Modified One-Generation Studies
NTP's Modified One-Generation (MOG) Reproduction Study design evolved from:
- NTP's changing its default exposure paradigm in rat cancer bioassays to include treatment exposure during pregnancy and early life,
- the increased knowledge of critical windows of exposure, which indicates the need for a larger focus on evaluating the potential for postnatal adverse effects, and
- the updates to standard study designs with more functional end points to assess how agents affect the reproductive and endocrine status of animals.
The classical study used to evaluate reproductive toxicity is the multigenerational reproduction experimental design. NTP has modified this classical study design to better utilize the animals produced and to reduce animal use by improved experimental design and statistical power.
NTP's Modified One-Generation Reproductive study design employs pregnant animals with dosing beginning at implantation and continued dosing of the dams throughout gestation and lactation. At weaning the offspring are administered the test article at the same dose level as their respective dam and are subsequently assigned to a number of different cohorts normally including:
- a subchronic toxicity cohort – to evaluate target organ toxicity, pathology, clinical pathology
- a teratology cohort – to evaluate prenatal development. One male and female offspring from each litter is selected and non-sibling matings are performed in each group and fetuses will be examined for abnormalities.
- a littering cohort – to evaluate breeding and littering for potential examination of the subsequent generation. One male and female offspring from each litter is selected and non-sibling matings are performed in each group. The pregnant dams deliver their litters and raise them to weaning.
- a developmental neurotoxicity (DNT) cohort – to evaluate neurobehavioral end-points and neurohistopathology. One male and one female offspring per litter are selected from at least 20 different litters. Neurobehavioral tests include motor assessment (motor activity and function), motor and sensory responses (pre-pulse inhibition of startle), and learning and memory (Morris Water maze). In addition, detailed clinical observations, developmental landmarks, and neurohistopathology in dams and pups will also be evaluated. For further details, see the Guidance Document for the Developmental Neurotoxicity arm of the MOG Study.
NTP's Modified One-Generation Study emphasizes a full evaluation of the F1 generation animals and uses fewer animals than the classical multigeneration study design, while generating information on the effects of agents on prenatal development, postnatal development, and reproduction.
For further design details, see the MOG Protocol template.