title: Evaluation of an alternative in vitro test battery for detecting reproductive toxicants.
abstract: The application of alternative methods in developmental and reproductive toxicology is challenging in view of the complexity of mechanisms involved. A battery of complementary test systems may provide a better prediction of developmental and reproductive toxicity than single assays. We tested twelve compounds with varying mechanisms of toxic action in an assay battery including 24 CALUX transcriptional activation assays, mouse cardiac embryonic stem cell test, ReProGlo assay, zebrafish embryotoxicity assay, and two CYP17 and two CYP19 activity assays. The battery correctly detected 11/12 compounds tested, with one false negative occurring, which could be explained by the absence of the specific mechanism of action of this compound in the battery. Toxicokinetic modeling revealed that toxic concentrations were in the range expected from in vivo reproductive toxicity data. This study illustrates added value of combining assays that contain complementary biological processes and mechanisms, increasing predictive value of the battery over individual assays.
authors.affiliation: Center for Health Protection, National Institute for Public Health and the Environment RIVM, Bilthoven, The Netherlands. aldert.piersma@rivm.nl
authors.forename: A H
authors.initials: AH
authors.lastname: Piersma
authors.forename: S
authors.initials: S
authors.lastname: Bosgra
authors.forename: M B M
authors.initials: MB
authors.lastname: van Duursen
authors.forename: S A B
authors.initials: SA
authors.lastname: Hermsen
authors.forename: L R A
authors.initials: LR
authors.lastname: Jonker
authors.forename: E D
authors.initials: ED
authors.lastname: Kroese
authors.forename: S C
authors.initials: SC
authors.lastname: van der Linden
authors.forename: H
authors.initials: H
authors.lastname: Man
authors.forename: M J E
authors.initials: MJ
authors.lastname: Roelofs
authors.forename: S H W
authors.initials: SH
authors.lastname: Schulpen
authors.forename: M
authors.initials: M
authors.lastname: Schwarz
authors.forename: F
authors.initials: F
authors.lastname: Uibel
authors.forename: B M A
authors.initials: BM
authors.lastname: van Vugt-Lussenburg
authors.forename: J
authors.initials: J
authors.lastname: Westerhout
authors.forename: A P M
authors.initials: AP
authors.lastname: Wolterbeek
authors.forename: B
authors.initials: B
authors.lastname: van der Burg
mesh_terms: D000826:Animal Testing Alternatives; D000818:Animals; D001141:Aromatase / Q000378:metabolism; D001681:Biological Assay; D002460:Cell Line; D002478:Cells, Cultured; D004625:Embryo, Nonmammalian / Q000187:drug effects; D053595:Embryonic Stem Cells / Q000187:drug effects; D006801:Humans; D051379:Mice; D051381:Rats; D011987:Receptors, Steroid / Q000378:metabolism; D015203:Reproducibility of Results; D012098:Reproduction; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism; D013723:Teratogens / Q000633:toxicity*; D018675:Toxicity Tests / Q000379:methods*; D015027:Zebrafish
chemical_list: D011987:Receptors, Steroid; D013723:Teratogens; D001141:Aromatase; D013254:Steroid 17-alpha-Hydroxylase