Toxicology
Lecture. Toxicology
Toxicology is the study of the adverse effects of chemicals on living organisms. A toxicologist is trained
to examine the nature of these effects and assess the probability of their occurrence. Toxicology testing
is conducted to determine the degree by which a substance damages organisms.
o Mechanistic toxicology - identifies the cellular, biochemical and molecular mechanisms by
which chemicals exert their toxic effects
o Descriptive toxicology - focused on toxicity testing to provide information on safety evaluation
and regulatory requirements
o Regulatory toxicology - the responsibility to decide is a drug or another chemical is of sufficiently
low risk to be marketed for a stated purpose
Types of toxic effects
o Death o Carcinogenetic
o Organ damage o Teratogenesis
o Mutagenesis o Neurotoxicity
Toxic effects are classified into 2 types
1. Systematic toxicity = refers to toxic effects caused as a result of absorption and distribution of
a substance that affects the whole body rather than a specific (local) area. Most chemicals that
produce systemic toxicity do not cause similar degree of toxicity in all organs, but usually cause
major toxicity to one or two organs. These are referred to as the target organs of toxicity for
that chemical.
2. Organ specific toxicity
o Reproductive toxicity = damage to the male of female reproductive organs.
o Hepatoxicity = toxicity to the liver, bile duct and gall bladder. Due to the extensive blood
supply and role in metabolism, the liver is highly susceptible to xenobiotics
o Nephrotoxicity = The kidney is susceptible to toxicants due to the high volume of blood
flow. It also filters large amounts of toxicants which can concentrate in the kidney
tubules.
o Neurotoxicity = damage to the cells of the central nervous system (brain and spine) as
well as the peripheral nervous system. It is the most common target of organ toxicity
o Immunotoxicity = toxicity of the immune system can take several forms:
hypersensitivity (allergy), immunodeficiency, uncontrolled proliferation (leukemia).
o Respiratory toxicity = relating to any effect on the upper respiratory system (nose,
pharynx, larynx, trachea) and lower respiratory system (bronchi, lung alveoli). 99% of
the world’s population is now breathing polluted air.
o Blood and cardiac toxicity = Xenobiotics acting directly on cells in the circulating blood,
bone marrow and heart.
, How are compounds poisonous? - Dose response relationships
Toxicology are the effects of toxicants on man. This all started with Socrates. He was sentenced to die
by drinking hemlock.
Paracelus is the founding father of toxicology. He stated that ““all substances are poisions: there is none
which is not a poision. The proper dose seperates a poision from a remedy”. Paracelus principle is
important activity of toxicologists. Usually, a graph with performance of a tested organisms
(growth/survival) is plotted as a function of concentration of a toxicant in water, soil or air.
Logarithmic dose-response curves are normally sigmoidal (S-shaped) and monophasic (having a single
phase). There are 2 types of concentration-response relationships:
o Response of the
endpoint decreases with
increasing concentration
o Response of the
endpoint increases with
increasing exposure
concentration
Concentration-response relationship
o NOEC (No Observed Effect Concentration) =
the highest test concentration that does not
cause a significant adverse effect (compared
to the corresponding control),
o NEL (No Effect Level),
o LOAC (Lowest Observed Effect
Concentration) = The lowest test
concentration that causes a significant
adverse effect (compared to the corresponding control)
o LD50 (median Lethal Dose 50)
o LC50 (median Lethal Concentration in soil, water, air or food)
o EC50 (Effective Concentration causing 50% effect)
➔ All these endpoints provide a measure of toxicity. The lower the endpoint value the more toxic
it is.
Use of concentration-response curve
Forward use Backward use
o Predict the effect caused by a o Estimate the exposure concentrations that
specific toxicant concentration triggers a certain response
o Derive chemical properties and trigger values
,The relative potency can be measured by
𝐸𝐶𝑥 𝑜𝑓 𝑎 𝑠𝑡𝑎𝑛𝑑𝑎𝑟𝑑
𝐸𝐶𝑥 𝑜𝑓 𝑎 𝑠𝑎𝑚𝑝𝑙𝑒
. The relative ratio is valid only
when the dose-response curves of the sample
and the standard are parallel and reach the
same maximum response (efficacy).
Dose-response curves are characterized by
1. Location (EC50, 2. Maximum response 3. Steepness of the curve
potency) (effectiveness)
𝐿𝐶50
The teratogenic index (TI) = 𝐸𝐶50
. A teratogen is
anything a person is exposed to or ingests during
pregnancy that's known to cause fetal abnormalities.
The higher the TI, the more specific the teratogenic
effects of the chemical compared to embryotoxicity as
measured by lethality.
