Professional Documents
Culture Documents
PRESENTED BY
SINDHU K
MVSC SCHOLAR,
DEPT OF VPT, COVAS.
TOXICITY STUDIES - INTRODUCTION
• Toxicology classically has been defined as the study of poisons & concerned with the
adverse effects of xenobiotics.
• Casarett 1996 defined it as a science that defines the limits of safety of chemical
agents for human & animal populations.
• Toxicological screening is very important for the development of new drugs and for
the extension of the therapeutic potential of existing molecules.
• The US-FDA states that it is essential to screen new molecules for pharmacological
activity and toxicity potential in animals (21CFR Part 314).
• Toxicity tests are mostly used to examine specific adverse events or specific end
points such as cancer, cardiotoxicity, and skin/eye irritation.
• Toxicity testing also helps calculate the No Observed Adverse Effect Level (NOAEL)
dose and is helpful for clinical trails.
HISTORY OF TOXICITY STUDIES
The use of sheep brain for the production of rabies vaccine has been
phased out in 1992
Classical swine fever virus vaccine is produced in PK-15 Cells instead using
large number of rabits
PPR, FMD and sheep pox vaccines are also produced using cell culture vero,
BHK-21 and vero cell culture system respectively.
The use of laboratory animals e.g., rabbit and G. pig has been now
abandoned for the isolation or typing of mycobacetria with the availability
of improved synthetic media.
BIOMEDICAL ETHICS
It has been estimated that approximately 20 million animals are being
used for testing and are killed annually; about 15 million of them are
used to test for medication and five million for products.
China has become one of the biggest countries using lab animals, as is
evident in the higher numbers and quality of lab animals (e.g., specific
pathogen free, or SPF1; genetically modified) increasingly used in
scientific research—16 million a year, compared to 12 million in the 25
European Union countries in 2005 (FELASA 2007)—and the increased
publication of animal experiment results in international journals.
,
Pharmacokinetic profile
Pharmacodynamic response
Species, sex, age of experimental animals
Susceptibility, sensitivity and reproducibility of test system
In vitro: Isolated organs, tissues cell-cultures
Mechanism of effect in vivo
In vivo
toxicological
models
IN-VIVO >< IN-VITRO
Preliminary Definitive
Test animals:
• Species/strain used and justification for choice made;
• Number, age, and sex of animals at start of test;
• Source, housing conditions, diet, etc.;
• Individual weights of animals at the start of the test.
OECD
Rabbit or Dog
Rectal tolerance studies Signs of pain, blood or mucous
histology examination of rectal mucosa
Ocular toxicity studies Albino Rabbit
Changes in cornea ,Iris & aqueous humor,
histological examination of eye
drug used for >6 months or frequent intermittent use for chronic diseases
ACUTE
• 401 ~ Acute Oral Toxicity
• 402 ~ Acute Dermal Toxicity
SUB CHRONIC
• MTD: Maximum Tolerated Dose. Is the highest dose that can be tolerated
without significant lethality from causes other than tumors.
(for EPA studies MTD for chronic studies with pesticides is a dose which
produces an approximate 10-15% decrement in body weight gain)
• HTD: Highest dose tested. Highest dose that can be expected to yield
results relevant to humans. This is a proposed new dose which would be
selected based on evaluation of results of sub-chronic studies.
VEHICLES USED FOR DOSING
• Salivation
• Piloerection
• Analgesia
• Muscle tone - hypotonia
- hypertonia
• GIT signs: dropping feces, emesis, diuresis(hematuria &
involuntary urination)
AUTONOMIC SIGNS
• Decreases = liver
• No change = heart, kidneys, prostrate, spleen, ovaries.
• Increases =adrenal gland, brain, epididymides, pituitary,
testes, thyroid, uterus.
Human studies
1. General considerations for clinical studies
2. Specific considerations for clinical studies
a. Protocol design
b. The study population
c. Statistical analyses
3. Sequence of clinical studies
a. Early clinical studies
b. Further clinical studies
4. Submitting reports of clinical studies to CFSAN (Center for Food
Patients Patients
Healthy subjects Patients
None Large scale Large scale
Safety and Small scale post-marketing
multicentre
tolerability efficacy studies studies studies
Genetic toxicity
Genetic toxicity
(in vivo)
(in vitro)
Non-clinical
• ,
REFERENCES