title: Use of physiologically based kinetic modeling-facilitated reverse dosimetry of in vitro toxicity data for prediction of in vivo developmental toxicity of tebuconazole in rats.
abstract: Toxicological hazard and risk assessment largely rely on animal testing. For economic and ethical reasons, the development and validation of reliable alternative methods for these animal studies, such as in vitro assays, are urgently needed. In vitro concentration-response curves, however, need to be translated into in vivo dose-response curves for risk assessment purposes. In the present study, we translated in vitro concentration-response data of the antifungal compound tebuconazole, obtained in the ES-D3 cell differentiation assay, into predicted in vivo dose-response data for developmental toxicity using physiologically based kinetic (PBK) modeling-facilitated reverse dosimetry. Using the predicted in vivo dose-response data BMD(L)10 values for developmental toxicity in rat were calculated and compared with NOAEL values for developmental toxicity data in rats as reported in the literature. The results show that the BMDL10 value from predicted dose-response data are a reasonable approximation of the NOAEL values (ca. 3-fold difference). It is concluded that PBK modeling-facilitated reverse dosimetry of in vitro toxicity data is a promising tool to predict in vivo dose-response curves and may have the potential to define a point of departure for deriving safe exposure limits in risk assessment.
authors.affiliation: Division of Toxicology, Wageningen University, Stippeneng 4, 6708 WE Wageningen, The Netherlands. Electronic address: hequn.li@hotmail.com.
authors.forename: Hequn
authors.initials: H
authors.lastname: Li
authors.affiliation: Division of Toxicology, Wageningen University, Stippeneng 4, 6708 WE Wageningen, The Netherlands.
authors.forename: Mengying
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Laboratory of Biochemistry, Wageningen University, Stippeneng 4, 6708 WE Wageningen, The Netherlands.
authors.forename: Jacques
authors.initials: J
authors.lastname: Vervoort
authors.affiliation: Division of Toxicology, Wageningen University, Stippeneng 4, 6708 WE Wageningen, The Netherlands.
authors.forename: Ivonne M C M
authors.initials: IM
authors.lastname: Rietjens
authors.affiliation: Division of Toxicology, Wageningen University, Stippeneng 4, 6708 WE Wageningen, The Netherlands; Experimental Toxicology and Ecology, BASF SE, Z 470, 67056 Ludwigshafen, Germany.
authors.forename: Bennard
authors.initials: B
authors.lastname: van Ravenzwaay
authors.affiliation: Division of Toxicology, Wageningen University, Stippeneng 4, 6708 WE Wageningen, The Netherlands.
authors.forename: Jochem
authors.initials: J
authors.lastname: Louisse
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005659:Fungicides, Industrial / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D008954:Models, Biological; D015394:Molecular Structure; D051381:Rats; D012680:Sensitivity and Specificity; D014230:Triazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*
chemical_list: D005659:Fungicides, Industrial; D014230:Triazoles; C087114:tebuconazole
keywords: Developmental toxicity; Embryonic stem cell test; In vitro–in vivo extrapolation; Physiologically based kinetic modeling; Reverse dosimetry; Tebuconazole