• Cross-species extrapolation is needed to assess the human relevance of effects observed in animals.
  • In vitro to in vivo extrapolation is needed to assess the in vivo relevance of effects observed in in vitro assays.
  • Both extrapolations have their own limitations. In vivo animal studies are ethically undesirable, while oversimplified in vitro assays will not reproduce key physiological processes that occur in humans in vivo.
  • Two extrapolations (in vitro/in vivo and animal/human) are required when assessing the relevance to humans in vivo of effects observed in animal cells or tissues in vitro. This is especially challenging.
  • Therefore the preferred option is to use physiologically relevant human in vitro models to explore and understand human in vivo biology.