhibition (1+1<2)
SYNERGISM- combination of chemicals may
produce a more pronounced effect than
would be expected (1+1>2)
› Latency time- time between first exposure and the
appearance of a detectable effect or response. The term
is often used for carcinogenic effects, where tumours may
appear a long time after the start of exposure and
sometimes long after the cessation of exposure.
Terms and Terminologies used in Toxicology
› Dose threshold- dose level below which no observable effect
occur.
› LD50 (effective dose)- the dose causing 50% lethality in an
animal population. The LD50 is often given in older
literature as a measure of acute toxicity of
chemicals. The higher the LD50, the lower is the
acute toxicity. A highly toxic chemical (with a low
LD50) is said to be potent.
ED50 (effective dose) is the dose causing a specific effect other than lethality in
50% of the animals.
NOEL (NOAEL) means the no observed (adverse) effect level, or the highest dose
that does not cause a toxic effect.
LOEL is the lowest observed effective dose on a dose-response curve, or the lowest
dose that causes an effect.
Terms and Terminologies used in Toxicology
› Safety factor- a formal, arbitrary number with which one
divides the NOEL or LOEL derived from animal
experiments to obtain a tentative permissible dose for
humans. This is often used in the area of food toxicology,
but may be used also in occupational toxicology.
› Extrapolations- theoretical qualitative or quantitative
estimates of toxicity (risk extrapolations) derived from
translation of data from one species to another or from
one set of dose-response data (typically in the high dose
range) to regions of dose-response where no data exist.
Extrapolations usually must be made to predict toxic
responses outside the observation range.
Terms and Terminologies used in Toxicology
› Systemic effects- are toxic effects in tissues distant from the
route of absorption.
› Target organ- primary or most sensitive organ affected after
exposure.
› Acute effects- occur after limited exposure and shortly (hours,
days) after exposure and may be reversible or irreversible.
› Chronic effects- occur after prolonged exposure (months,
years, decades) and/or persist after exposure has ceased.
› Acute exposure - exposure of short duration, while chronic
exposure is long-term (sometimes life-long) exposure.
› Tolerance- may occur when repeat exposures result in a lower
response than what would have been expected without
pretreatment.