TOXICOLOGY AND

SAFETY
ASSESSMENT
(OTC and DANGEROUS DRUGS)
 What is Toxicology/Safety
Pharmacology?
◦ “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.”
• “Safety Pharmacology studies
are defined as those studies that
investigate the potential
undesirable pharmacodynamic
effects of a substance on
physiological functions in
relation to exposure in the
therapeutic range and above.”
The Science of Poisons

• The science that deals with the

adverse effects of chemicals on
living organisms and assesses
the probability of their
occurrence.
 Paracelsus (1493-1541)
The Father of Modern Toxicology

• “All substances are poisons,

there is none which is not a
poison. The right dose
(exposure) differentiates a
poison and a remedy.”
 Toxicology Today
• Mechanistic toxicology: The study of how a
chemical causes toxic effects by investigating its
absorption, distribution, and excretion.

• Descriptive toxicology: The toxic properties of

chemical agents are systematically studied for
various endpoints using a variety of different
organisms.

• Clinical toxicology: They study of toxic effects of

various drugs in the body, and are also concerned
with the treatment and prevention of drug toxicity in
the population.
 Drug Toxicity
• Toxicity can be defined as the
relative ability of a substance to
cause adverse effects in living
organisms. This relative ability is
dependent upon several
conditions.
 Factors influencing toxicity

• Dose – determines whether the

effects of the chemical are toxic,
nontoxic or beneficial. In general,
a given amount of a toxic agent
will elicit a given type and
intensity of response.
 Factors influencing toxicity

• Route of entry - Biological

results can be different for the
same dose, depending on
whether the chemical is inhaled,
ingested, applied to the skin, or
injected. Natural barriers impede
the intake and distribution of
material once in the body.
 Factors influencing toxicity

• Duration and frequency of

exposure - There is a difference
in type and severity of effects
depending on how rapidly the
dose is received (duration) and
how often the dose is received
(frequency).
 Factors influencing toxicity

• Duration and frequency of

exposure
– Acute exposures - are usually
single incidents of relatively short
duration--a minute to a few days.
– Chronic exposures - involve
frequent doses at relatively low
levels over a period of time
ranging from months to years.
 Factors influencing toxicity

• Variations between different

species (interspecies) - For the
same dose received under
identical conditions, the effects
exhibited by different species
may vary greatly. A dose which is
lethal for one species may have
no effect on another.
 Factors influencing toxicity

• Variations among members of the

same species (intraspecies) -
Within a given species, not all
members of the population respond
to the same dose identically. Some
members will be more sensitive to
the chemical and elicit response at
lower doses than the more resistant
members which require larger doses
for the same response.
 Factors influencing toxicity

• Variations among members of

the same species (intraspecies)
– Age and Maturity
– Gender and Hormonal Status
– Genetic Makeup
– State of Health
• Environmental Factors
• Chemical Combinations
Mechanisms of
Toxicity
 Step 1 – Delivery from the
site of exposure to the target

Theoretically, the intensity of a

toxic effect depends primarily on
the concentration and persistence
of the ultimate toxicant at its site
of action.
 Step 1 – Delivery from the
site of exposure to the target
• Ultimate toxicant is the
chemical species that reacts with
the endogenous target molecule
 Step 1 – Delivery from the
site of exposure to the target

• Life cycle of a toxicant

– Absorption
– Distribution
– Degradation
– Reabsorption
 Step 1 – Delivery from the
site of exposure to the target

• Degradation – metabolism of
xenobiotics.
• A xenobiotic is a chemical
substance found within
an organism that is not naturally
produced or expected to be
present within the organism.
 Step 1 – Delivery from the
site of exposure to the target
• Reabsorption
– Toxicants delivered into the renal
tubules may diffuse back across
the tubular cells into the
peritubular capillaries.
Step 2 – Reaction of the ultimate
toxicant with the target molecule

• Types of reactions:
– Noncovalent binding – temporary
– Covalent binding – permanent
 Step 3 – Cellular dysfunction and
resultant toxicities

Each cell in a multicellular organism

carries out defined programs. Some of
these programs control the ongoing
(momentary) activity of differentiated
cells, determining whether they secrete
more or less of a substance, whether
they contract or relax, and whether
they transport and metabolize
nutrients at higher or lower rates.
 Step 4 – Inappropriate repair and
adaptation

