(OTC and DANGEROUS DRUGS)

◦ “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 that deals with the
adverse effects of chemicals on
living organisms and assesses
the probability of their
occurrence.
• “All substances are poisons,
there is none which is not a
poison. The right dose
(exposure) differentiates a
poison and a remedy.”
• 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.
• 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.
• 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.
• 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.
• 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).
• 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.
• 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.
• 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.
• Variations among members of
the same species (intraspecies)
– Age and Maturity
– Gender and Hormonal Status
– Genetic Makeup
– State of Health
• Environmental Factors
• Chemical Combinations
Theoretically, the intensity of a
toxic effect depends primarily on
the concentration and persistence
of the ultimate toxicant at its site
of action.
• Ultimate toxicant is the
chemical species that reacts with
the endogenous target molecule
• Life cycle of a toxicant
– Absorption
– Distribution
– Degradation
– Reabsorption
• 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.
• Reabsorption
– Toxicants delivered into the renal
tubules may diffuse back across
the tubular cells into the
peritubular capillaries.
• Types of reactions:
– Noncovalent binding – temporary
– Covalent binding – permanent
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.
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
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.
• Genotoxicity
• Cytotoxicity
• Neurotoxicity
• (Other)
• In genetics, genotoxicity
describes the property of
chemical agents that damage
the genetic information within a
cell causing mutations which
may lead to cancer.
• Cells present expression of
genotoxic mutation by either
DNA repair or apoptosis.
However, the damage may not
always be fixed leading to
mutagenesis.
• The purpose of genotoxicity
testing is to determine if a
substance will influence genetic
material or may cause cancer.
• They can be performed in
bacterial yeast or mammalian
cells.
• With the knowledge from the
tests, one can control early
development of vulnerable
organisms to genotoxic
substances.
• 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).
• 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.
• 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
• 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.
• 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.
• 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.
• 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 testing is used to
identify potential neurotoxic
substances targeting the central
nervous system.
• 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.
• 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.
• 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.
• Deleterious effects of a
xenobiotic on the functioning of
the immune system.
• 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 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.
• 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.
• Integration of the newer approaches to routine
Safety Pharmacology studies may significantly
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.
• 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 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.
• 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
• Chemotherapy - the name
assigned to that branch of
selective toxicity which is
concerned with the removal of
parasites from man and his
tended animals
1. Selectivity through
Accumulation
-Selectivity through
accumulation is sometimes
only a matter of gross
morphology(overall biological
structure)
• Accumulation implies some or
all of the following:
– Efficient transport to the outside of
the cell
– A favourable permeability
mechanism
– A satisfactory storage mechanism
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.
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.
• 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.