20 Acute Subacute and chronic studies

Question 1

Toxicological screening is very important for
used to examine
is helpful in

Answer 1

development of new drugs and
extension of therapeutic potential of existing molecules
US FDA states that
It is essential to screen new molecules for pharmacological activity and toxicity potential in animals

Toxicity tests are mostly used to examine
Specific adverse events or
Specific end points such as cancer, cardiotoxicity, and skin/eye irritation

Toxicity testing
Helps in calculating the No Observed Adverse Effect Level (NOAEL) dose, and
Is helpful for clinical trails

Benefit–risk ratio can be calculated
Prediction of therapeutic index
Therapeutic index = “Maximum tolerated dose “ /”Minimum curative dose”
Larger ratio, better safety of the drug

Question 2

Therapeutic index

Answer 2

Therapeutic index = “Maximum tolerated dose “ /”Minimum curative dose”

Question 3

Relevant Test Models

Answer 3

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

Question 4

Toxicity studies - in vitro and in vivo

Answer 4

In vitro studies
Designed to establish a concentration-effect relationship
In Vivo studies
Designed to define the dose-response relationship of the adverse effect observed
Investigate the time course of the adverse effect
e.g. onset and duration of response

Question 5

Types of Toxicity Studies

Answer 5

Single dose studies
Acute toxicity studies
Harmful in single or short term
exposure
Repeated dose studies
Sub-acute
Causes effect by multiple
doses or long exposure
Chronic studies
Cause effect upon repeated
dosage or life time exposure

TYPES

Local toxicity studies
Allergenicity/Hypersensitivity toxicology studies
Genotoxicity studies, and
Carcinogenicity/Oncogenicity studies

Question 6

Acute Toxicity Studies

Answer 6

It is defined as the adverse effects occurring following
-Oral or dermal administration of
-A single dose of a substance,
or
-Multiple doses given within24
hours
-An inhalation exposure of 4 hours
Oral administration is the most common form of acute systemic toxicity testing

The preferred species are
Rat for oral and inhalation testing, and
Rat or rabbit for dermal testing

-Limit test: Dose of 2000 (or 5000) mg/kg b.w. is administered
-The animals are observed for 14
days for
Death, or
Signs of toxicity: morphological,
biochemical, pathological
-Considered safe if no death or
toxicity
Main Test
Performed to determine LD50 if animals die in Limit test

Question 7

Data recorded during acute toxicity studies include

Answer 7

Daily body weight and body weight changes
Individual weights of animals at the day of dosing, in weekly intervals thereafter, and at time of death or sacrifice
Date and time of death, if prior to scheduled sacrifice
Time course of onset of signs of toxicity and whether these were reversible for each animal
Necropsy findings and histopathological findings for each animal

Question 8

Signs recorded during acute toxicity studies include

Answer 8

Increase/decrease in motor activity
Tremors and ataxia, convulsions
Sedation, hypnosis, muscle relaxation
Analgesia, lacrimation, diarrhoea, salivation
Writhing, respiration depression, skin colour
Cannibalism, etc.

Question 9

Subacute and Chronic Toxicity Testing

Answer 9

It is defined as specific target organ/systemic toxicity arising from a repeated exposure to an agent
It is used for
Evaluating chronic toxic effects on various organ systems, and
Establish a no observed effect level

Repeated dose toxicity testing consists of oral, dermal, and inhalation studies

Subacute/sub-chronic
-Subacute repeated dose studies (28‐day) and
-Sub-chronic repeated dose studies (90‐day)

Chronic
-Usually 12 months
-Could be shorter (6/9 months) or longer (18/24 months)

Preferred animal species

Subacute/sub-chronic studies
In rodents (preferably rats)

Chronic studies
In rodents (preferably rats), and
Non-rodent species

The endpoints for repeat dose testing consist of :
Evaluation of clinical observations
Blood analysis
Whole body gross necropsy, and
Histopathology of all organs and tissues

Question 10

Subacute and Chronic Toxicity Testing - objectives

Answer 10

The objectives include
Identification of hazardous properties of a chemical
Identification of target organs
Characterization of the dose:response relationship

Identification of :
-No‐observed‐adverse‐effect level (NOAEL) or
-Point of departure for establishment of a Benchmark Dose

Prediction of chronic toxicity effects at human exposure levels
Provision of data to test hypotheses regarding mode of action