1. Toxicology Testing in Animals
Part 1

2. Animal data does not always
predict human risk

3. GEN 5173: Embryology, Prenatal Diagnosis, and Teratogens
Developmental Toxicity
Testing in Animals
• With one exception, all known human
teratogens have been teratogenic in one or
more animal species.
• Different species show marked differences
in sensitivities and responses to
compounds.
• The animals showing teratogenicity may
be different from those used for clinical
animal studies before release of a new
medication.

4. GEN 5173: Embryology, Prenatal Diagnosis, and Teratogens
Embryotoxicity
• Embryotoxicity: When a substance
given to a pregnant animal during any
portion of gestation results in
significant pregnancy loss, either by
preventing implantation or by post-
implantation death

5. GEN 5173: Embryology, Prenatal Diagnosis, and Teratogens
Fetotoxicity
• Fetotoxicity: When a substance given
to a pregnant animal during any
portion of gestation leads to offspring
showing signs of delayed
development compared to controls
– It is almost always accompanied by and
is considered to be the result of maternal
toxicity.

6. GEN 5173: Embryology, Prenatal Diagnosis, and Teratogens
Maternal Toxicity
• Maternal Toxicity: When a substance
given to a pregnant animal during any
portion of gestation leads to
deleterious effects on behavior,
excretion, appearance, body weight,
organ weight and/or organ function

7. GEN 5173: Embryology, Prenatal Diagnosis, and Teratogens
Inter-species variability
• An agent that is teratogenic in one
species may or may not…
– have teratogenic effects in a second
species
– produce the same effects in a second
species
– produce effects that vary in frequency
between species

8. GEN 5173: Embryology, Prenatal Diagnosis, and Teratogens
Intra-species variability
• Within a single species, the
teratogenic effects and frequencies
may vary based on maternal and fetal
genetic susceptibility, placental and
hormonal factors and other maternal-
fetal factors

9. GEN 5173: Embryology, Prenatal Diagnosis, and Teratogens
NOAEL vs. LOAEL
• NOAEL (No Observable Adverse Effects
Level): Highest dose at which no effects
are noted
• LOAEL (Lowest Observable Adverse
Effects Level): Lowest dose at which
effects are noted. It is equivalent to a
threshold dose

10. GEN 5173: Embryology, Prenatal Diagnosis, and Teratogens
Interpreting Animal Studies
• Advantages
– easily controlled conditions
– usually provide large litters with short
gestational period
– provide mechanisms/models
– occasional models for humans

11. GEN 5173: Embryology, Prenatal Diagnosis, and Teratogens
Interpreting Animal Studies
• Disadvantages
– Different metabolism and physiology than
humans
– Marked interspecies variation
– Dose equivalency is not always clearly
calculated
– Animals are usually exposed to long term high
doses
– No one species has been found to be most
predictive (even primates)
– May predict risk, but malformations are not
always the same

12. GEN 5173: Embryology, Prenatal Diagnosis, and Teratogens
History of Animal
Teratogenicity Testing
• Prior to 1964...
– No government standards
– Three generation studies:
1. Toxicity
2. Fertility
3. State of reproductive organs
– No pregnancy studies

13. GEN 5173: Embryology, Prenatal Diagnosis, and Teratogens
Current FDA Guidelines
1. Fertility/general reproductive
performance
• Gonadal function
• Estrous cycles
• Mating behavior
• Conception rates
• Early gestational stages

14. GEN 5173: Embryology, Prenatal Diagnosis, and Teratogens
Current FDA Guidelines
2. Teratological study
• Embryotoxicity
• Teratogenic potential
3. Perinatal and postnatal studies
• Late fetal development
• Labor, delivery
• Lactation
• Neonatal viability
• Growth of the newborn

15. GEN 5173: Embryology, Prenatal Diagnosis, and Teratogens
Ideal Criteria for Animal
Model
• Mammalian maternal-placental-embryonic
relationship
• Comparable metabolic rates and pathways to
man
• Developmental patterns should parallel those
in man
• Easy to breed, short gestation, large litters,
economically housed and easily handled