WELCOME

WELCOME

UNDER THE GUIDENCE OF BYMISS MEENU SINGH SUMANGALI.MASST. PROFESSOR M.PHARM DEPARTMENT OF PHARMACOLOGY PHARMACOLOGYCMRCP HYDERABAD

TESTS FOR TERATOGENICITY

Teratogenicity:

The capability of producing fetal malformation

A teratogen is an agent that can produce a permanent alteration of structure or function in an organism exposed during embyronic or fetal life

Teratogen:

A given teratogen may be organ specific.

It may be species specific. It can be dose specific.

Basic Characteristics of teratogen:

Teratology:

Teratology is the study of abnormalities of physiological development.

It is often thought of as the study of human “birth defects”, but it is much broader than that, taking in other non-birth developmental stages, including “puberty “; and other non-human life forms, including plants.

Critical periods:

STAGE OF EXPOSURE

OUTCOME(S)

Pre-implantation Embryonic lethality

Implantation to time of organogenesis

Morphological defects

Fetal → neonatal stage Functional disorders, growth retardation, carcinogenesis

Historical Teratogens:

Thalidomide

Accutane

Diethylstilbestrol(DES)

Alcohol

CLEFT LIP

PHOCOMELIA

AMELIA / PHOCOMELIA

TESTS FOR

TERATOGENICITY

Testing Protocols:

Under the guidelines of FDA Under the guidelines of ICH

Tests under FDA:

Multigenerational studies

Single generational studiesa) Segment I:Evaluation of Fertility

and Reproductive Performanceb) Segment II: Assessment of

Developmental Toxicityc) Segment II: Postnatal

Evaluation

Tests under ICH:

Fertility Assessment

Postnatal Evaluation and Pregnancy State Susceptibility

Assessment of Developmental Toxicity

Multigenerational Study:

The animals are mated.

Continuous exposure of a rodent species (usually mice)

F1

Exposed shortly after weaning (30–40 days of age)

The effects of the test is monitored through each generation.

The measured parameters : Fertility Litter size Neonatal viability

F2F3

Evaluation of Fertility and Reproductive Performance:

Male rodents are treated for 70 days and nonpregnantfemales for 14 days .Treatment is continued in the females during Mating Pregnancy Lactation

50% of the females are killed and the fetuses are examined for presence of malformations. The other 50% areallowed to give birth. After weaning, these offspring are killed and necropsied

Assessment of Developmental Toxicity:

Treatment of pregnant females only during implantation through organogenesis

One day prior to birth, the animals are killed

Fetuses examined for 1.viability 2.Bodyweight 3. presence of malformation

Postnatal Evaluation:

Pregnant animals are treated from the last trimester of pregnancy until weaning.

Evaluation: Parturition process Late fetal development Neonatal survival Growth Presence of any

malformations

Fertility Assessment:

1. 3.

Males Females

Exposed for four weeks before mating

Two weeks before mating

Evaluation Evaluation

Reproductive organs weight Fertility

Histological analysis Litter size

Sperm count & mobility Viability of conceptus

Postnatal Evaluation and Pregnancy State Susceptibility:

Comparing the degree of toxicity of the non pregnant female to that of the pregnant female

Evaluation : Maternal toxicity Growth Functional

development(off springs)

Assessment of Developmental Toxicity: Pregnant animals are exposed from implantation through organogenesis

The study is conducted using atleast two species, one rodent and one non rodent.

One day prior to birth , the animals are killed & fetuses are examined.

Evaluation : Viability Body weight Presence of malformation

Alternative Test Methods:

Micro mass test ( cells from the limb buds & brains of rat embroys)

Whole embrio culture test(whole embryos of rats)

Embryonic stem cell test

Conclusions: Understanding the mechanisms of the

induction of birth defects is key to determine how to prevent these effects.

Further increasing the accuracy of experimental animal extrapolation will aid in the interpretation of experimental data in order to more accurately determine the risk of a given compound to elicit birth defects in humans

Please, give only good fertilizer…