Developmental Toxicology

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Developmental Toxicology

• Cao Yi
• Section of Toxicology

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Basic conception

• Terotagenesis Production of visually detectable
  birth defects
• Developmental Toxicity any adverse effect of
  toxicant on a developing organism, especially a
  embryonic organism.
• Teratogen A teratogen significantly increase the
  occurrence of structural or functional
  abnormalities in offspring when given to either
  parent before conception, the female during
  pregnancy, or directly to the developing
  organism, without producing severe toxicity to
  exposed parent.

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The three basic types of developmental toxicity
Embryolethality Failure to conceive, spontaneous abortion or still birth
Embryotoxicity Growth retardation or delayed growth of specific organ systems
Teratogenecity Irreversible condition that leave permanent defects in live offspring
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Chemicals cause developmental toxicity by two
methods

• Act directly on cells of the embryo causing cell
  death or cell damage, leading to abnormal organ
  development.
• Induce a mutation in a parents germ cell which
  is transmitted to the fertilized ovum. Some
  mutated fertilized ova develop into abnormal embry

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Mechanism of teratogenic action

• Cytotoxic agents affect via alternation in
  replication, transcription, translation and cell
  division.
• Effects on growth
• Non-specific developmental toxins
• Perturbation in marternal/plancental homeostasis

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Effects depend on Embryo age

1. Predifferentiation stage Embryo relatively
   resistant. (prior to organogenesis)
2. Embryonic stage embryo extremely sensitive.
   (organogenesis)
3. Fetal stage fetus less sensitive.
   (differentiation, maturation, growth)
4. Neonatal stage still some sensitivity
   (carcinogenesis)

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Reproductive toxicity tests

• Reproductive toxicity testing is intended to
  determine the effects of substances on gonadal
  function, conception, birth, and the growth and
  development of the offspring
• The oral route id preferred

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Reproductive toxicity tests
Species Rat is recommended
Age Young adults
Number of animals 20 of each sex per dose level
Dosage Three dose levels recommended, highest dose should produce toxicity but not mortality in parents lowest dose should not produce toxicity
Observation period Test substance given to parental animals prior to mating ,during pregnancy and through weaning of F1 offspring substance then given to selected F1 offspring during their growth into adulthood, mating, and production of an F2 generation, until the F2 generation is 21 days old
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Developmental toxicity tests

• Developmental toxicity testing detects the
  potential for substances to produce
  embryotoxicity and birth defects.

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