This document discusses various types of long-term toxicity tests for drugs, including allergenicity/hypersensitivity tests using guinea pigs, genotoxicity studies looking for early cancer effects using bacterial and mammalian cell assays, in vivo chromosomal damage tests in rodents, carcinogenicity/oncogenicity lifetime bioassays in animals, and teratogenicity studies to assess a drug's ability to cause birth defects when administered to a pregnant mother, which can occur during three stages of fetal development. The type and timing of any fetal exposure depends on the drug's pharmacokinetics in the maternal system.

1. Long Term Toxicity
Tests
(Teratogenicity, Oncogenicity, Mutagenicity & Allergenicity)
RVS Chaitanya Koppala

2. ALLERGENICITY/HYPERSENSITIVITY
TOXICOLOGY STUDIES
Guinea Pig Maximization
test
Local lymph node assay
Determination of Maximum non irritant or
minimum irritant dose
Evaluation of Erythema and oedema
Mice of one sex(either male or female)
Drug treatment given on ear skin
Auricular lymph node dissection after 5 days
Increase in 3h-thymidine used for evaluation

3. GENOTOXICITY STUDIES
To detect early tumorigenic effects in cases of chronic illness
In vitro tests:
Test for gene mutation in Bacteria
Cytogenetic evaluation of chromosomal damage in
mammalian cells
E.g.; Ames’s Salmonella Assay detects increased number of
aberrations in metaphase chromosomes
DNA strand breaks, DNA repair or recombination,
Measurements of DNA adducts

4. IN VIVO TESTS
 In vivo test for chromosomal damage using mammalian hematopoietic
cells.
 Chromosome damage in rodent hematopoietic cells
E.g.; Micronucleus Assay

5. CARCINOGENICITY/ ONCOGENICITY STUDIES
life-time bioassays
carcinogenicity studies are performed on:
drug used for >6 months or frequent intermittent use for chronic
diseases
chemical structure of drug indicates carcinogenic potential
therapeutic class of drugs which have produced positive
carcinogenicity

6. TERATOGENICITY
 Capacity of a drug to cause foetal abnormalitites when administered to
the pregnant mother.
 Placenta does not consider a strict barrier and any drug can cross it to a
greater or lesser extent.
 The embryo is one of the most dynamic biological systems

7.  Drugs can affect the foetus at 3 stages
1. Fertilization and implantation- conception to 17 days (unnoticed failure
of pregnancy)
2. Organogenesis- 18-55 days of gestation most vulnerable period,
deformaties are produced.
3. Growth and development-56days onward developmental and funcitonal
abnormalities can occur e.g. ACE inhibitors can cause hypoplasia of
organs lungs, kidneys.

8.  The type of malformation depends upon the drug as well as the
stage at which exposure to the teratogen occurred.
 Foetal exposure depends on the blood level and duration for
which the drugs remains in maternal ciruclation.
 The teratogenic potential of a drug is to be considered against
the background of congenital abnormalities

11.  Therefore wise to avoid all the drugs during pregnancy unless compelling
reasons, exist for their use regardless of the assigned pregnancy category.
 Frequency of spontaneous as well as drug induced malformations.
Especially neural tube defects may be reduced by folate therapy during
pregnancy.