Therapeutic index (TI) is a ratio that compares the blood
concentration at which a drug becomes toxic and the
concentration at which the drug is effective. The larger the
therapeutic index, the safer the drug is. The therapeutic index
𝐿𝐷50
can be measured by 𝐸𝐷50.
The benchmark dose (BMD) is the
dose/concentration that produces a
predetermined change in the response rate of
an adverse effect. The default BMR is a 5% or
10% change in the response rate of an adverse
effect relative to the response of a control
group. The BMD is found using a statistical
model, and this gives a confidence interval for
the estimated BMD. Thus, the BMD is a range
not a fixed number.
, Window of causality = essential trace metals are
detrimental at low (essential for survival) and high (toxic)
concentrations. Examples are Iron, Koper. There is a
difference between the typical dose response curve for
essential trace metals (left) and non-essential trace
metals (right).
Case studies
o In the study about tyrosine kinase inhibitors. Plot the offspring of worms (brood size) was
plotted against the concentration. In this way the NOAEL, LOAEL, Acute toxicity was determined.
o In the study about PFDA, the total brood size, brood period and embryotic lethal was plotted.
o In the study about cherry juice, the lifespan was measured and showed that cherry juice
prolonged the life span and the EC50 is much higher (enhances health span).
How are humans and the environment exposed? – Exposure routes
We all come into contact with chemicals every day. Some chemical exposure is safe, but some is not.
People respond to chemicals differently – some have extreme sensitivity and greater body burden while
others are seemingly unaffected. We are all effected to some extent by toxic exposure.
Exposure to chemicals may come from many sources
o Environmental o Dietary
o Occupational o Accidental
o Therapeutic o Deliberate
Exposure routes Exposure routes may be age dependent
o Oral via alimentary track (all animals) (e.g. via food o Fetus (e.g. umbilical cord,
and water) placenta)
o Contact (topical) (e.g. via skin, cuticle, body wall) o Baby (e.g. breast milk)
o Respiratory (e.g. via lung or trachea) o Young children (e.g. pica)
o Special routes (e.g. via injection)
Classification of toxic effects
Rate Toxic effects can have an immediate effect or an delayed effect.
Possibility for repair Toxic effects can have a reversable effect or an irreversible effects.
Site of action Toxic effects can have a local effect at site of first contact or a systematic
effect on target organs or unborn embryo.
Lecture. Toxicology
Toxicology is the study of the adverse effects of chemicals on living organisms. A toxicologist is trained
to examine the nature of these effects and assess the probability of their occurrence. Toxicology testing
is conducted to determine the degree by which a substance damages organisms.
o Mechanistic toxicology - identifies the cellular, biochemical and molecular mechanisms by
which chemicals exert their toxic effects
o Descriptive toxicology - focused on toxicity testing to provide information on safety evaluation
and regulatory requirements
o Regulatory toxicology - the responsibility to decide is a drug or another chemical is of sufficiently
low risk to be marketed for a stated purpose
Types of toxic effects
o Death o Carcinogenetic
o Organ damage o Teratogenesis
o Mutagenesis o Neurotoxicity
Toxic effects are classified into 2 types
1. Systematic toxicity = refers to toxic effects caused as a result of absorption and distribution of
a substance that affects the whole body rather than a specific (local) area. Most chemicals that
produce systemic toxicity do not cause similar degree of toxicity in all organs, but usually cause
major toxicity to one or two organs. These are referred to as the target organs of toxicity for
that chemical.
2. Organ specific toxicity
o Reproductive toxicity = damage to the male of female reproductive organs.
o Hepatoxicity = toxicity to the liver, bile duct and gall bladder. Due to the extensive blood
supply and role in metabolism, the liver is highly susceptible to xenobiotics
o Nephrotoxicity = The kidney is susceptible to toxicants due to the high volume of blood
flow. It also filters large amounts of toxicants which can concentrate in the kidney
tubules.
o Neurotoxicity = damage to the cells of the central nervous system (brain and spine) as
well as the peripheral nervous system. It is the most common target of organ toxicity
o Immunotoxicity = toxicity of the immune system can take several forms:
hypersensitivity (allergy), immunodeficiency, uncontrolled proliferation (leukemia).
o Respiratory toxicity = relating to any effect on the upper respiratory system (nose,
pharynx, larynx, trachea) and lower respiratory system (bronchi, lung alveoli). 99% of
the world’s population is now breathing polluted air.
o Blood and cardiac toxicity = Xenobiotics acting directly on cells in the circulating blood,
bone marrow and heart.
, How are compounds poisonous? - Dose response relationships
Toxicology are the effects of toxicants on man. This all started with Socrates. He was sentenced to die
by drinking hemlock.
