title: Toward in vitro biomarkers for developmental toxicity and their extrapolation to the in vivo situation.
abstract: BACKGROUND
  Reliable in vitro and in silico assays as alternatives for in vivo developmental toxicity studies are urgently needed, for the replacement, reduction and refinement (3Rs) of animal use in toxicological research. Therefore, relevant biomarkers for in vivo developmental toxicity in in vitro assays are needed.
  
  
  METHODS
  The present review gives an overview of alternative assays, as described in literature, for in vivo developmental toxicity, including the effects (readouts) assessed in these assays. The authors discuss how these data may be used to obtain relevant biomarkers for in vivo developmental toxicity, and how in vitro effect data can be translated to the in vivo situation using physiologically based kinetic (PBK) modeling.
  
  
  CONCLUSIONS
  Relevance of readouts in in vitro developmental toxicity assays as predictive biomarkers for in vivo developmental toxicity should be evaluated by comparing the obtained in vitro effect concentrations with in vivo internal concentrations at dose levels causing developmental toxicity. Extrapolation of the in vitro effect concentrations to in vivo dose levels using PBK modeling (i.e., reverse dosimetry) is promising in its use to derive points of departure for risk assessment, enabling the use of in vitro toxicity data in the safety assessment of compounds.
authors: Wageningen University, Division of Toxicology, Tuinlaan 5, 6703 HE Wageningen, The Netherlands. jochem.louisse@wur.nl
authors: Jochem
authors: J
authors: Louisse
authors: Miriam
authors: M
authors: Verwei
authors: Ruud A
authors: RA
authors: Woutersen
authors: Bas J
authors: BJ
authors: Blaauboer
authors: Ivonne M C M
authors: IM
authors: Rietjens
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D018570:Risk Assessment; D018675:Toxicity Tests / Q000379:methods* / Q000639:trends
chemical_list: D015415:Biomarkers; D004364:Pharmaceutical Preparations