Many toxicants alter

macromolecules, which eventually
cause damage at higher levels of
the biological hierarchy in the
organism. Progression of toxic
lesions can be intercepted by repair
mechanisms operating at
molecular, cellular, and tissue levels
 Step 4 – Inappropriate repair and
adaptation

Another strategy whereby the

organism can resist the noxious
chemical is by increasing its own
readiness to cope with it and with
its harmful effects. This
phenomenon is called adaptation.
 Early Toxicity Testing
• Genotoxicity
• Cytotoxicity
• Neurotoxicity
• (Other)
 Genotoxicity
• In genetics, genotoxicity
describes the property of
chemical agents that damage
the genetic information within a
cell causing mutations which
may lead to cancer.
 Genotoxicity
• Cells present expression of
genotoxic mutation by either
DNA repair or apoptosis.
However, the damage may not
always be fixed leading to
mutagenesis.
 Genotoxicity
• The purpose of genotoxicity
testing is to determine if a
substance will influence genetic
material or may cause cancer.
 Genotoxicity
• They can be performed in
bacterial yeast or mammalian
cells.
 Genotoxicity
• With the knowledge from the
tests, one can control early
development of vulnerable
organisms to genotoxic
substances.
 Cytotoxicity
• Cell cytotoxicity refers to the
ability of certain chemicals or
mediator cells to destroy living
cells. By using a cytotoxic
compound, healthy living cells
can either be induced to
undergo necrosis (accidental cell
death) or apoptosis
(programmed cell death).
 Cytotoxicity
• Given this information, the ability to
accurately measure cytotoxicity can
prove to be a very valuable tool in
identifying compounds that might
pose certain health risks in humans.
This can be of vital importance
during the research phase of
developing new pharmaceutical
products to ensure the safety of the
end-users.
 Cytotoxicity
• Cells exposed to a cytotoxic
compound can respond in a
number of ways. If the insult is
lethal, the cells may undergo
necrosis, during which they lose
membrane integrity and die
rapidly, or the cells may follow
another pathway of cell death,
such as apoptosis or autophagy
 Cytotoxicity
• Cells exposed to a sublethal
insult may stop actively growing
and dividing (a decrease in cell
proliferation). Any of these
responses can be measured
individually or with multiplex
assays to monitor whole cells or
subcellular components or
organelles.
 Cytotoxicity
• Parameters frequently measured
—individually or in multiplex—
include induction of superoxide,
depletion of glutathione,
decrease or loss of
mitochondrial membrane
potential, and reduction in
overall viability.
 Cytotoxicity
• Cell viability can be assayed by
parameters as diverse as the redox
potential of the cell population, the
integrity of cell membranes, or the
activity of cellular enzymes such as
esterases. These parameters each
provide a different snapshot of cell
health, and can individually or together
form the basis of an assay for cell
viability, cytotoxicity, or drug efficacy.
 Cytotoxicity
• The analysis of cell proliferation is crucial
for cell growth and differentiation studies
as well as cancer research, and is often used
to evaluate both compound toxicity and
inhibition of tumor cell growth during drug
development. Markers for measuring cell
proliferation include average DNA content
and cellular metabolism in a population.
We have developed assays that report total
cell number or total live cells, or provide
single-cell indication of DNA synthesis.
 Neurotoxicity
• Neurotoxicity testing is used to
identify potential neurotoxic
substances targeting the central
nervous system.
 Neurotoxicity
• A preliminary indication of neurotoxicity may
be obtained from acute toxicity tests. The
repeated dose toxicity test ,however,
includes assessment of neurotoxicological
effects so as to obtain as much information as
possible. The method should help to identify
chemicals with neurotoxic potential, which
may require further in-depth investigation of
this aspect. Additionally, it is important to
consider the potential of substances to cause
specific neurotoxic effects that may not be
detected in other toxicity studies.
 Immunotoxicity
• Adverse effects on the
functioning of both local and
systemic immune systems that
result from exposure to toxic
substances, including
environmental contaminants,
chemicals in occupational
environment, and direct and
indirect food additives.
 Immunotoxicity
• May be exhibited as either a
suppression of the immune
response, leading to decreased
host resistance to infectious
agents or tumor cells, or an
