Animal Toxicity Studies

Akanksha Tripathi
PVDRC &PV Batch
I .C.R.I
New Delhi 1
Toxicology-The science or study of poison

 why study toxicology?

-Benefit risk ratio can be calculated.

-Prediction of therapeutic window.

-Therapeutic index= maximum tolerated

dose/minimum curative
dose

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Why Do We Require Non Clinical
Studies In animal Before
Administration To Man?
 Pharmacological effects are same in man as in animal.

 Toxic effect in species will predict adverse effect in man.

 Exposure of experimental animals to toxic agents in

high doses to discover possible hazards to human
beings who are exposed to much lower doses.

 Risk assessment can be made by comparison of toxic

doses in test species with predicted therapeutic dose in
man.

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General Principles In
Toxicological Studies

 Study should comply with GLP.

 Performed by trained and qualified staff.

 Use of standardized and calibrated equipments.

 SOP’s followed in laboratory tasks.

 All document should be preserved for minimum

5 years after marketing of the drug.

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 Types Of Toxicology Studies

Systemictoxicology studies- 1)single dose study 2)repeated

dose study.

Reproductivetoxicology study-1)male fertility 2)Female

reproduction and development studies.

Local toxicity studies.

Hypersensivity studies.

Genotoxicity studies.

Carcinogenicity studies.

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Importance Of Animal Toxicity
Studies
 Give information about data on acute toxicity, kinetics and
metabolism of the drug and organ sensitivity.

 To determine if the proposed clinical protocols in man are

reasonably safe to initiate.

 Estimate a “safe” starting dose for phase 1 clinical study.

 To inform clinical investigators about the animal toxicities

associated with the compound.

 To determine the safety monitoring measures.

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Limitations Of Animal Toxicity
Trials
 Toxicity testing is time-consuming and
expensive.

 Large number of animals must be used.

 Extrapolation of toxicity data from animals to

humans is not completely reliable.

 Rare adverse effects are unlikely to be

detected.

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Role of PETA

 In 1997 ,people for Ethical Treatment Of

Animals(PETA) filmed staff inside
Huntington life sciences( HLC) in the
UK,Europe’s largest animal testing facility,
hitting puppies, shouting at them and
stimulating sex acts

 The employees were dismissed and

prosecuted, and HLS’s license to perform
animal experiment was revoked for 6
months.

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A monkey in a restraint tube filed by PETA

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Acts And Guidelines

 Animal welfare act(1966).

 NIH- The guide for the care and use of

Laboratory Animals(1985).

 Institute of animal care and use

committee.

 Appendix 111 for SCHEDULE Y.

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Alternatives to Animals in Testing

Alternatives to the use of animals in toxicity testing

include replacing animal tests with non-animal methods,
as well as modifying animal-based tests to reduce the
number of animals used and to minimize pain and
distress. Non-animal tests are generally faster and less
expensive than the animal tests they replace and improve
upon.

To date, several non-animal test methods have been

formally validated and accepted by some countries as
replacements for an existing animal test. Examples
include the following:

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Continues…
An embryonic stem cell test, using mouse-derived cells to
assess potential toxicity to developing embryos, has been
validated as a partial replacement for birth-defect testing in
rats and rabbits.

Human skin model tests are now in use, which has been
accepted almost universally as a total replacement for skin
corrosion studies in rabbits.

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 Continues…
 The use of human skin leftover from surgical procedures
or donated cadavers can be used to measure the rate at
which a chemical is able to penetrate the skin.

 Micro dosing can provide information on the safety of

experimental drug and how it is metabolized in the body
by administering an extremely small one-time dose that
is well below the threshold necessary for any potential
pharmacologic effect to take place.

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Conti…
 While effective non-animal test methods become
more and more numerous, animal-based
toxicology remains, as researcher Thomas Hartung
wrote, “frozen in time, using and accepting the
same old animal models again and again, often
without stringent examination of their validity.”

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Standard Techniques For Sacrificing
Animals And Physiological Salt
Solution
 Mechanical methods-
 Pithing
 Decapitation

 Chemical methods-

 An anesthetics

Physiological salt solution-

sodium chloride, potassium chloride, calcium chloride,

sodium bicarbonate,glucose,potassium dihydrogen
phosphate, magnesium chloride
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Basic Instruments Used For
Isolated Tissue Experiments
 Isolated organ bath
 The recording devices

 simple lever

 frontal writing lever

For aeration-
 Supply of oxygen
 Uniform distribution of drug due to

bubbling
 Maintenance of pH

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Conclusion..
 Toxicity studies are costly in terms of both
animal and resources.

 In the future, it is possible that the need for

the animal studies will be further minimized
by the use of low dose & ultra low dose
studies in human.

 New computed technologies.

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