1 Models in Toxicology - 4 Juni 2024

Models in Toxicology
DAN
2024
Toxicology and Toxicity Test
• Toxicology is the study of the adverse effects of

chemical, physical, or biological agents on
people, animals, and the environment.
• In order to study the adverse effects of those
potentially harmful agents on living species, the
only way is by doing toxicity test.
• BUT it would be unethical to expose humans
to varying doses of potentially harmful
chemicals in order to observe the effects.
Toxicity Test
• Toxicity test is applied to several
substances such as industrial
chemicals, pharmaceuticals and
consumer care products, which
might be toxic for human.
• Toxicity tests characterize the
level of toxicity of several
substances via the dose-
response relationship and the
target organ.
Models in toxicology
• In vitro
• Jain, A. K., Singh, D., Dubey, K., Maurya, R., Mittal, S., & Pandey, A. K. (2018).
Models and methods for in vitro toxicity. In In vitro toxicology (pp. 45-65).
Academic Press.
• In vivo (animal model)
• Ethics-3Rs (https://www.nc3rs.org.uk/who-we-are/3rs)
In vitro
models
• The term in vitro is derived from
the Latin phrase, which means
“the technique of performing a
given procedure in an artificial
environment outside the living
organism”.
• Cell-Line Model ATCC
• Cek Jain et al., 2018
Cell-Line Model
Cell-Line Model
• Cytotoxicity Assessment
• Genotoxicity Assessment
• Mutagenicity
1.
Cytotoxicity
Assay
• Cytotoxicity is the
attribute of being
toxic to the cells.
Most of the assays
having a broad
range of different
cytotoxic endpoints
are now being used
to measure the
cellular responses
toward a toxic
chemical.
Micronucleus Comet
2. Genotoxcity
• Comet assay
• Micronucleus assay
• Chromosome
Chromosome aberration
aberration test
• Apoptosis detection
assay (Annexin V/PI
staining, TUNEL Assay,
Caspase level)
Apoptosis detection assay

3. Mutagenicity
• Forward Gene Mutation Assay (Mammalian Model)

• Ames Test
3. Mutagenicity
• Forward Gene Mutation Assay (Mammalian Model)
FIGURE 3.3 A hypothetical representation of forward gene

mutation assay on either adherent cells (V79) or cells in
suspension.
3. Mutagenicity
• Forward Gene
Mutation Assay
Non-Mammalian
Model: Ames Test
In Vivo/Animal Model
• Animals are useful models to predict the

toxicity of chemicals in humans because
they have similar cell organelles, cells
and organs.
• If the model is not close to human,
uncertainity of results increase.
• Toxicity tests can be performed in
several laboratories and the same
results must be obtained in different
labs (tests must be objective).
Ethics
Ethics-3Rs (https://www.nc3rs.org.uk/who-we-are/3rs)
• The concept of 3Rs (reduce, refine and replace animal use) was first
proposed by William Russell and Rex Burch in the “Principles of Humane
Experimental Technique”.
• In 1981 guideline for acute oral toxicity required the use of only five
animals per sex per dose group, with three dose groups per test which
were chosen, to span the LD50 test.
Body Surface Dose Conversion Between
Animal and Human
Figure 1 Schematic
representation of
five steps to
estimate starting
dose in human
studies
The use of the safety factor should be
based on the possibility that humans
may be more sensitive to the toxic
effects of a therapeutic agent than
predicted by the animal models, that
bioavailability may vary across
species, and that the models tested do
not evaluate all possible human
toxicities. In general, one should
consider using a safety factor of at
least 10.
AED  HED
HED  AED
Human Equivalent Dose

(161 mg/kg BW)
Rat Mice
(1000 mg/kg BW) (1980 mg/kg BW)
Group Assignment (4 people)
• Find one Animal Model.
• Found its pros (e.g. its similarity to human, quick and easy to breed,
etc.), and cons (e.g. expensive, difficult to maintain, etc.)
• Found one scientific article using this model in toxicity test (Q2-Q1,
after 2020). Explain briefly (random group will be selected to present
next week).
• Each group should find different animal model.
• Deadline 10/6/2024 23:59, submit PPT and report.

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Models in Toxicology

• Toxicology is the study of the adverse effects of

Apoptosis detection assay

• Forward Gene Mutation Assay (Mammalian Model)

FIGURE 3.3 A hypothetical representation of forward gene

• Animals are useful models to predict the

Human Equivalent Dose

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