Paracelus is the founding father of toxicology. He stated that ““all substances are poisions: there is none
which is not a poision. The proper dose seperates a poision from a remedy”. Paracelus principle is
important activity of toxicologists. Usually, a graph with performance of a tested organisms
(growth/survival) is plotted as a function of concentration of a toxicant in water, soil or air.
Logarithmic dose-response curves are normally sigmoidal (S-shaped) and monophasic (having a single
phase). There are 2 types of concentration-response relationships:
o Response of the
endpoint decreases with
increasing concentration
o Response of the
endpoint increases with
increasing exposure
concentration
Concentration-response relationship
o NOEC (No Observed Effect Concentration) =
the highest test concentration that does not
cause a significant adverse effect (compared
to the corresponding control),
o NEL (No Effect Level),
o LOAC (Lowest Observed Effect
Concentration) = The lowest test
concentration that causes a significant
adverse effect (compared to the corresponding control)
o LD50 (median Lethal Dose 50)
o LC50 (median Lethal Concentration in soil, water, air or food)
o EC50 (Effective Concentration causing 50% effect)
➔ All these endpoints provide a measure of toxicity. The lower the endpoint value the more toxic
it is.
Use of concentration-response curve
Forward use Backward use
o Predict the effect caused by a o Estimate the exposure concentrations that
specific toxicant concentration triggers a certain response
o Derive chemical properties and trigger values
,The relative potency can be measured by
𝐸𝐶𝑥 𝑜𝑓 𝑎 𝑠𝑡𝑎𝑛𝑑𝑎𝑟𝑑
𝐸𝐶𝑥 𝑜𝑓 𝑎 𝑠𝑎𝑚𝑝𝑙𝑒
. The relative ratio is valid only
when the dose-response curves of the sample
and the standard are parallel and reach the
same maximum response (efficacy).
Dose-response curves are characterized by
1. Location (EC50, 2. Maximum response 3. Steepness of the curve
potency) (effectiveness)
𝐿𝐶50
The teratogenic index (TI) = 𝐸𝐶50
. A teratogen is
anything a person is exposed to or ingests during
pregnancy that's known to cause fetal abnormalities.
The higher the TI, the more specific the teratogenic
effects of the chemical compared to embryotoxicity as
measured by lethality.
Therapeutic index (TI) is a ratio that compares the blood
concentration at which a drug becomes toxic and the
concentration at which the drug is effective. The larger the
therapeutic index, the safer the drug is. The therapeutic index
𝐿𝐷50
can be measured by 𝐸𝐷50.
The benchmark dose (BMD) is the
dose/concentration that produces a
predetermined change in the response rate of
an adverse effect. The default BMR is a 5% or
10% change in the response rate of an adverse
effect relative to the response of a control
group. The BMD is found using a statistical
model, and this gives a confidence interval for
the estimated BMD. Thus, the BMD is a range
not a fixed number.
, Window of causality = essential trace metals are
detrimental at low (essential for survival) and high (toxic)
concentrations. Examples are Iron, Koper. There is a
difference between the typical dose response curve for
essential trace metals (left) and non-essential trace
metals (right).
Case studies
o In the study about tyrosine kinase inhibitors. Plot the offspring of worms (brood size) was
plotted against the concentration. In this way the NOAEL, LOAEL, Acute toxicity was determined.
o In the study about PFDA, the total brood size, brood period and embryotic lethal was plotted.
o In the study about cherry juice, the lifespan was measured and showed that cherry juice
prolonged the life span and the EC50 is much higher (enhances health span).
How are humans and the environment exposed? – Exposure routes
We all come into contact with chemicals every day. Some chemical exposure is safe, but some is not.
People respond to chemicals differently – some have extreme sensitivity and greater body burden while
others are seemingly unaffected. We are all effected to some extent by toxic exposure.
Exposure to chemicals may come from many sources
o Environmental o Dietary
o Occupational o Accidental
o Therapeutic o Deliberate
Exposure routes Exposure routes may be age dependent
o Oral via alimentary track (all animals) (e.g. via food o Fetus (e.g. umbilical cord,
and water) placenta)
o Contact (topical) (e.g. via skin, cuticle, body wall) o Baby (e.g. breast milk)
o Respiratory (e.g. via lung or trachea) o Young children (e.g. pica)
o Special routes (e.g. via injection)
Classification of toxic effects
Rate Toxic effects can have an immediate effect or an delayed effect.
Possibility for repair Toxic effects can have a reversable effect or an irreversible effects.
Site of action Toxic effects can have a local effect at site of first contact or a systematic
effect on target organs or unborn embryo.