enhancement of the immune
response, which can exaggerate
autoimmune diseases or confer
hypersensitivity.
 Immunotoxicity
• Deleterious effects of a
xenobiotic on the functioning of
the immune system.
 Immunotoxicity tests
• are designed to detect adverse
effects of xenobiotics on the
immune system including all the
relevant cells, organs and
mechanisms of immune
response, whether or not there is
a measurable disturbance in host
resistance.
 SAFETY
PHARMACOLOGY
 Safety Pharmacology
• Safety pharmacology is the study of
the potential undesirable
pharmacodynamics effects of a
substance in relation to dosage within
the substance's therapeutic range and
above. It is a rapidly developing
discipline that uses the basic
principles of pharmacology in a
regulatory-driven process to
generate data to inform risk/benefit
assessment.
 Safety Pharmacology
• The aim of Safety Pharmacology is to
characterize the
pharmacodynamics/pharmacokinetic
relationship of a drug’s adverse effects
using continuously evolving methodology.
It includes within its hold over a regulatory
requirement to predict the risk of rare
lethal events. The key issues for Safety
Pharmacology are detection of an adverse
effect liability, projection of the data into
safety margin calculation and finally
clinical safety monitoring.
 Safety Pharmacology
• Integration of the newer approaches to routine
Safety Pharmacology studies may signi ficantly
enhance the scope of Safety Pharmacology by
refining and providing mechanistic insight to
potential adverse effects associated with test
compounds. The purpose of this review is to provide
a combined and comprehensive overview of both
current practices and newer technologies, followed
by the emerging concepts in Safety pharmacology
studies: risk determination assessments, Use of
drugs with dependence liability integration of
Safety pharmacology endpoints into regulatory
toxicology studies, drug–drug interactions and
future directions in Safety pharmacology.
SELECTIVE
TOXICITY
 Selective Toxicity
• A chemical produces injury to one
kind of living matter without harming
another form of life even though the
two may exist in intimate contact.
• Uneconomic / undesirable form – the
living matter that is injured or to be
eliminated
• Economic / desirable form – the
matter protected or to be preserved.
 Selective Toxicity
• Selective Toxicity also refers to
the ability of the drug to target
sites that are relative specific to
the microorganism responsible
for infection.
– Sometimes these sites are unique
to the microorganism or simply
more essential to survival of the
microorganism than to the host.
 Selective Toxicity
• NEED FOR SELECTIVE
TOXICITY - The need of
selective toxicity is multi-
disciplinary in life sciences.
Examples are in agriculture,
domestication of animals and
human medicine
 Selective Toxicity
• Chemotherapy - the name
assigned to that branch of
selective toxicity which is
concerned with the removal of
parasites from man and his
tended animals
 Scientific Basis for Selective
Toxicity
1. Selectivity through
Accumulation
-Selectivity through
accumulation is sometimes only a
matter of gross
morphology(overall biological
structure)
 Scientific Basis for Selective
Toxicity
• Accumulation implies some or
all of the following:
– Efficient transport to the outside of
the cell
– A favourable permeability
mechanism
– A satisfactory storage mechanism
 Scientific Basis for Selective
Toxicity
2. Selectivity through comparative
biochemistry
-It is thought that all living matter had
a common biochemistry, which, if
universal, would offer no biochemical basis
for selective toxicity. This thought is not
true. It is a well-known fact that one
species functions differently from
another, which clearly indicates that there
is actually marked biochemical
difference.
 Scientific Basis for Selective
Toxicity
3. Selectivity through comparative
cytology
-It is an established fact that plants
and animals have outstanding
cytological differences. For example,
the cell wall and chloroplast are
found in plants, but not in animals,
likewise muscle cells and nerve cells
are found only in animals but not in
plants.
 Advantages of Selective
Toxicity
• 1. Use of selectively toxic agents in controlling
weeds.
• 2. Use of selectively toxic agents in controlling
insect pests.
• 3. Use of selectively toxic agents in seed
protection.
• 4. Use of selectively toxic agents in veterinary
practice.
• 5. Use of selectively toxic agents in cure of
diseases of economical animals.
• 6. Use of selectively toxic agents in controlling
infectious diseases of human.