title: The use of in vitro toxicity data and physiologically based kinetic modeling to predict dose-response curves for in vivo developmental toxicity of glycol ethers in rat and man.
abstract: At present, regulatory assessment of systemic toxicity is almost solely carried out using animal models. The European Commission's REACH legislation stimulates the use of animal-free approaches to obtain information on the toxicity of chemicals. In vitro toxicity tests provide in vitro concentration-response curves for specific target cells, whereas in vivo dose-response curves are regularly used for human risk assessment. The present study shows an approach to predict in vivo dose-response curves for developmental toxicity by combining in vitro toxicity data and in silico kinetic modeling. A physiologically based kinetic (PBK) model was developed, describing the kinetics of four glycol ethers and their embryotoxic alkoxyacetic acid metabolites in rat and man. In vitro toxicity data of these metabolites derived in the embryonic stem cell test were used as input in the PBK model to extrapolate in vitro concentration-response curves to predicted in vivo dose-response curves for developmental toxicity of the parent glycol ethers in rat and man. The predicted dose-response curves for rat were found to be in concordance with the embryotoxic dose levels measured in reported in vivo rat studies. Therefore, predicted dose-response curves for rat could be used to set a point of departure for deriving safe exposure limits in human risk assessment. Combining the in vitro toxicity data with a human PBK model allows the prediction of dose-response curves for human developmental toxicity. This approach could therefore provide a means to reduce the need for animal testing in human risk assessment practices.
authors.affiliation: Division of Toxicology, Wageningen University, 6703 HE Wageningen, The Netherlands. jochem.louisse@wur.nl
authors.forename: Jochem
authors.initials: J
authors.lastname: Louisse
authors.forename: Esther
authors.initials: E
authors.lastname: de Jong
authors.forename: Johannes J M
authors.initials: JJ
authors.lastname: van de Sandt
authors.forename: Bas J
authors.initials: BJ
authors.lastname: Blaauboer
authors.forename: Ruud A
authors.initials: RA
authors.lastname: Woutersen
authors.forename: Aldert H
authors.initials: AH
authors.lastname: Piersma
authors.forename: Ivonne M C M
authors.initials: IM
authors.lastname: Rietjens
authors.forename: Miriam
authors.initials: M
authors.lastname: Verwei
mesh_terms: D000085:Acetates / Q000493:pharmacokinetics / Q000633:toxicity; D000826:Animal Testing Alternatives; D000818:Animals; D002478:Cells, Cultured; D019295:Computational Biology; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000378:metabolism; D047108:Embryonic Development / Q000187:drug effects*; D005026:Ethylene Glycols / Q000493:pharmacokinetics* / Q000633:toxicity*; D006801:Humans; D008954:Models, Biological; D011237:Predictive Value of Tests; D051381:Rats; D018570:Risk Assessment; D013723:Teratogens / Q000493:pharmacokinetics* / Q000633:toxicity*
chemical_list: D000085:Acetates; D005026:Ethylene Glycols; D013723:Teratogens; C043618:ethylene glycol monopropyl ether; C415326:phenoxyacetic acid