Toxicology Testing in Animals Part 1

Animal data does not always predict human risk

GEN 5173: Embryology, Prenatal Diagnosis, and Teratogens

Developmental Toxicity Testing in Animals

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.

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

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.

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

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

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

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

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

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

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

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

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

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