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
• With one exception, a...
GEN 5173: Embryology, Prenatal Diagnosis, and Teratogens
Embryotoxicity
• Embryotoxicity: When a substance
given to a preg...
GEN 5173: Embryology, Prenatal Diagnosis, and Teratogens
Fetotoxicity
• Fetotoxicity: When a substance given
to a pregnant...
GEN 5173: Embryology, Prenatal Diagnosis, and Teratogens
Maternal Toxicity
• Maternal Toxicity: When a substance
given to ...
GEN 5173: Embryology, Prenatal Diagnosis, and Teratogens
Inter-species variability
• An agent that is teratogenic in one
s...
GEN 5173: Embryology, Prenatal Diagnosis, and Teratogens
Intra-species variability
• Within a single species, the
teratoge...
GEN 5173: Embryology, Prenatal Diagnosis, and Teratogens
NOAEL vs. LOAEL
• NOAEL (No Observable Adverse Effects
Level): Hi...
GEN 5173: Embryology, Prenatal Diagnosis, and Teratogens
Interpreting Animal Studies
• Advantages
– easily controlled cond...
GEN 5173: Embryology, Prenatal Diagnosis, and Teratogens
Interpreting Animal Studies
• Disadvantages
– Different metabolis...
GEN 5173: Embryology, Prenatal Diagnosis, and Teratogens
History of Animal
Teratogenicity Testing
• Prior to 1964...
– No ...
GEN 5173: Embryology, Prenatal Diagnosis, and Teratogens
Current FDA Guidelines
1. Fertility/general reproductive
performa...
GEN 5173: Embryology, Prenatal Diagnosis, and Teratogens
Current FDA Guidelines
2. Teratological study
• Embryotoxicity
• ...
GEN 5173: Embryology, Prenatal Diagnosis, and Teratogens
Ideal Criteria for Animal
Model
• Mammalian maternal-placental-em...
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Toxicology testing in animals narrated part 12013

  1. 1. Toxicology Testing in Animals Part 1
  2. 2. Animal data does not always predict human risk
  3. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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

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